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Marine Natural Products and Related Compounds as Anticancer Agents: an Overview of their Clinical Status Karina Petit* and Jean-François Biard LUNAM Université, Université de Nantes, MMS, F-44000 Nantes, France Abstract: Marine ecosystems constitute a huge reservoir of biologically active secondary metabolites. Consequently during the last past few decades, several marine-derived molecules have been approved for anticancer treatment or are under clinical trials. This review reports the present state of the art of the sixteen molecules approved or currently on the clinical pipeline for anticancer chemotherapy. The molecules are classified according to their current status in the phase (approved / phase IV / phase III / phase II / phase I) and data are updated to April 2012.

Keywords: Brentuximab vedotin, Clinical trials, Cytarabine, Elisidepsin, Eribulin, ILX-651, KLH, Marine natural products, MMAE, MMAF, Plinabulin, plitidepsin, PM00104, PM01183, PM060184, Salinosporamide A, Trabectedin, TZT-1027. INTRODUCTION Natural products play a significant role in the discovery and development of new drugs. They can be used both as therapeutic agents and as lead compounds. From 01/1981 to 12/2010, among the 1 355 new active substances approved for therapeutical indications, 742 (55%) can be considered as natural products or inspired by natural products [1]. As the WHO predicts an increase of cancer deaths to over 13.1 million in 2030 [2], the antitumor drug discovery constitutes a great challenge among prevention, early-detection and care strategies. Natural products have already proven to be a vast source of novel chemotherapeutic agents. According to a recent survey of Newman and Cragg [1], 206 anticancer drugs have been registered from 1940s to 2010, and 112 of them (54%) are natural products or derived therefrom. The oceans constitute a huge reservoir of such natural products. To date, more than 22 000 marine new molecules have been reported in the literature [3]. Some of them exhibited various biological activities and are currently under clinical trials or used as models to synthetize therapeutic agents [4-6]. However, it is remarkable that lots of efforts are devoted to the search of promising new anticancer drugs: over 183 marine molecules involved in preclinical and clinical trials in 2006, 136 (74%) were investigated in anticancer studies [7]. Beyond the health aspects, the pharmaceutical value of marine natural products for anticancer drug discovery ranges from US $563 billion - 5.69 trillion [8], motivating the pharmaceutical laboratories on the discovery of new and efficient molecules. So, exploring the marine environment represents an exciting tool to find novel compounds with great therapeutical potentials. The chemical characteristics of the molecules are easy to find but their current clinical status is more difficult to establish.This is reflected in the numerous articles referenced in ScienceDirect: 5 248 articles deal with “marine natural products” and “clinical trials”, including 3 280 with “cancer” (27th September 2012). Among these bibliographic data, most of them indicate a global state of development without any detail on the status (recruiting, completed or terminated). Consequently this article provides a detailed overview of the clinical status of marine compounds in the field of anticancer (updated April 2012).

*Address correspondence to this author at the University of Nantes, Faculty of Pharmacy, MMS – EA2160, 9 rue Bias, F-44000 Nantes, France; Tel: + 33 2 51 12 56 87; E-mail: [email protected] 1875-5992/13 $58.00+.00

METHODOLOGY The establishment of an exhaustive list of all the marine molecules involved at least in one anticancer clinical trial has been made on the basis of several reviews of particular relevance [9-19]. The searchable online databases below have been useful to find up-to-date informations about the clinical status of those molecules: Cochrane library [20], Clinical Trials [21], WHO [22], Institut National du Cancer [23], European Union Clinical Trials Register [24], IFPMA Clinical Trials Portal [25], Canadian Cancer Trials [26], National Cancer Institute [27], Current Controlled Trials [28], the Marine Pharmaceuticals Pipeline [29], Internet Drug Index [30], Japanese Clinical Trials Registry [31], Japan Medical Association Center for Clinical Trials [32]. Finally websites of the sponsor or collaborator companies have provided up-to-date informations: Aska Pharmaceutical [33], Bedford laboratories [34], Biosyn [35], Eisai [36], Enzon Pharmaceuticals [37], Genzyme Corporation [38], Nereus Pharmaceuticals [39], PharmaMar [40] and Seattle Genetics [41]. Marine molecules currently in the anticancer pipeline are summarized in Table 1. Further details can either be obtained in the corresponding paragraph or by the supporting information data. Moreover some molecules (cytarabine, KLH and trabectedine) being too much involved in clinical trials, results have been limited to the most pertinent period for each product. Approved Marine-Derived Drugs Cytarabine, Arabinosyl cytosine, Cytosine arabinoside, Ara-C Cytarabine (Fig. 1) dates back more than 50 years. It was the first modern marine-derived drug. It is a synthetic derivative inspired from the unusual marine nucleosides spongothymidine and spongouridine isolated from the sponge Tethya crypta in the 1950’s, which contained an arabinoside sugar rather than a ribose [42]. Unexpected antiviral properties led to examination of their mode of action as reverse transcriptase inhibitors and to the synthesis of a number of antiviral and anti-cancer drugs [43]. Cytarabine received first FDA approval in 1969. Today, cytarabine (Cytosar-U®) is approved to be used with other drugs to treat acute lymphoblastic leukemia, acute myeloid leukemia and chronic myelogenous leukemia. Cytarabine is also approved to be used alone to prevent and treat meningeal leukemia. It is given as intrathecal therapy [44]. As 748 studies using cytarabine were registrated in ClinicalTrials.gov, we decided to limit our panel to the Open

© 2013 Bentham Science Publishers

604 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 4 Table 1.

Petit and Biard

Current Status of Marine-Derived Natural Products in Anticancer Clinical Trials

Status

Compound Name

Chemical Class

Source Organism

Production

Company

Cytarabine = Ara-C

Nucleoside

Sponge, Thetya crypta

Synthesis, analogue of spongothymidine

Bedford, Enzon

Keyhole Limpet Hemocyanin (KLH)

Glycoprotein

Mollusk, Megathura crenulata

Extraction

Biosyn Arzneimittel GmbH

Trabectedin = ET-743

Tetrahydroisoquinolone alkaloid

Tunicate, Ecteinascidia turbinata

Hemisynthesis

PharmaMar

Macrolide

Sponge, Halichondria okadai

Synthesis, analogue of halichondrin B

Eisai Inc.

Phase II to III, various cancers (NSCLC…)

Eribulin mesylate = E7389, ER-086526, NSC-707389, B1939

Approved in USA, Adcetris, Hodgkin Lymphoma and sALCL

Brentuximab vedotin = SGN-35 = MMAE

Peptide

Mollusk, Dolabella auricularia

Synthesis, analogue of dolastatin10, antibodydrug conjugate

Seattle Genetics, Millenium: The Takeda Oncology Company

Phase II

Plinabulin = NPI-2358 = KPU-2

Diketo-piperazine

Fungus, Aspergillus ustus

Synthesis, analogue of halimide

Nereus Pharmaceuticals

Plitidepsin = dehydrodidemnin B

Cyclic depsipeptide

Tunicate, Trididemnum solidum

Synthesis

PharmaMar

Phase I in combination Phase I to II, Irvalec

Elisidepsin = PM02734

Depsipeptide

Mollusk, Elysia rufescens and his diet green alga Bryospis sp.

Synthesis, analogue of kahalalide F

PharmaMar

Phase I to II, Zalypsis©

PM00104

Tetrahydroisoquinoline alkaloid

Nudibranch, Joruna funebris

Synthesis, inspired by jorumycin, renieramycins, ET-743

PharmaMar

Phase I to II

PM01183 = lurbinectedin

Alkaloid

Tunicate, Ecteinascidia turbinata

Synthesis, analogue of ET-743

PharmaMar

Phase I to II

ILX-651 = Tasidotin, Synthadotin

Pentapeptide


Synthesis, analogue of dolastatin15

Genzyme Corporation

Phase I to II

TZT-1027 = auristatin PE = soblidotin

Peptide


Synthesis, analogue of dolastatin10

Aska Pharmaceutical

Phase I to II

MMAE/ MMAE + antibody: PSMA-ADC, ASG-5ME, CR011-vcMMAE, BAY794620, SGN-35, Glembatumumab vedotin CDX-011

Peptide


Synthesis, analogue of dolastatin 10, antibodydrug conjugate

Seattle Genetics

Phase I

MMAF + antibody: AGS-16M8F, SGN-75

Peptide


Synthesis, analogue of dolastatin 10, antibodydrug conjugate

Seattle Genetics

Phase I, Marizomib

Salinosporamide A = NPI0052

-lactone lactam

Bacterium, Salinospora tropica

Synthesis

Nereus Pharmaceuticals

Phase I

PM 060184

Unspecified

Sponge

Synthesis

PharmaMar

Approved, Cytosar-U , leukemia; Depocyt , lymphomatous meningitis

Phase I to IV in combination therapies Approved, Immucothel, bladder cancer Phase I to III, various cancers (myeloma, lymphoma…) Approved in EU, Yondelis, sarcoma Phase I to III for various cancers (ovarian...) Approved, Halaven, breast cancer

Phase I to II, alone, Aplidin©

Studies from 01/01/2011 to 15/05/2012 in which cytarabine is one of the main drug in use (several trials in various phases involve

NH2 N O HO O HO OH Fig. (1). Structure of Cytarabine, Ara-C.

N

cytarabine in association with other chemotherapeutic drugs). All these clinical trials are listed in Table S1 (supporting information). Cytarabine is mainly tested against acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkin’s and non Hodgkin’s lymphoma. Currently 17 Phase I, 33 Phase II, 14 Phase III and 5 Phase IV are ongoing. We report here the topic of the 6 most pertinent studies from the years 2011-2012: - Comparison of high-dose cytarabine (HiDAC) or conventional standard-dose multiagent chemotherapy [45], - Comparison of CHOP with two protocols (PETHEMALAL3/97 and BURKIMAB) in AIDS-related Burkitt's lymphoma or leukemia [46],

Clinical Status of Marine Natural Products

Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 4

605

Fig. (2). Structure and organization of native KLH [35].

