A clinical trial for patients with acute myeloid leukemia ...

Accepted Article Preview: Published ahead of advance online publication A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials G Montalban-Bravo, X Huang, E Jabbour, G Borthakur, C D DiNardo, N Pemmaraju, J Cortes, S Verstovsek, T Kadia, N Daver, W Wierda, Y Alvarado, M Konopleva, F Ravandi, Z Estrov, N Jain, A Alfonso, M Brandt, T Sneed, H-C Chen, H Yang, C Bueso-Ramos, S Pierce, E Estey, Z Bohannan, H M Kantarjian, G Garcia-Manero

Cite this article as: G Montalban-Bravo, X Huang, E Jabbour, G Borthakur, C D DiNardo, N Pemmaraju, J Cortes, S Verstovsek, T Kadia, N Daver, W Wierda, Y Alvarado, M Konopleva, F Ravandi, Z Estrov, N Jain, A Alfonso, M Brandt, T Sneed, H-C Chen, H Yang, C Bueso-Ramos, S Pierce, E Estey, Z Bohannan, H M Kantarjian, G Garcia-Manero, A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials, Leukemia accepted article preview 31 October 2016; doi: 10.1038/leu.2016.303. This is a PDF ﬁle of an unedited peer-reviewed manuscript that has been accepted for publication. NPG are providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its ﬁnal form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Received 4 July 2016; revised 21 August 2016; accepted 30 August 2016; Accepted article preview online 31 October 2016

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2016 Macmillan Publishers Limited. All rights reserved.

A Clinical Trial for Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes Not Eligible for Standard Clinical Trials 1

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Guillermo Montalban-Bravo , Xuelin Huang , Elias Jabbour , Gautam Borthakur , Courtney D. 1 1 1 1 1 DiNardo , Naveen Pemmaraju , Jorge Cortes , Srdan Verstovsek , Tapan Kadia , Naval 1 1 1 1 1 Daver , William Wierda , Yesid Alvarado , Marina Konopleva , Farhad Ravandi , Zeev 1 1 1 1 1 2 Estrov , Nitin Jain , Ana Alfonso , Mark Brandt , Troy Sneed , Hsiang-Chun Chen , Hui 1 3 1 1 1 Yang , Carlos Bueso-Ramos , Sherry Pierce , Elihu Estey , Zachary Bohannan , Hagop M. 1 1 Kantarjian and Guillermo Garcia-Manero 1

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Departments of Leukemia , Biostatistics and Hematopathology University of Texas MD Anderson Cancer Center, Houston, Texas

Address correspondence to: Guillermo Garcia-Manero MD Department of Leukemia University of Texas MD Anderson Cancer Center 1515 Holcombe Blvd Houston, TX 77015 Fax: 713-745-4612 Phone: 713-745-3428 e-mail: [email protected] Running title: A Study for Patients with MDS and AML Ineligible to Clinical Trials Conflicts of interest: GG-M work has been supported by Celgene, maker of azacitidine, and Merck, maker of vorinostat. Merck supported in part this study. GG-M has served as a consultant and speaker for both Celgene and Merck.

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ABSTRACT

Most clinical trials exclude patients with poor performance or comorbidities. To study whether patients with these characteristics can be treated within a clinical trial, we conducted a study for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with poor performance, organ dysfunction or comorbidities. Primary endpoint was 60-day survival. Study included stopping rules for survival and response. Treatment consisted on a combination of azacitidine and vorinostat. Thirty patients (16 with MDS, 14 with AML) were enrolled. Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. No stopping rules were met. Main adverse events (AEs) where grade 1-2 gastrointestinal toxicities. In view of these results, we expanded the study and treated 79 additional patients: 27 with azacitidine (AZA) and 52 with azacitidine and vorinostat (AZA+V). Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rate was 79% (AZA = 67%, AZA+V = 85%, p=0.07). Median overall survival was 7.6 months (4.5-10.7). Median event-free survival was 4.5 months (3.55.6). Main AEs included grade 1-2 gastrointestinal toxicities. Our results suggest this subset of patients can be safely treated within clinical trials and derive clinical benefit. Relaxation of standard exclusion criteria may increase the pool of patients likely to benefit from therapy.