-

Cytarabine at the lower dose in acute myeloid leukemia induction therapy [47], - Addition of gemtuzumab ozogamicin to induction chemotherapy in acute myeloblastic leukemia for younger patients [48], - Comparison of decitabine (DAC) to patient's choice with physician's advice or low-dose cytarabine (Ara-C) in older patients with acute myeloid leukemia [49], - Comparison of clofarabine plus cytarabine compared to Ara-C alone [50]. Keyhole Limpet Hemocyanin (KLH) Native KLH (Fig. 2) is a hemocyanin (copper-containing extracellular respiratory protein) isolated from the sera of the marine mollusk Giant Keyhole Limpet, Megathura crenulata. Hemocyanins are oxygen-transport proteins in a variety of arthropods and mollusks. KLH is obtained by a non-lethal hemolymph sera collection procedure from live animals (aquaculture) [51]. Native KLH is available as commercial-scale GMP-grade product [52]. Keyhole Limpet Immunocyanin (KLI) is a mixture of subunits of the native KLH with a molecular mass of about 400 kDa developed by Biosyn Arzneimittel GmbH for use in its bladder cancer clinical trials (Immucothel®) and as carrier protein (Vacmune®) for the manufacturimg of vaccines and for general immunological research [53]. Immucothel® was approved for marketing in the Netherlands in 1997 and in South Korea and Austria in 2002 as an immunotherapy for non-invasive (Ta, T1 and CIS) bladder cancer. The USPTO (United States Patent and Trademark Office) has given the Immucothel trademark serial number of 75070926. So this treatment is available to US citizens, but limited to investigational use by Federal Law (21 CFR 50, 56, and 312). KLH is as a strong antigen/immunogenic compound and was used beginning in the 1960’s as a monitor of immune reactivity.

The first report for the use of KLH in treatment of cancers dates back to 1974. Olson et al. [54] reported a markedly reduced incidence of tumor recurrence in 10 patients with superficial bladder cancer who received 5 mg of subcutaneous KLH as a sensitizing dose followed by 200 g intradermally to assess cellular immune competence [55]. Both crude KLH and Immucothel® appeared to be effective immunotherapies of use in the treatment of transitional cell carcinoma [56]. Intravesical chemotherapy is used to reduce the risk of tumor recurrence after resection of superficial bladder cancer, however with a modest benefit. BCG immunotherapy is relatively more effective than chemotherapy, but with strong side effects and up to 60 % of patients will eventually fail to respond. KLH seems to be an effective alternative immunotherapy with minimal toxicity. KLH therapy, therefore, would appear to be an ideal treatment for intermediate or even low risk bladder tumor patients [55, 57, 58]. Out its use in immunotherapy of the bladder cancer, KLH is the most widely employed carrier proteins in the production of antibodies for research, biotechnology and therapeutic applications, including preparation of vaccines in the field of oncology (lymphoma, cutaneous melanoma, bladder, breast, colon and other cancers), because of its large size and numerous epitopes, the abundance of lysine residues for coupling haptens, and its phylogenetically distance from mammalian proteins. Many results of clinical trials were published from 1984 to 1996 for the use of KLH as main active product for the immunotherapy of the bladder cancer and, in some cases, of renal carcinoma [59-67]. Since 1996, more than 100 clinical trials appeared in the clinical databases. Some of them used native KLH as adjuvant and are not considered here, except for the treatment of melanoma, for which some results were reported. Tables 2a-2i list the remaining trials for these KLH-based cancer vaccines.

606 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 4 Table 2a.

Petit and Biard

Current Cancer Clinical Trials for KLH in Multiple Myeloma First Received (dd/mm/yyyy)

Phase

Status

Product

Ref.

01/11/1999

I

Completed

id-KLH

NCT00002787*

01/03/2007

II

Completed

id-KLH

NCT00019097

30/07/2010

II

Recruiting

id-KLH

NCT01174082

30/08/2011

II

Recruiting

id-KLH

NCT01426828

*ClinicalTrials.gov registry’s number

Table 2b.

Table 2c.

Table 2d.

Table 2e.

Table 2f.

Current Cancer Clinical Trials for KLH in Multiple Lymphomas First Received

Phase

Status

Product

Ref.

21/01/2000

II

Completed

id-KLH

NCT00004197

06/06/2001

III

Unknown

id-KLH

NCT00017290

21/02/2008

II

Unknown

id-KLH

NCT00621036

08/04/2009

I

Completed

id-KLH

NCT00878410

Current Cancer Clinical Trial for KLH in Myeloid Leukemia First Received

Phase

Status

Product

Ref.

08/09/2005

II

Unknown

WT1-KLH

NCT00153582

Current Cancer Clinical Trials for KLH in Prostate Cancer First Received

Phase

Status

Product

Ref.

01/11/1999

I

Completed

Thompson-Friedenreich-KLH

NCT00003819

13/06/2008

I

Unknown

MUC-2 protein-KLH

NCT00698711

Current Cancer Clinical Trials for KLH in Breast Cancer First Received

Phase

Status

Product

Ref.

01/11/1999

III

Completed

THERATOPE vaccine

NCT00003638

10/12/1999

II

Completed

MUC-1-KLH

NCT00004156

14/02/2002

I

Completed

Heptavalent Antigen-KLH

NCT00030823

Current Cancer Clinical Trial for KLH in SCLC

First Received

Phase

Status

Product

Ref.

28/01/2000

II

Completed

Polysialic Acid-KLH /N-Propionylated Polysialic Acid-KLH

NCT00004249

Table 2g.

Table 2h.

Current Cancer Clinical Trial for KLH in Neuroblastoma First Received

Phase

Status

Product

Ref.

29/05/2009

I

Recruiting

GD2L and GD3L antigens-KLH

NCT00911560

Current Cancer Clinical Trial for KLH in Glioma First Received

Phase

Status

Product

Ref.

24/11/2010

I

Not Yet Open

SVN53-67/M57-KLH

NCT01250470

Clinical Status of Marine Natural Products Table 2i.


607

Current Cancer Clinical Trials for KLH in Melanoma

First Received

Phase

Status

Product

Ref.

06/04/2000

III

Active

GM2-KLH

NCT00005052

10/12/2003

I-II

Recruiting

DC + KLH

NCT00074230

07/09/2004

I

Completed

PBMC + gp100:209-217(210M) peptide, Montanide ISA-51, KLH

NCT00091143

25/07/2005

I

Active

KLH + melanoma peptides + adjuvant (Montanide or DC)

NCT00124124

08/09/2005

II

Active

Multiepitope peptide + GM-CSF and KLH

NCT00153569

18/10/2006

I

Completed

DC + KLH

NCT00390338

17/06/2008

I

Completed

DC + KLH

NCT00700167

05/03/2010

I-II

Recruiting

DC + KLH

NCT01082198

25/08/2010

I-II

Recruiting

DC + KLH

NCT01189383

Some data are available: - Id-KLH (Mitumprotimut-T): KLH with an IgG as a vaccine for follicular lymphoma [68, 69] or B cell lymphoma [70]. - Theratope (STn-KLH): aberrant mucin sialyl-Tn (STn) antigen conjugated to KLH for breast cancer [71, 72] and adenocarcinoma [73]. - GM2-KLH: GM2 or GD2 ganglioside melanoma-specific antigens conjugated to KLH [74-76]. Trabectedin, Ecteinascidin, ET-743 Trabectedin or Ecteinascidin-743 (ET-743) is a tetrahydroisoquinolone alkaloid (Fig. 3) first isolated from the Caribbean marine tunicate Ecteinascidia turbinata, a colony forming tunicate that grows in the coastal platform of several temperate seas [77, 78]. Originally extracted from the tunicate, ET743 is nowadays produced in industrial scale by a hemi-synthetic process from Cyanosafracin B, itself available through fermentation of the bacteria Pseudomonas fluorescens [79]. Trabectedin is a DNA guanine-specific minor groove binding agent [80], which blocks the cell cycle and affects the organization and assembly of the microtubule network [81]. ET-743 has shown high preclinical activity against a number of human solid tumor cell lines and xenografts, including sarcomas [82]. Trabectedin (Yondelis®) was granted orphan designation (EU/3/01/039) by the European Commission on 30 May 2001 for the treatment of soft tissue sarcoma, and, thereafter, for the treatment of ovarian cancer (EU/3/03/171, 17 October 2003) [83]. Following positive results of the clinical studies, the European Commission granted a marketing authorisation valid throughout the European Union for Yondelis® to Pharma Mar, S.A., on 17 September 2007. Product number of Yondelis® is: EMEA/H/C/ 000773 [84]. On 12/10/2007, the Committee for Medicinal Products for Human Use (CHMP – EMEA) considered by consensus that the HO H3C

NH O

O

O O O

O

CH3 CH3

HO

S

H H

H3C H3C

N N

H

O O

CH3

OH

Fig. (3). Structure of Trabectedin, Ecteinascidin, ET-743.

risk-benefit balance of Yondelis® in the “treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents; efficacy data are based mainly on liposarcoma and leiomyosarcoma patients,” was favorable and therefore recommended the granting of the marketing authorisation under exceptional circumstances [85]. On 24/09/2009, Yondelis® in combination with pegylated liposomal doxorubicin (PLD) is indicated for the treatment of patients with relapsed platinum-sensitive ovarian cancer [86]. Trabectedin is also approved in South Korea. For the U.S. market, Centocor Ortho Biotech Products (Johnson & Johnson) announced (Nov 2008) the submission of a new drug application to the U.S. Food and Drug Administration (FDA) for trabectedin when administered in combination with Doxil for the treatment of women with relapsed ovarian cancer. Complete response letter from the FDA was negative and the agency requested additional informations, including overall survival data. On April 2011, Johnson & Johnson has voluntarily withdrawn this new drug application in the USA, based on the FDA’s recommendation that an additional Phase III study should be conducted [87]. Under a licensing agreement with PharmaMar SA, Centocor Ortho Biotech Products has worldwide marketing rights for trabectedin except in Europe, where the product is marketed by PharmaMar SA and in Japan, where PharmaMar SA and Taiho Pharmaceutical Co. Ltd. have a licensing agreement to develop and commercialize Yondelis®. Today, PharmaMar [88] indicates that trabectedin is marketed for relapsed ovarian cancer and soft tissue sarcoma in 2nd and 3rd line, at the end of a phase III for soft tissue sarcoma with translocation in 1st line, and in phase II for paediatric and breast cancers. As many clinical trials (37) are registered in the databases, we have chosen to present only the currently recruiting or ongoing clinical trials for trabectedin. There are listed in the tables below according to the types of cancers (Tables 3a-3g). Most of the recently published results (2009-2012) [89-99] relate conclusions of the trials comparing the combination of trabectedin and doxorubicine (Pegylated Liposomal Doxorubicin, PLD) with doxorubicine alone in subjects with advanced relapsed ovarian cancer (trials 2, 3 and 4 above, and others as ET743-OVA301 - NCT00113607 received on June 2005). Detailed topics are: correlation of CA-125 and RECIST [89], health-related quality of life/patient-reported outcomes [90], dose schedules [91], platinumfree interval [92, 96, 97], tumor-related events [93], efficacy and safety [94, 95] and partially platinum-sensitive subpopulation [98, 99].


Petit and Biard

Current Cancer Clinical Trials for Trabectedin in Ovarian Cancer

First Received

Phase

Status

Type of Cancer

Ref.

13/11/2007

III

Ongoing

Advanced relapsed ovarian cancer

2004-005276-16*

23/07/2009

Ib/II

Ongoing

Ovarian Cancer

2009-011041-12

01/06/2011

III

Recruiting

Ovarian Cancer

NCT01379989

14/10/2011

III

Ongoing

Ovarian Cancer

2010-022949-17

*EudraCT number

Table 3b.

Current Cancer Clinical Trials for Trabectedin in Advanced Malignancies

First Received

Phase

Status

Type of Cancer

Ref.

23/12/2010

Phase I

23/12/2010

Phase I

Recruiting

Neoplasm Metastases

NCT01273480

Recruiting

Neoplasm Metastases, Hepatic Insufficiency

23/12/2010

Phase I

NCT01273493

Recruiting

Neoplasm Metastases

NCT01267084

No results are available for these trials with pharmacokinetics purposes [21].

Table 3c.

Current Cancer Clinical Trials for Trabectedin in Sarcomas

First Received

Phase

Status

Type of cancer

Ref. 2004-002106-29

13/05/2005

II

Ongoing

Liposarcoma or Leiomyosarcoma

13/09/2005

III

Recruiting

Sarcoma

NCT00210665

13/07/2007

II

Ongoing

Localized myxoid / round cell liposarcoma

2007-000035-25

22/10/2008

III

Ongoing

Translocation-Related Sarcomas (First-Line Therapy)

2008-002326-11

20/11/2008

III

Recruiting

Translocation-Related Sarcomas (First-Line Therapy)

NCT00796120

04/06/2009

II

Ongoing

Sarcoma

2008-008922-55

13/04/2010

II

Recruiting

Sarcoma

NCT01104298

12/05/2010

II

Ongoing

Leiomyosarcoma

2009-012430-70

25/08/2010

II/III

Recruiting

Sarcoma

NCT01189253

23/02/2011

II

Recruiting

Soft Tissue Sarcoma, Uterine Sarcoma

NCT01303094

26/04/2011

III

Recruiting

Liposarcoma, Leiomyosarcoma

NCT01343277

20/07/2011

I

Ongoing

Soft Tissue Sarcoma

JPRN-JapicCTI-101169*

29/08/2011

I

Recruiting

Leiomyosarcoma, Liposarcoma

NCT01426633

*Japan Primary Registries Network

Table 3d.

Current Cancer Clinical Trial for Trabectedin in Breast Cancer

First Received

Phase

Status

Type of Cancer

Ref.

01/08/2007

II

Ongoing

Metastatic Breast Cancer

2007-000794-31

Table 3e.

Current Cancer Clinical Trial for Trabectedin in Prostate Carcinoma

Table 3f.

First received

Phase

Status

Type of cancer

Ref.

24/08/2006

II

Ongoing

Advanced Prostate Carcinoma

2006-002276-17

Current Cancer Clinical Trial for Trabectedin in Pancreatic Cancer First Received

Phase

Status

Type of Cancer

Ref.

20/04/2011

Phase II

Ongoing

Pancreatic Cancer

NCT01339754

No results are available [21].

Table 3g.

Current Cancer Clinical Trial for Trabectedin in NSCLC

First Received

Phase

Status

Type of cancer

Ref.

26/08/2008

II

Ongoing

NSCLC

2007-006681-15



609

All these studies conclude that the addition of trabectedin to PLD results in superior efficacy in patients, with no added decrement to overall health status and a manageable safety. In the field of ovarian and peritoneal cancer, another result relates a phase II positive estimation of activity of the combination docetaxel-trabectedin. This combination was well tolerated and appeared more active than the historical control of single agent taxane therapy in those with recurrent ovarian and peritoneal cancer after failing multiple lines of chemotherapy [100]. Most recent results (2009-2012) show that trabectedin may now be considered as an important new option to control advanced softtissue sarcomas in patients after failure of available standard-ofcare therapies [101-103]. Trabectedin is a cost-effective treatment of metastatic soft-tissue sarcoma patients [104], and has a specific activity in myxoid/round cell liposarcoma [105, 106]. Co-treatment with dexamethasone improves the safety of trabectedin [107]. Otherwise, trabectedin is safe but did not demonstrate sufficient activity as a single agent for children with relapsed paediatric sarcomas [108], neither in uterine leiomyosarcoma [109-110]. Another study relates the efficacy of trabectedin for advanced sarcomas versus compassionate use programs [111], and two other studies evaluate different doses schedules [112, 113]. Efficacy of trabectedin treatment was demonstrated in HER2+ and in BRCA1/2 mutation carrier patients with pretreated progressive metastatic breast cancer. RNA overexpression of XPG may help to identify patients most likely to respond to trabectedin treatment [114, 115]. Two phase II results have been recently published: - A 50% PSA decline was observed for 18 men (castrationresistant prostate cancer) treated by trabectedin. Ongoing translational studies are designed to identify patients most likely to benefit from trabectedin treatment [116], - Two different trabectedin schedules showed modest activity in metastatic castration-resistant prostate cancer [117]. Customized treatment with trabectedin according to composite gene signature (XPG and/or ERCC1 overexpression, and BRCA1 underexpression) was well tolerated, but had modest activity in NSCLC patients pretreated with platinum. Further clinical trials with trabectedin as single agent in this indication are not warranted [118].

of halichondrin B have hampered efforts to develop this product as a new anticancer drug. Eribulin mesylate is marketed by Eisai Inc. under the tradename Halaven®. Interestingly, eribulin mesylate is a water-soluble product with great chemical stability [123].

Safety of Trabectedin One occurrence of trabectedin-related rhabdomyolysis has been published [119], and two retrospective pooled analyses appear in 2009 [120] and 2011 [121]. As results, single-agent trabectedin treatment was reasonably well tolerated. Trabectedin can be administered for prolonged periods to patients with sustained clinical benefit without cumulative toxicities over time.

Advanced Solid Tumors (Tables 4a-4e) Only Phase I clinical trials have been conducted for eribulin mesylate in advanced solid tumors. The 13 Phase I clinical trials have been initiated to study the effectiveness, to demonstrate the clinical activity and to measure the dose-limiting toxicity (DLT), the maximum tolerated dose (MTD), pharmacokinetics, safety, the recommended dose, and the anti-tumor effects of eribulin mesylate. The first-in-man trial of E7389 included various primary tumor sites such as lung (9), breast (4), and bladder (2) and demonstrated 2 partial responses (NSCLC; bladder) and 3 minor responses (NSCLC, breast, and thyroid) [136]. Others results appeared in 2009 for some different doses schedules and were limited by neutropenia and fatigue [137, 138]. In 2011, results of others trials were published: - NCT00326950: eribulin mesylate exhibited manageable tolerability. DLT was neutropenia [139], - NCT01106248: QT interval prolongation was independent of eribulin mesylate [140], - NCT00908908: about metabolism and excretion of [14C]eribulin mesylate, where no major metabolites were detected in plasma [141].

Conclusion Efficacy of trabectedin treatment is confirmed for the soft-tissue sarcomas, mainly liposarcomas, and is currently in progress for other types of sarcomas. The combination trabectedin-pegylated liposomal doxorubicin is also effective to treat ovarian cancer, and promising results are obtained for the combination of trabectedindocetaxel. Phase II clinical trials are rather positive against breast cancer and prostate cancer whereas trabectedin is not warranted for the NSCLC. Eribulin mesylate, Halaven® Eribulin mesylate (E7389, ER-086526, NSC-707389 or B1939) is a structurally simplified and pharmaceutically optimized analogue of halichondrin B [122, 123] (Fig. 4). Halichondrin B itself is a cytotoxic macrolide isolated from Halichondria sponges [124, 125]. However, scarcity of the sponge and very low content

CH3 OH

H2N

O H O

O O H3C

O H

H CH2

O O

S

O

O OH

CH3

O O

O

H2C

Fig. (4). Structure of Eribulin mesylate. Eribulin mesylate acts by suppression of microtubule growth [126], binding high affinity sites at the plus ends of existing microtubules [127, 128] and blocks the cell cycle, triggering apoptosis of cancer cells [129, 130]. Halaven® was approved in the USA (November 2010), EU (March 2011), Japan (April 2011) and Asia, to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease, including both anthracycline- and taxane-based chemotherapies [131, 132]. However, in the UK, the National Institute for Health and Clinical Excellence (NICE) has not been able to recommend this product on the basis of side effects and the fact that it was not cost-effective enough [133]. According to Eisai Inc. [134], clinical trials are currently ongoing for a variety of other tumors: prostate cancer (Phase II), sarcoma (phases II and III), NSCLC (phase III). Novel analogues of eribulin mesylate are currently in preclinical evaluation [135]. All available clinical trials for eribulin mesylate alone or in combination with other active product are listed below according to the type of cancer involved (Tables 4a-4x).


Petit and Biard

Current Cancer Clinical Trials for Eribulin Mesylate in Advanced Solid Tumors

First Received

Phase

Status

Objectives

Ref.