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INTRODUCTION Participation in clinical trials is fundamental for the development of new therapeutic interventions. New drugs are first studied in the context of clinical trials not only to test specific clinical hypothesis, but also to protect patients from unanticipated side effects of such 1

therapy . Importantly, for the patient and the physician, there is an expectation that the investigational therapy will have a beneficial clinical effect. This is particularly important for 2

patients for whom there is no optimal standard of care . Despite this need, only 3-5% of 3

patients with cancer treated in the United States currently enroll in clinical trials . Although enrollment rates may differ regionally, there are a number of reasons for such low rate of participation, with clinical trial eligibility criteria likely representing one of them. Most clinical studies in oncology exclude patients with comorbidities, active or recent malignancies, organ dysfunction or poor performance status. How these criteria protect patients is unclear. Although some of them are based on clinical reasoning it seems that these criteria are in place more to protect the drug or intervention being studied than the patient itself. Additionally, such stringent criteria not only may limit the access of “unfit” patients to potentially beneficial therapies, but also limit our ability to extrapolate the safety and efficacy outcomes of new drugs being tested in conventional clinical trials to this subset of patients 4

with unfavorable clinical features . Of importance, patients with such characteristics and poor expected outcomes represent the population that could benefit the most from investigational 5-7

approaches considering their otherwise dismal prognosis . This is particularly important in patients with leukemia in whom tissue infiltration or disease burden may result in organ dysfunction or poor performance that could be reversible with appropriate therapy

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. In view

of this, it seems necessary to determine whether excluding these patients from new therapeutic interventions within monitored clinical trials is ultimately beneficial, and if development of clinical trials for this subset of patients is safe and feasible. To test this concept we designed a clinical trial for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) with organ dysfunction, poor performance, other malignancies or other comorbidities. Patients were treated with azacitidine

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, a hypomethylating agent (HMA), and vorinostat

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, a histone deacetylase

(HDAC) inhibitor. This treatment modality was selected based on the acceptable toxicity

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profile of azacitidine

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and vorinostat , and existing preclinical data suggesting a potential

synergistic effect of combining HMA with HDAC inhibitors

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. The study was designed with

stopping rules for survival and response. In view of the results of this initial study, suggesting it is both feasible and safe to treat this group of patients within a clinical trial, we expanded the study to increase the treated patient population and allow further experience in the development of clinical trials for this group of patients.

MATERIAL AND METHODS Study Design and Patient Population We conducted a study for patients ineligible to conventional clinical trials, due to organ dysfunction, poor performance, other malignancies or comorbidities at the University of Texas MD Anderson Cancer Center (MDACC) following institutional guidelines. The study was registered at clinicaltrial.gov as NCT00948064. We enrolled patients older than 17 years of age with previously untreated AML or MDS (intermediate-2 or higher risk by IPSS

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at least one of the following inclusion criteria: serum creatinine  2 mg/dL, total bilirubin  2 mg/dL, ECOG Performance Status (PS) equal to 3 or 4, or ineligibility to participate on a protocol of higher priority due to comorbidities, other active malignancies or malignancies with a remission period of less than 2 years. Diagnosis was confirmed at MDACC and classified 21

following the revised 2016 WHO critera . Pregnant patients were excluded from study participation. Main exclusion criteria included presence of favorable cytogenetic abnormalities, such as inv(16), t(16;16), t(8;21), or t(15;17) due to available effective standard of care therapies

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, prior anti-leukemic therapy (except hydroxyurea for cytoreduction in case of

proliferative disease); not being able to receive oral medications due to the oral route of administration of vorinostat; prior therapy with histone deacetylase inhibitors; active hepatitis A, B, or C infection due to risk of potential hepatic toxicity with both azacitidine and vorinostat; or known allergy or sensitivity to vorinostat or azacitidine. Study was designed with predefined stopping rules for survival and response that were generated by the use of a Bayesian sequential monitoring design for single-arm clinical 24

trials .

Multc

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Lean

desktop

v1.1


program

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(https://biostatistics.mdanderson.org/SoftwareDownload/Default.aspx) was used to generate this model. To define the minimum expected survival and response rates that would trigger these stopping rules, prior data of 181 patients treated at our institution who met the study´s eligibility criteria was used. This data was also used to determine the study sample size and patient cohort sizes. In this group, 50% of patients had a survival of at least 60 days, and the complete response rate (CR) was 28%. The maximum sample size was 30. For the survival stopping rule, the study would stop if survival by Day 60 was unlikely (chance