03/10/2002

I

Completed

To study the effectiveness

NCT00047034

19/09/2003

I

Completed

To demonstrate clinical activity

NCT00069277

19/09/2003

I

Completed

To define MTD

NCT00069264

16/05/2006

I

Completed

To investigate DLT, MTD, PKs, safety, RD, and anti-tumor effects 14

NCT00326950

20/05/2009

I

Completed

To investigate Metabolism and elimination of [ C]-labelled

NCT00908908

14/04/2010

I

Completed

To assess the impact on the ECG

NCT01106248

09/09/2010

I

Terminated

To determine DLT and MTD

JapicCTI-101270

Table 4b.

Current Cancer Clinical Trials for Eribulin Mesylate with Platin-Derivatives in Advanced Solid Tumors

First Received

Phase

Status

Objectives

Ref.

21/12/2005

I

Recruiting

To investigate MTD, safety and anti-tumor activity

NCT00268905

20/12/2006

I

Recruiting

To determine side effects and best dose

NCT00415324

Combination of eribulin mesylate with carboplatin was tolerated and showed preliminary activity [142]. One partial response (ovarian cancer), 4 minor responses (NSCLC 2, endometrial cancer 1, head and neck cancer 1) and 8 stable diseases were obtained [143]. Two recent reviews were published in 2011 and 2012 about this topic [144, 145]. Otherwise, 6 results of phase II trials of eribulin mesylate alone in patients with heavily pretreated (anthracycline, taxane, capecitabine) advanced breast cancer were published. In 2007 [146] and 2009 [147], the regimen of eribulin mesylate was refined. The response rate was 11.5% and neutropenia was the most common toxicity. In 2008 [148] and 2009 [149], eribulin mesylate demonstrated activity and a manageable tolerability profile. The clinical benefit rate was 17.1%. In 2010 and 2011, two studies [150, 151] evaluated the efficacy and safety of eribulin mesylate in Japanese patients with advanced breast cancer. Overall survival was 11.1 months. Following these promising results, two open-labels, randomized, controlled, parallel-group phase III studies have been initiated: Table 4c.

- In study 301 (ongoing: NCT00337103 and ECT 2005-00400926), 1102 patients were enrolled and randomized to receive either eribulin mesylate or capecitabine (approximately 550 patients in each arm) [152]. No results are yet available for this study. - In study 305 (completed: NCT00388726; ongoing: ECT 2006001949-34) [EMBRACE: Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician's Choice (TPC) Versus Eribulin mesylate E7389], eribulin mesylate monotherapy and treatment of the physician's choice were compared for overall survival; 762 patients were enrolled in two groups: 508 pts received eribulin mesylate and 254 patients a TPC (ratio 2:1) [153]. Results demonstrated a significant increase in overall survival for patients treated with eribulin mesylate when compared with TPC (13.1 and 10.6 months, respectively) [144, 145, 153, 154]. These conclusions led to the approval of eribulin mesylate by the USA (15/11/2010) and EU (17/03/2011) regulatory authorities as third single-agent after anthracycline and taxane in advanced breast cancer.

Current Cancer Clinical Trial for Eribulin Mesylate with Gemcitabine in Advanced Solid Tumors

First Received

Phase

Status

Objectives

Ref.

11/12/2006

I

Unknown


NCT00410553

Table 4d.

Current Cancer Clinical Trial for Eribulin Mesylate with Ketoconazole in Advanced Solid Tumors

First Received

Phase

Status

Objectives

Ref.

22/10/2009

I

Completed

To determine the influence of ketoconazole on the PKs

NCT01000376

No results are available for this combination [21].

Table 4e.

Current Cancer Clinical Trials for Eribulin Mesylate with reduced hepatic function or with impaired renal function in Advanced Solid Tumors

First Received

Phase

Status

Objectives

04/02/2008

I

Completed

To investigate Hepatic impairment according to the Child-Pugh system

NCT00706095

01/08/2011

I

Recruiting

To determine PKs and Safety in subjects with impaired renal function

NCT01418677

No results are available for this combination [21].

Ref.



Breast Cancer (Tables 4f-4l) Table 4f.

Current Cancer Clinical Trials for Eribulin Mesylate in Breast Cancer

First Received

Phase

Status

Objectives

Ref.

29/11/2004

II

Completed

To evaluate efficacy and safety

NCT00097721

27/10/2005

II

Completed


NCT00246090

09/12/2005

II

Ongoing

To evaluate efficacy and safety after treatement by anthracycline, taxane, and capecitabine

2005-003656-35

13/06/2006

III

Completed

To study E7389 versus capecitabine

NCT00337103

13/10/2006

III

Completed

To compare E7389 versus treatment of physician’s choice

NCT00388726

27/11/2006

III

Ongoing

To study E7389 versus capecitabine

2005-004009-26

27/03/2007

III

Ongoing

To compare E7389 versus treatment of physician’s choice

2006-001949-34

04/02/2008

II

Completed


NCT00633100

20/08/2009

II

Completed


NCT00965523

28/12/2010

II

Ongoing


NCT01268150

20/07/2011

II

Recruiting


NCT01401959

31/07/2011

II

Recruiting

To determine efficacy and safety as the first line therapy

JPRN-UMIN000006086

29/09/2011

IV

Recruiting

To investigate the post-marketing surveillance

NCT01463891

04/01/2012

II

Recruiting


JPRN-UMIN000006965

24/01/2012

II

Recruiting


JPRN-UMIN000007121

Table 4g.

Current Cancer Clinical Trials for Eribulin Mesylate with Trastuzumab in Breast Cancer

First Received

Phase

Status

Objectives

Ref.

31/12/2010

II

Recruiting

To evaluate safety and efficacy as first line treatment

NCT01269346

20/07/2011

II

Recruiting

To evaluate eribulin mesylate as adjuvant therapy with Trastuzumab

NCT01401959

12/09/2011

I

Recruiting

To measure DLT, tolerability and safety

NCT01432886

Table 4h.

Current Cancer Clinical Trial for Eribulin Mesylate with Carboplatin in Breast Cancer

First Received

Phase

Status

Objectives

Ref.

01/06/2011

II

Recruiting

To determine the effects of the combination

NCT01372579

Table 4i.

Current Cancer Clinical Trial for Eribulin Mesylate with Trastuzumab and Carboplatin in Breast Cancer

First Received

Phase

Status

Objectives

Ref.

05/06/2011

I/II

Recruiting

To measure safety and efficacy of the combination

NCT01388647

Table 4j.

Current Cancer Clinical Trials for Eribulin Mesylate with Capecitabine in Breast Cancer

First Received

Phase

Status

Objectives

Ref.

03/12/2009

I/II

Ongoing

To study the combination

2009-011217-24

24/03/2011

I/II

Recruiting

To study the combination

NCT01323530

19/09/2011

II

Recruiting

To determine feasibility study of the combination

NCT01439282

Table 4k.

Current Cancer Clinical Trial for Eribulin Mesylate with Ramucirumab (IMC-1121B) in Breast Cancer

First Received

Phase

Status

Objectives

Ref.

31/08/2011

II

Recruiting

To measure efficacy and safety of the combination

NCT01427933

611

612 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 4 Table 4l.

Petit and Biard

Current Cancer Clinical Trials for Eribulin Mesylate with Doxorubucin and Cyclophosphamide in Breast Cancer

First Received

Phase

Status

Objectives

Ref.

22/03/2011

II

Recruiting

To determine feasibility of dose-dense doxorubicin and cyclophosphamide followed by eribulin mesylate

NCT01328249

13/10/2011

II

Recruiting

To determine feasibility of eribulin mesylate followed by dose-dense doxorubicin and cyclophosphamide

NCT01498588

Results of all these studies are not yet available [21].

Table 4m.

Current Cancer Clinical Trials for Eribulin Mesylate in NSCLC

First Received

Phase

Status

07/01/2005

II

16/11/2006

II

13/10/2011

III

Recruiting

To compare efficacy and safety of eribulin mesylate with treatment of physician's choice

NCT01454934

11/11/2011

III

Ongoing

To compare efficacy and safety of eribulin mesylate with treatment of physician's choice

2011-000724-15

Table 4n.

Objectives

Ref.

Completed

To determine response rate, overall survival, safety/tolerability

NCT00100932

Completed

To study the effects of eribulin mesylate in NSCLC patients pretreated by a taxane

NCT00400829

Current Cancer Clinical Trials for Eribulin Mesylate with Pemetrexed in NSCLC

First Received

Phase

Status

17/05/2010

I/II

Ongoing

To measure safety and tolerability

NCT01126736

02/06/2010

I/II

Ongoing

To compare Eribulin mesylate + Pemetrexed versus Pemetrexed

2009-016047-19

Table 4o.

Objectives

Ref.

Current Cancer Clinical Trial for Eribulin Mesylate with Erlotinib in NSCLC

First Received

Phase

Status

Objectives

Ref.

12/04/2010

II

Unknown

To study different dose regimens

NCT01104155

NSCLC (Tables 4m-4o) Eribulin mesylate has entered in phase III for NSCLC in 2011 after some phase I and II trials. Some results are available for eribulin mesylate used alone in phase II. None are yet published for phase III, neither for trials of combinations. In 2005, 94 patients with recurrent and/or metastatic NSCLC received E7389: 6 partial responses and 33 stable diseases were observed [155]. In 2011, eribulin mesylate has been tried in a group of 66 patients stratified by taxane-sensitivity: taxanesensitive (TS) or taxane-resistant (TR). The median overall survival was 12.6 months in the TS subgroup and 8.9 months in the TR subgroup [156]. In 2012, median duration of response, progressionfree survival, and overall survival were 5.8, 3.4, and 9.4 months, respectively, for 103 patients. Eribulin mesylate is active and well tolerated as second- or later-line chemotherapy [157]. Table 4p.

Soft-Tissue Sarcoma (STS) (Tables 4p-4q) As for NSCLC, eribulin mesylate has entered in phase III for STS in 2011 after some phase I and II trials. In these studies, eribulin mesylate is used alone in phase II and in combination with dacarbazine in phase III. In 2009, 39 patients with leiomyosarcoma and 30 with other subtypes of soft-tissue sarcoma were treated with eribulin mesylate. The median progression free survival (PFS) in leiomyosarcoma was 3 months, the median overall survival (OS) 18 months, with 65% of patients alive at 1 year. The median PFS in other subtypes was 2 months, the median OS 8 months, with 26% of patients alive at 1 year. As a conclusion, eribulin mesylate deserves further study in leiomyosarcoma [158]. In 2011 (results for NCT00413192), same conclusion was obtained with 128 patients treated with

Current Cancer Clinical Trials for Eribulin Mesylate in STS

First Received

Phase

Status

Objectives

Ref.

23/10/2006

II

Ongoing

To measure efficacy and safety

2005-004272-20

15/12/2006

II

Ongoing

To determine therapeutic activity and safety

NCT00413192

21/10/2011

II

Recruiting


NCT01458249

Table 4q.

Current Cancer Clinical Trials for Eribulin Mesylate with dacarbazine in STS

First Received

Phase

Status

Objectives

Ref.

31/03/2011

III

Recruiting


NCT01327885

23/06/2011

III

Ongoing


2010-024483-17

No results are yet available [21].



613

Bladder cancer (Tables 4r-4s): Table 4r.

Current Cancer Clinical Trial for Eribulin Mesylate in Bladder Cancer

First received

Phase

Status

Objectives

Ref.

16/08/2006

I/II

Recruiting


NCT00365157

Table 4s.

Current Cancer Clinical Trial for Eribulin Mesylate with Gemcitabine in Bladder Cancer

First Received

Phase

Status

Objectives

Ref.

17/05/2010

I/II

Suspended

To evaluate safety and tolerability

NCT01126749

Other Types of Cancer (Tables 4t-4x) Table 4t.

Current Cancer Clinical Trial for Eribulin Mesylate in Ovarian Cancer

First Received

Phase

Status

Objectives

Ref.

11/12/2006

I

Unknown

To study side effects and best dose

NCT00410553

Table 4u.

Current Cancer Clinical Trial for Eribulin Mesylate with Gemcitabine in Ovarian Cancer

First Received

Phase

Status

Objectives

Ref.

07/06/2006

II

Unknown


NCT00334893

No results are yet available for this combination [21].

Table 4v.

Current Cancer Clinical Trials for Eribulin Mesylate in Prostate cancer

First Received

Phase

Status

17/01/2006

II

Completed


NCT00278993

28/04/2006

II

Ongoing


2005-004271-37

13/06/2006

II

Unknown


NCT00337077

Table 4w.

Objectives

Ref.

Current Cancer Clinical Trials for Eribulin Mesylate in Head and Neck Cancer

First Received

Phase

Status

Objectives

Ref.

13/06/2006

II

Completed


NCT00337129

Table 4x.

Current Cancer Clinical Trials for Eribulin Mesylate in Pancreatic Cancer

First Received

Phase

Status

Objectives

Ref.

29/09/2006

II

Completed


NCT00383760

eribulin mesylate, based on PFS at 12 weeks in leiomyosarcoma and adipocytic sarcoma [159]. In 2009 40 patients with advanced urothelial cancer were treated (35 with transitional cell carcinoma, 3 adenocarcinoma, 1 squamous cell carcinoma and 1 small cell advanced urothelial cancer). One complete response and 13 partial responses were obtained, all in patients with transitional cell carcinoma [160]. Two cohorts of patients with recurrent epithelial ovarian cancer were enrolled: 37 platinum-resistant (PR) patients and 36 platinumsensitive (PS). For the PR group, 2 partial responses (5.5%), 16 stable diseases (44%) and a progression-free survival (PFS) of 1.8 months were observed; 7 partial responses (19%) and a PFS of 4.1 months for the PS group were obtained [161].

On 108 patients with metastatic castration-resistant prostate cancer with or without previous taxane exposure, PSA decreases of more than 50% were achieved in 22.4% and 8.5% of taxane-naive and taxane-pretreated patients, respectively. A good activity and a relatively favorable toxicity profile were observed [162]. In 2009, 40 patients without prior chemotherapy for squamous cell carcinoma of the head and neck (SCCHN) were enrolled; 2 partial responses were observed (5%). The estimated median PFS was 3 months and median overall survival was 7 months. Eribulin mesylate was well tolerated, but did not show significant results [163]. The study published in 2011 included 15 patients with gemcitabine refractory pancreatic cancer. No complete or partial

614 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 4 H3C

CH3

CH3 O H3C H3C H3C O

H N O

O

CH3 O

NH CH3

N

H

H3C

CH3

N

O H3 C N

CH3 H

OH

Fig. (5). Structure of Monomethylauristatin E (MMAE).

responses were obtained, and therefore the study was closed after the first stage has been achieved [164]. Eribulin mesylate has been approved in monotherapy to treat patients with breast cancer; several studies are in progress involving eribulin mesylate in multichemotherapy treatment. It is active and well tolerated in second- or late-line therapy to treat NSCLC, so phase III studies are in progress. Monotherapy has provided promising results against leiosarcomas whereas combination with dacarbazine is currently in phase III. A good antitumor activity has been observed regarding prostate cancer whereas bladder, ovarian, neck, head and pancreatic cancers were less sensitive. Brentuximab Vedotin, SGN-35, Adcetris® Brentuximab vedotin is a dolastatin-derived (Fig. 5) (see § “2.7 Auristatin-derived” for details and review [165]). Table 5.

Petit and Biard

Brentuximab vedotin is an antibody-drug conjugate (ADC) marketed as Adcetris®. It has been approved by the US FDA in August 2011 to treat Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). The active compound is monomethyl auristatin E (MMAE), a synthetic derivative of the dolastatin 10 backbone, linked to a monoclonal anti-CD30 antibody. It is also known as SGN-35 [165, 166]. Brentuximab is “the first new FDA-approved treatment for Hodgkin Lymphoma since 1977 and the first specifically indicated to treat systemic anaplastic large cell lymphoma” [167]. However several investigations are still conducted for patients with Hodgkin lymphoma or anaplastic large cell lymphoma: - pharmacological and safety studies, - interest of the combination with multi-agent chemotherapy, - pre-treatment before autologous stem cell transplant, - treatment for particular patients (children or old patients). Table 5 summarizes all the currently clinical trials. Phase I results showed that Brentuximab vedotin was well tolerated and induced objective response [166, 168-170]. Objective responses in Phase II were obtained in 75% of patients with relapsed or refractory Hodgkin lymphoma [171] and up to 86% of patients with systemic anaplastic large cell lymphoma [172]. Marine-Derived Compounds in Clinical Trials Plinabulin, NPI-2358, KPU-2 Plinabulin (= tBu-PLH = KPU-2 = NPI-2358) was developed from halimide by a modification at the phenyl ring which remarkably enhanced the activity [173] (Fig. 6). Halimide (phenylahistin (PLH) = phenylhistin = NPI-2350) is a fungal

Current Cancer Clinical Trials for Brentuximab Vedotin

First Received

Phase

Status

Type of Cancer

Ref.

01/02/2007

I

Completed

CD30+ hematologic malignancies

NCT00430846

27/03/2008

I

Terminated


NCT00649584

18/02/2009

II

Ongoing

HL

NCT00848926

19/03/2009

II

Ongoing

NHL or sALCL

NCT00866047

+

24/07/2009

II

Recruiting

CD30 hematologic malignancies

NCT00947856

02/12/2009

I

Enrolling by invitation


NCT01026415

02/12/2009

I

Completed


NCT01026233

29/01/2010

I

Ongoing

HL

NCT01060904

06/04/2010

III

Recruiting

Residual HL

NCT01100502

03/09/2010

III

Approved

HL or sALCL

NCT01196208 NCT01309789

+

25/02/2011

I

Ongoing

CD30 mature T-cell and NK-cell neoplasm

10/05/2011

II

Recruiting

CD30+ lymphoproliferative disorders

NCT01352520

08/07/2011

II

Recruiting

Recurrent adult HL

NCT01393717

14/07/2011

II

Recruiting

Cutaneaous T-cell lymphoma

NCT01396070

+

NCT01421667

19/08/2011

II

Recruiting

CD30 NHL

18/10/2011

II

Recruiting

HL

NCT01476410

24/10/2011

II

Recruiting

CD30+ non lymphomateous malignancies

NCT01461538

12/12/2011

I/II

Recruiting

HL or sALCL

NCT01492088

09/01/2012

II

Recruiting

HL

NCT01508312

09/02/2012

II

Recruiting

HL

NCT01534078

27/03/2012

III

Not yet open

Cutaneaous T-cell lymphoma

NCT01578499

02/04/2012

II

Not yet open

HL

NCT01569204

13/04/2012

I

Not yet open

HL

NCT01578967



First results of this two arms study demonstrated marked antitumor activity of the combination compared to the control arm, with an acceptable safety profile [191, 192].

H N

O

N

CH3

O

H

H3C N H3C

N H

Fig. (6). Structure of Plinabulin, NPI-2358, KPU-2.

diketopiperazine metabolite isolated from the marine fungus Aspergillus ustus [174], patented in 1999, which inhibited the growth of colon carcinoma cells and ovarian carcinoma cells in vitro and prolonged the survival of mice in a leukemia model [175, 176]. No clinical trial was initiated because of rapid synthesis of plinabulin. Plinabulin has a colchicine-like tubulin depolymerization activity in A549 human lung carcinoma cells [177]. It binds in the boundary region between - and -tubulin near the colchicine binding site [178, 179]. Plinabulin has potent in vitro anti-tumor activity against various human tumor cell lines and maintains activity against tumor cell lines with various multidrug-resistant (MDR) profiles [177]. In addition, p linabulin induces apoptotic cell death in multiple myeloma cell lines and tumor cells from patients with multiple myeloma, associated with mitotic growth arrest [180]. Plinabulin is a vascular disrupting agent. It can decrease the blood perfusion in tumor in early time [181]. Comparison study with three tubulin-depolymerizing agents with vascular-disrupting activity (colchicine, vincristine and combretastatin A-4 CA4) showed that the activity of plinabulin in human umbilical vein endothelial cells was more potent than either colchicine or vincristine, the profile of CA4 approached that of plinabulin [177]. In murine tumor models, plinabulin produces tumor regression alone and synergistically with agents such as paclitaxel, docetaxel and irinotecan [182]. In vivo studies showed that plinabulin was well tolerated and significantly inhibited tumor growth and prolonged survival in a human multiple myeloma murine xenograft model [180]. Overall, preclinical studies indicated plinabulin had a favorable safety and activity profile leading to the initiation of clinical trials [183] (Table 6). A phase I study has been conducted by Nereus Pharmaceuticals (NCT00322608). Dose-escalation results were obtained for plinabulin used alone on patients with solid tumors and lymphoma [184-186] and on patients with NSCLC [187], all giving a favorable safety profile. The antitumor activity of docetaxel is enhanced when it is used in combination with plinabulin to treat NSCLC [182, 188, 189]. Based on these results, Nereus Pharmaceuticals initiated a randomized Phase I-II open-label study clinical trial (ADVANCE study) comparing docetaxel to plinabulin plus docetaxel in patients with advanced NSCLC who have failed an initial therapy, with the intent of demonstrating an improvement in overall survival [190]. Table 6.

Other Analogues of Phenylahistin Structure–activity relationship studies on plinabulin analogues resulted in synthesis of other benzophenone derivatives (KPU-105, KPU-133 and others). Some of these exhibited 30-times higher cytotoxicity than plinabulin [193-195]. Plitidepsin, Dehydrodidemnin B, Aplidin® Plitidepsin (Dehydrodidemnin B, Aplidin®) is a welldocumented marine cyclic depsipeptide of the didemin family [196]. Naturally produced by the tunicate Aplidium albicans, it is currently obtained by chemical synthesis (Fig. 7). CH3

O O N

N

H3C

O H3C

O

H3C

O

CH3

CH3

NH NH

O

CH3

O

H3C

O

NH

O

N O

O

CH3

CH3 O H3C

HO

O

N

CH3 CH3 O

CH3

Fig. (7). Structure of Plitidepsin, dehydrodidemnin B. Plitidepsin has shown both in vitro and in vivo activity against human cancer cells at nanomolar concentrations. Pro-apoptotic concentrations of plitidepsin induce early oxidative stress, which results in a rapid and persistent activation of both JNK and p38 MAPK, of the epidermal growth factor receptor (EGFR) and of the non-receptor protein-tyrosine kinase Src. In human leukemia cell line MOLT-4, plitidepsin induces inhibition of VEGF secretion which blocks the VEGF/VEGFR-1 autocrine loop necessary for the growth of these cells [197-199]. Aplidin® has entered in clinical trials in 2003 with PharmaMar as sponsor [200]. Tables below summarize the 14 clinical trials listed in the databases: 8 of them use plitidepsin alone (Table 7) and 6 others in combination with dexamethasone, dacarbazine, cytarabine and sorafenib or gemcitabine (Table 8). According to Pharmamar, plitidepsin is currently in phase III in relapsed/refractory multiple myeloma and in phase II in relapsed/refractory T-cell lymphoma. Results for phase I have been published for schema, doses, adverse events and evolution of the disease [201-204]. Results for phases I/II or II have been obtained with: o partial responses and/or stable diseases for renal carcinoma [205] and melanoma [206], o limited activity for thyroid carcinoma [207-208] and multiple myeloma [209],

Current Cancer Clinical Trials for Plinabulin

First Received

615

Phase

Status

Type of Cancer

Ref.

04/05/2006

I

Completed

Refractory solid tumors or lymphoma

NCT00322608

26/02/2008

I/II

Completed

Advanced NSCLC

NCT00630110

616 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 4

Petit and Biard

- Plitidepsin with carboplatin: stable diseases for colorectal , melanoma, ovary and gastrointestinal tumors [215] and advanced solid tumors or lymphomas [216], - Plitidepsin with bevacizumab: both products can be safely combined, and prolonged disease stabilizations are still ongoing [217]. Elisidepsin, PM02734, Irvalec® Elisidepsin is a new synthetic depsipeptide belonging to the kahalalides family (Fig. 8). Kahalalides are marine compounds isolated from the mollusk Elysia rufescens and its diet green alga Bryopsis sp. [218]. One of these, kahalalide F, was administered in some phases I and II to patients with NSCLC [219] and advanced androgen refractory prostate cancer [220]. However kahalalide F

o clinical activity for neuroblastoma [210] and NSCLC [211], o no responses for SCLC [212]. Partial results have been published: - Plitidepsin with dexamethasone: more partial responses, longer progression free survival, but same overall survival in combination [213], - Plitidepsin with dacarbazine: partial responses and stable diseases for melanoma [214] - Plitidepsin with cytarabine; sorafenib or gemcitabine: no results available, For two others combinations, no referenced trials were found in the clinical trials databases: Table 7.

Current Cancer Clinical Trials for Plitidepsin

First Received

Phase

Status

Type of Cancer

Ref.

16/09/2004

II

Ongoing

Aggressive NHL

2004-001117-34

30/03/2005

II

Ongoing

Relapsed or Refractory NHL

2004-002692-16

31/03/2005

II

Ongoing

Urothelium carcinoma

2004-001118-15

27/10/2008

II

Terminated

Prostate cancer

NCT00780975

17/04/2009

II

Completed

Leukemia, lymphoma

NCT00884286

19/05/2009

II

Ongoing

Dedifferentiated liposarcoma

2009-010980-18

22/06/2010

II

Completed

Myelofibrosis

NCT01149681

06/09/2010

II

Ongoing

Myelofibrosis

2010-019790-15

Table 8.

Current Cancer Clinical Trials for Plitidepsin in Combinations

First Received

Phase

Combination/Status

Type of Cancer

Ref.

27/09/2005

II

+ Dexamethasone/ Completed

Multiple myeloma

NCT00229203

16/05/2006

I/II

+ Dacarbazine / Ongoing

Unresectable advanced melanoma

2005-001161-34

24/10/2008

I/II

+ Cytarabine / Terminated

Relapsed/Refractory leukemia

NCT00780143

07/11/2008

I

+ Sorafenib or Gemcitabine / Recruiting

Advanced solid tumors, lymphoma

NCT00788099

31/03/2010

III

+ Dexamethasone / Recruiting)

Relapsed/Refractory Multiple Myeloma

NCT01102426

06/05/2010

III

+ Dexamethasone / Ongoing

Relapsed/Refractory Multiple Myeloma

2009-016138-29

H3 C O

H N

O

NH H3C H3C

CH3

NH

O

O

NH

CH3

O CH3 O

O H3C

NH O

H3C

CH3

NH H3C

NH2

NH O O

O

NH

NH

NH N

O CH3

H3C O F OH F

F

O CH3

O NH

H3 C

Fig. (8). Structure of Elisidepsin, PM02734.

CH3

H3C

H3C

H3C

O OH

NH

CH3

Clinical Status of Marine Natural Products Table 9.


Current Cancer Clinical Trials for Elisidepsin

First Received

Phase

Status

Type of Cancer

27/11/2006

I

Terminated

Advanced malignant solid tumors

NCT00404521

18/11/2008

II

Ongoing

NSCLC

2008-004908-31

16/04/2009

I

Recruiting

Advanced malignant solid tumors

NCT00884845

01/09/2010

Ib/II

Ongoing

Advanced or metastatic esophageal, esophagogastric junction or gastric cancer

2010-020325-40

Table 10.

617

Ref.

Current Cancer Clinical Trials for PM00104

First Received

Phase

Status

Type of Cancer

Ref.

01/08/2006

I

Terminated

Solid tumors, lymphoma

NCT00359294

12/05/2009

II

Terminated

Uterine cervical cancer, endometrial cancer

NCT00900562

08/02/2010

II

Ongoing

Recurrent/refractory multiple myeloma

2009-016054-40 NCT01222767 2010-020994-18

08/10/2010

II

Recruiting

Ewing's sarcoma, neuroectodermal tumor, Askin's tumor of the chest wall, extraosseous Ewing's sarcoma

21/10/2010

II

Ongoing

Advanced and/or metastatic urothelial carcinoma

disappears recently on the PharmaMar “products under clinical development” list [221]. Elisidepsin is a synthetic derivative which is active against a wide range of tumor types: breast, colon, pancreas, lung and prostate, among others [222]. In vitro, elisidepsin induces depletion of ErbB3 and inhibition of Akt signaling pathway [221]. The direct correlation between ErbB3 expression and in vitro sensitivity to elisidepsin sustains the notion of a pharmacodynamic effect of this compound on this pathway [223]. However, other studies show evidence that the preferential changes in the distributions and association states of ErbB and GPI-anchored proteins are secondary to alterations in the cell membrane induced by elisidepsin (change in the order and fluidity of the plasma membrane). So, elisidepsin induces internalization of GPI-anchored proteins and ErbB3, although the effect of elisidepsin is independent of ErbB proteins [224]. In other way, there was positive evidence of synergism when pharmacologically relevant concentrations of elisidepsin and erlotinib are used in combination against a panel of human NSCLC cell lines. This study prompted PharmaMar to implement a phase I programme to define the feasibility, pharmacological interactions and activity of the combination of continuous erlotinib with weekly intravenous infusions of elisidepsin [223] (Table 9). Other in vitro experiments showed a synergistic effect between elisidepsin and platinum compounds in different cell lines [225]. A phase I dose-escalation study, mainly on patients with colorectal cancer, showed that elisidepsin lacked of bone marrow toxicity, hair loss, mucositis and severe vomiting. Dose-limiting toxicity was hepatotoxicity, with a grade 3–4 asymptomatic, reversible transaminase elevation [226]. In another phase I result, association of elisidepsin with carboplatin led to infra-optimal doseintensity of elisidepsin and this schedule was not recommended for further development for advanced solid tumors [225]. The IMAGE (phase Ib/II) study of elisidepsin in pretreated advanced gastroesophageal cancer was initiated in October 2010. The first cohort has been completed for both arms [227] in December 2010. No result is now available, neither for the phase II study (2008-004908-31). PM00104, Zalypsis® PM00104 is a novel synthetic tetrahydroisoquinoline alkaloid related to the marine natural compounds jorumycin (extracted from the skin and mucus of the nudibranch Joruna funebris) and

the family of renieramycins, issued from sponges and tunicates [5; 228] (Fig. 9). It is also related to trabectedin [229]. A reactive carbinolamine group of this structure leads to the formation of a covalent bond with the amino group of selected guanines in the DNA double helix [230]. F F F H3C N HO NH

O

N CH3

HO

O

O O

O CH3

O

CH3

CH3

Fig. (9). Structure of PM00104.

Zalypsis® turned out to be the most potent agent tested in multiple myeloma, with IC50 values from picomolar to low ® nanomolar ranges. Zalypsis provoked induction of apoptosis, cell cycle arrest and DNA double-strand breaks [231]. The mean IC50 value was 7 nM and leukemia and stomach tumor cell lines were amongst the most sensitive [230]. Zalypsis® administration in four murine xenograft models of human cancer demonstrated significant tumor growth inhibition that was highest in the Hs746t gastric cancer cell line with no weight loss of treated animals [230]. Several clinical trials have been initiated (Table 10). Three results of the phase I trials were published: -

Pharmacokinetics data and safety profile are available [232] [233]. In a third study involving patients with mainly colon and breast cancers, a combination of PM00104 with carboplatin suggests an overlapping toxicity that hampers dose escalation of either of the compounds [234].


Petit and Biard

PM01183, Lurbinectedin PM01183 is a novel synthetic agent derived from trabectedin (Fig. 10) and is also known as Lurbinectedin.

N CH3

H

N O

H3C

CH3

O

O N

O

N CH3

O H3C

CH3

CH3 CH3

NH

N H O

O

O

O

O

O

CH3

N H3C

CH3

H H

H3C H3C

N N O

Fig. (11). Structure of ILX-651, Tasidotin, Synthadotin.

CH3 H

O OH

Fig. (10). Structure of PM01183, Lurbinectedin. The product covalently binds to the minor groove of the DNA, which may result in delayed progression through S phase, cell cycle arrest in the G2/M phase and cell death. This structural modification is accompanied by different pharmacokinetics in cancer patients. PM01183, as trabectedin, interferes with the nucleotide excision repair (NER) machinery: the repair of specific NER substrates is then attenuated. These results provided a basis to support clinical trials of PM01183 alone or in combination with cisplatin [235-237]. In preclinical studies, the compound displayed a potent cytotoxic activity against tumor cell lines of different origin. It is currently being tested in phase I clinical trials for solid tumors and in phase II for metastatic pancreatic cancer [238] (Table 11). All studies are sponsored by Pharmamar. A first-in-man study began in April 2009 and defined the phase II recommended dose in patients with solid cancers, mainly colorectal and pancreatic/biliary tract cancer [239]. ILX-651, Tasidotin, Synthadotin Tasidotin is an orally active synthetic pentapeptide derivative of the marine depsipeptide dolastatin 15 (issued from the Mollusk Dolabella auricularia) (Fig. 11). T asidotin inhibits cell proliferation mainly by suppressing spindle microtubule dynamics. Tasidotin is a relatively weak prodrug for the active tasidotin Ccarboxylate metabolite [240]. Tasidotin induces a G2-M block in treated cells ultimately resulting in apoptosis. Antitumor activity is confirmed in vivo in preclinical xenograft models of pediatric sarcomas [241]. Phase I dose-escalation studies have been conducted. Results are available, all for patients with advanced solid tumors [242-244]. Some phase I/II or II studies (Table 12) have been announced to further evaluate the efficacy of tasidotin (Sponsors: Genzyme from Table 11.

CH3

N

H3 C

CH3

HO

S

CH3

H

2003 to 2004; Ergomed Clinical Research Limited from 2009 to 2011). According to the Genzyme Web Site [245], the results of the phase II trials (2003-2004) showed that tasidotin (intra-venously) was well tolerated, but did not show sufficient efficacy to warrant further single agent development using this route of administration. Subsequently, tasidotin has re-entered preclinical studies. Based on these new preclinical data, recent phase I/II trials (2009-2011 in Table 9) were designed to investigate tasidotin as hydrochloride salt for an orally administration after new preclinical data for patients with advanced, refractory neoplasms. Auristatin Derivatives: TZT-1027, MMAE and MMAF The dolastatins family was first discovered in 1980 [246]. Up to now 27 dolastatins are described from the Indian Ocean specimen (dolastatin 1-18, Pettit’s team) and from the Pacific Ocean specimen (dolastatin A-I, Yamada’s team) [247]. These molecules are peptides isolated from the sea hare Dolabella auricularia. They are characterized by several unique amino acids subunits and displayed a strong cytostatic activity on various human cancer cell lines [248]. However the dolastatins 10 and 15 were the most powerful compounds of the series (IC50 2.10-9 to 1.8.10-11 M). Some extensive structural modifications of dolastatins 10 and 15 provided new molecules currently in clinical trials. The dolastatin 15 skeleton/backbone served as a model for the synthesis of ILX-651 (see above). The dolastatin 10 inspired the structure of auristatin PHE (soblidotin or TZT 1027) (Fig. 12), monomethylauristatins E and F (MMAE, MMAF) (Fig. 12). Investigations are conducted either on the pure molecule (soblidotin) or on antibody-drug conjugate (ADC). The concept of ADC comprises a humanized monoclonal antibody, targeting various antigens, conjugated to a cytotoxic compound (MMAE or MMAF). The antibody selectively binds to the antigen expressed on tumor cell surfaces then releases the active molecule in higher local concentrations. The target specificity allows the enhancement of the antitumor activity and the reduction of many toxic effects. However effectiveness of treatment is dependant of the overexpression of the target antigen on tumor cells.


First Received

Phase

Status

Type of Cancer

Ref.

06/04/2009

I

Completed

Advanced solid tumors

NCT00877474

09/03/2011

I

Recruiting

Acute leukemia

NCT01314599

26/07/2011

I

Recruiting


NCT01405391

05/09/2011

II

Ongoing

Metastatic pancreatic cancer

2010-024292-30



Current Cancer Clinical Trials for ILX-651

First Received

Phase

Status

Type of Cancer

Ref.

09/09/2003

II

Completed

Advanced or metastatic melanoma

NCT00068211

25/02/2004

II

Completed

NSCLC

NCT00078455

29/04/2004

II

Completed

Hormone-refractory prostate cancer

NCT00082134

22/10/2009

I/II

Ongoing

Solid tumors and metastatic melanoma

2009-011498-34

22/06/2011

I/IIa

Ongoing

Aggressive NHL

2011-000124-15

-

MMAE is conjugated via a valine-citrulline linker to: a monoclonal antibody against the prostate-specific membrane antigen (PSMA) (product name: PSMA-ADC) - a monoclonal antibody to the epitope AGS-5 (product name: ASG-5ME) (valine-citrulline maleimidocaproyl linker) - a monoclonal antibody against the extra-cellular domain of glycoprotein NMB (GPNMB) (product names: CR011vcMMAE, CDX-011)

a monoclonal antibody targeting carbonic anhydrase CA-IX (product name: BAY79-4620) a monoclonal antibody targeting nectin-4 (product names: ASG-22ME, AGS-22M6E) an anti-CD30 monoclonal antibody (product names: SGN35, brentuximab vedotin: see above) MMAF is linked via a maleimidocaproyl linker to: an anti-AGS-16 monoclonal antibody (product name: AGS-16M8F)

-

-

-

H 3C

H3C CH3

CH3 O H 3C

O

N

N

H 3C H 3C

H

H3 C

CH3

H3C H3C

H 3C

N

O

O

N

H3C

H

H3C

NH CH3

N

O

CH3

H3C

H

O

N O

O

H

H3 C

H3C

CH3

CH3

CH3 H

HO

OH

Auristatin PHE

O

H

O CH3

H N

H3 C N

N

H O

N

H3C

N

O

N

O

NH CH3

O

H

O

CH3

H3 C

N

CH3

CH3 O

CH3

CH3 H 3C

H3C

CH3

CH3O

O

O

MMAE

MMAF

Fig. (12). Structures of the dolastatin 10 derivatives: Auristatin PHE, MMAE and MMAF.

Table 13.

Current Cancer Clinical Trials for Soblidotin or TZT

First Received

Phase

Status

Type of Cancer

Ref.

05/06/2003

II

Completed

Locally advanced or metastatic NSCLC

NCT00061854

08/07/2003

II

Completed

Advanced or metastatic STS

NCT00064220

04/11/2003

I

Withdrawn

(in combination with gemcitabine); locally advanced or metastatic solid tumors

NCT00072228

08/11/2004

II

Ongoing

STS

2004-001108-11

Table 14.

619

Current Cancer Clinical Trials for MMAE

Antibody Conjugate

Target

First Received

Phase

Status

Type of Cancer

Ref.

PSMA-ADC

PSMA

09/08/2011

I

Recruiting

Metastatic prostate cancer

NCT01414283

PSMA-ADC

PSMA

09/08/2011

I

Recruiting

Metastatic prostate cancer

NCT01414296

ASG-5ME

AGS-5

19/07/2010

I

Ongoing

Pancreatic neoplasm

NCT01166490

ASG-5ME

AGS-5

21/10/2010

I

Recruiting

Prostate neoplasm

NCT01228760 NCT00412828

CDX-011

GPNMB

18/12/2006

I/II

Completed

Melanoma

CDX-011

GPNMB

23/06/2008

I/II

Completed

Metastatic breast cancer

NCT00704158

CDX-011

GPNMB

30/06/2010

II

Ongoing

Breast cancer

NCT01156753

BAY79-4620

CA-IX

04/11/2009

I

Ongoing


NCT01028755

BAY79-4620

CA-IX

08/02/2010

I

Terminated


NCT01065623

AGS22-M6E

Nectin-4

29/07/2011

I

Recruiting

Malignant solid tumors

NCT01409135

620 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 4 Table 15.

Petit and Biard

Current Cancer Clinical Trials for MMAF

Antibody Conjugate

Target

First Received

Phase

Status

AGS-16M8F

AGS-16

29/04/2010

I

SGN-75

Anti-CD70

13/11/2009

I

-

an anti-CD70 monoclonal antibody (product name: SGN75) Several clinical trials involve ADC with “SGN” term from Seattle Genetics. However only SGN-35 and SGN-75 are marinederived natural products. Tables 13-15 summarize the current clinical trials involving auristatin derivatives. Phase I studies provided pharmacokinetics data and safety profile [249, 250]. However phase II studies results were consistent with previous findings but no confirmed responses were seen [251]. Cl CH3 O O N

O HO

H

H

Fig. (13). Structure of Salinosporamide A, NPI0052.

All results available concluded on the promising activity of MMAE (regardless the target) and provided pharmacokinetics data, safety profile and objective responses [252-255]. First results of the phase I study were encouraging: SGN-75 has been well tolerated and has induced objective responses [256]. Salinosporamide A, NPI0052, Marizomib® Salinosporamide A is a cytotoxic proteasome inhibitor from a novel microbial source, the marine bacterium Salinospora tropica [257, 258]. Synthesis was rapidly developed [259], however production for clinical trials was achieved through a saline fermentation process using S. tropica strain NPS21184 [5].

Table 16.

Type of Cancer

Ref.

Recruiting

Advanced renal cell carcinoma

NCT01114230

Ongoing

CD70+ metastatic renal cell carcinoma or relapsed or refractory NHL

NCT01015911

As a proteasome inhibitor, salinosporamide A (bicyclic lactone -lactam, Fig. 13) is distinct from bortezomib in its chemical structure, mechanisms of action, and effects on proteasomal activities. Moreover it overcomes resistance to conventional and bortezomib therapies. In vivo studies using human multiple myeloma xenografts showed that salinosporamide A is well tolerated, prolongs survival, and reduces tumor recurrence. These preclinical studies provided the basis for phase-I clinical trial in relapsed/refractory multiple myeloma patients [260, 261]. Eligibility included patients with multiple myelomas, lymphomas, leukemias and solid tumors. Failure with bortezomib treatment or diagnoses with no demonstrated significant efficacy of other proteasome inhibitors are not exclusion criteria [262, 263]. Preclinical development ended in December 2006, and clinical trials started in 2006 (Phase I solid tumors and lymphoma) and 2007 (Phase I multiple myeloma) with Nereus Pharmaceuticals as sponsor [263]. According to Nereus Pharmaceuticals overview, initial single agent Phase 1 studies demonstrated the pharmacodynamic, pharmacokinetic and safety profiles of salinosporamide A (Table 16). Evidence of anti-cancer activity was seen in a number of tumor types such as melanoma and myeloma. Patients continue to enroll in several of these studies to confirm these initial findings. Based on these results, a clinical trial is being conducted to assess salinosporamide A in combination with the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid or SAHA, Zolinza) in patients with advanced pancreatic carcinoma, NSCLC and melanoma for which further standard approved therapy is not available [264] (Table 17). Many abstracts and posters [264-277] are available, but no published manuscripts. Patients with melanoma, pancreatic carcinoma or NSCLC were given escalating doses of weekly salinosporamide A in combination with vorinostat. Although no responses were demonstrated, 61% of evaluable patients demonstrated stable disease with 39% having decreases in tumor measurements. The combination of full dose

Current Cancer Clinical Trials for Salinosporamide A

First Received

Phase

Status

Type of Cancer

Ref.

06/11/2006

I

Recruiting

Refractory solid tumors or lymphomas

NCT00396864

13/04/2007

I

Recruiting

Multiple myeloma

NCT00461045

26/02/2008

I

Recruiting

Advanced malignancies

NCT00629473

Table 17.

Current Cancer Clinical Trial for Salinosporamide A with vorinostat

First Received

Phase

Status

Type of Cancer

Ref.

22/04/2008

I

Recruiting

NSCLC, pancreatic cancer, melanoma or lymphoma

NCT00667082

Table 18.


First Received

Phase

Status

Type of Cancer

Ref.

09/02/2011

I

Recruiting


NCT01299636



621

Status of Some Marine-derived Molecules

Current Status

Disease Investigated

Drug

Previous Status (Oncological CT)

Chemical Class

Source Organism

Phase II, unknown, 2008, NCT00606164

Alzheimer’s disease

Bryostatin 1

Many tumors investigated, Phase I/II

Polyketide (macrocyclic lactone)

Bryozoan, Bugula neritina

Phase I/II, recruiting, 2011, NCT01379209

Graft-versus-host disease

Phase I/II, completed, 2006, NCT00363155

Hepatitis B

KRN-7000

Myeloma, Phase I/II, 2008, NCT00698776; Solid tumors, Phase I, 1999, NCT00003985

-galactosyl-ceramide

Analogue from agelasphins from the Sponge, Agelas mauritianus

Phase I/II, completed, 2006, NCT00352235

Chronic Hepatitis C Infection

Phase III, terminated, 2005, NCT00139282; Phase III, ongoing, 2005, ECT 2005-001235-30; Phase II, terminated, 2006, NCT00333476; Phase II, terminated, 2004, NCT00094120; Phase II, terminated, 2004, NCT00089830

Age-Related Macular Degeneration

Aminosterol

Shark, Squalus acanthias

Squalamine = MSI-1256F

Prostate cancer, Phase II, 2005, NCT00244920; Ovarian cancer, Phase II, 2001, NCT00021385

Lymphoma, Phase II, 2000, NCT00005579 Acute Leukemia, Phase II, 1999, NCT00003693 Mollusc, Dolabella auricularia Not investigated

Dolastatin 10

Kidney Cancer, Phase II, 1999, NCT00003914

Linear pentapeptide

Liver cancer, Phase II, 1999, NCT00003557 Pancreatic Cancer, Phase II, 1999, NCT00003677 Prostate Cancer, Phase II, 1999, NCT00003626 Not investigated

Dolastatin 10

Linear pentapeptide

Mollusc, Dolabella auricularia

Cartilage (proteoglycan)

Shark, Squalus acanthias and Sphyrna lewini

Soft Tissue Sarcoma, Phase II, 1999, NCT00003778 Advanced colorectal or breast cancer, Phase III, 2001, NCT00026117

Not investigated

Neovastat = AE-941

Multiple Myeloma, Phase III, 2001, NCT00022282 Kidney cancer, Phase III, 2000, NCT00005995 NSCLC, Phase III, 2000, NCT00005838

Not investigated

E7974 = Hemiasterlin

Solid tumors, Phase I, 2005, NCT00165802; NCT00121732; NCT00130169

Tripeptide

Sponge, Hemiasterella minor

Not investigated

Kahalalide F

NSCLC, Phase II, 2004, ECT 2004-001253-29

Cyclic depsipeptide

Mollusc, Elysia rufescens and Algae diet Bryopsis sp.

Not investigated

Cematodin = LU103793

Phase I, 1996-1998

Linear peptide

Analogue of dolastatin 15 from the Mollusc, Dolabella auricularia

Not investigated

Cryptophycin52 = LY355703

NSCLC, Phase II, 2003-2005

Cyclic depsipeptide

Cyanobacterium, Nostoc sp. strain GSV224

Not investigated

Didemnin B

Many tumors investigated (breast, colorectal, renal, SCLC, ovarian, …), Phase II, 19921998

Cyclic depsipetide

Tunicate, Trididemnum solidum

Not investigated

Discodermolid e = XAA296A

Solid tumors, Phase I, 2004

Polyketide

Sponge, Discodermia dissolute

Not investigated

ES-285 = spisulosine


Alkylamino alcohol

Mollusc, Spisula (=Mactromeris) polynyma

Not investigated

Girolline = RP 49532A


Alkaloid

Sponge, Cymbastela (=Pseudaxinyssa) cantharella


Petit and Biard

Table 19. contd…. Drug

Previous Status (Oncological CT)

Chemical Class

Source Organism

Not investigated

HTI-286 = Taltobulin = SPA-110


Peptide

Analogue of hemiasterlin from the Sponge, Hemiasterella minor

Not investigated

LAF-389


-Lactam peptide

Derivative from bengamide B from the Sponge, Jaspis digonoxea

Not investigated

NVP-LAQ 824


Indolic cinnamyl hydroxamate

Derivative from psammaplin from the Sponge, Psammaplysilla sp.

Current Status

Disease Investigated

salinosporamide A with vorinostat is tolerable in patients with safety findings consistent with either drug alone [278]. PM060184 PM060184 is the most recently marine-derived syntheticallyproduced compound from PharmaMar in clinical trial. None structural details are available. However, Zeltia/PharmaMar indicates that the native product was extracted from a marine sponge from the Indian Ocean [279]. The product has shown antitumor activity in vitro and in vivo and a favorable safety profile in preclinical toxicology studies. The purposes of the first Phase I trial are to identify the dose limiting toxicity, the maximum tolerated dose and the recommended dose of PM060184 (Table 18). Additionally, the drug's pharmacokinetic profile will be defined and a preliminary evaluation of its antitumor activity in patients will be performed [280]. No findings have thus far been published [21]. Stopped Marine-Derived Drugs Some marine natural products and relative products are wellknown to be or to have been in clinical trials. Some of them have been recently reoriented to other diseases or stopped. This list is not exhaustive but concerns very well-known molecules in marine pharmacology (Table 19). However molecules stopped in preclinical trials are not mentioned.

[2] [3]

[4]

[5]

[6] [7]

[8]

[9]

[10] [11] [12]

CONCLUSION AND FUTURE PROSPECTS The oceans represent a significant resource for the discovery of new drugs. Marine organisms, such as invertebrates and microbial sources, provide both new molecules and lead compounds. Several molecules are currently on the pharmaceutical market for various disease areas, mostly in the area of cancer, but also for pain and antiviral treatments. The current pipeline of marine-derived molecules in anticancer clinical trials suggests that some new approvals will be soon effective. Drugs from the sea are not a promise anymore: they are a reality.

[13]

[14]

[15]

[16]

CONFLICT OF INTEREST The author(s) confirm that this article content has no conflict of interest.

[17]

ACKNOWLEDGEMENTS

[18]

Declared none. SUPPLEMENTARY MATERIAL Supplementary material is available on the publisher’s web site along with the published article.

[19]

[20]

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Clinical Status of Marine Natural Products [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42]

[43] [44]

[45]

[46]

[47]

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Received: June 18, 2012

Revised: October 23, 2012

Accepted: October 24, 2012

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