Phase I and Pharmacokinetic Study Of

Published OnlineFirst August 14, 2020; DOI: 10.1158/1078-0432.CCR-20-1412

CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY

Phase I and Pharmacokinetic Study of Romidepsin in Patients with Cancer and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study Roisin M. Connolly1,2, Eric Laille3, Ulka Vaishampayan4, Vincent Chung5, Karen Kelly6, Afshin Dowlati7, Olatunji B. Alese8, R. Donald Harvey8, Paul Haluska9, Lillian L. Siu10, Shivaani Kummar11, Richard Piekarz12, S. Percy Ivy12, Nicole M. Anders1, Melinda Downs1, Ashley O’Connor1, Angela Scardina1, Jacqueline Saunders1, Gary L. Rosner1, Michael A. Carducci1, and Michelle A. Rudek1,13, for the ETCTN-9008 Study Team

ABSTRACT ◥ Purpose: Romidepsin dosing recommendations for patients with Results: Thirty-one patients received one dose of romidepsin and malignancy and varying degrees of hepatic dysfunction was lacking were evaluable for pharmacokinetic analyses in normal (n ¼ 12), at the time of regulatory approval for T-cell lymphoma. We con- mild (n ¼ 8), moderate (n ¼ 5), and severe (n ¼ 6) cohorts. Adverse ducted a multicenter phase I clinical trial (ETCTN-9008) via the events across cohorts were similar, and dose-limiting toxicity NCI Organ Dysfunction Working Group to investigate safety, first occurred in two patients (mild and severe impairment cohorts). cycle MTD, and pharmacokinetic profile of romidepsin in this The MTD was not determined because the geometric mean AUC setting. values of romidepsin in moderate (7 mg/m2) and severe (5 mg/m2) Patients and Methods: Patients with select advanced solid tumors impairment cohort were 114% and 116% of the normal cohort or hematologic malignancies were stratified according to hepatic (14 mg/m2). function. Romidepsin was administered intravenously on days 1, 8, Conclusions: Data from the ETCTN-9008 trial led to changes in and 15 of a 28-day cycle and escalation followed a 3 þ 3designin the romidepsin labeling to reflect starting dose adjustment for moderate and severe impairment cohorts. Blood samples for detailed patients with cancer and moderate and severe hepatic impairment, pharmacokinetic analyses were collected after the first dose. with no adjustment for mild hepatic impairment.

Introduction cell-cycle arrest and differentiation, induce cell death, reduce angio- genesis, and modulate the immune system (1, 2). Histone deacetylase (HDAC) inhibitors are a class of epigenetic Romidepsin is an HDAC inhibitor that targets both class I and II modifiers that have been found in preclinical tumor models to induce HDAC enzymes and is approved for use in cutaneous T-cell lymphoma (CTCL; refs. 3, 4) and peripheral T-cell lymphoma (PTCL; refs. 5, 6). It is a bicyclic depsipeptide with a disulfide bond that is 1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Med- converted by cellular reducing activity to yield a free sulfhydryl moiety, icine, Baltimore, Maryland. 2Cancer Research at UCC, College of Medicine and which is thought to bind to the zinc in the HDAC active site pocket (7). Health, University College Cork, Ireland. 3Bristol Myers Squibb (formerly Celgene The recommended dose and schedule of romidepsin is 14 mg/m2 Corporation), Summit, New Jersey. 4Karmanos Cancer Center, Wayne State 5 6 intravenously over 4 hours on days 1, 8, and 15 of a 28-day cycle (8). University, Detroit, Michigan. City of Hope, Duarte, California. Comprehensive Romidepsin is extensively metabolized in liver and excreted primarily Cancer Center, University of California Davis Medical Center, Sacramento, California. 7Case Comprehensive Cancer Center, Case Western Reserve Univer- through bile, and as such patients with impaired hepatic function were sity, Cleveland, Ohio. 8Winship Cancer Institute of Emory University, Atlanta, excluded from early phase trials (9). As a postmarketing requirement, Georgia. 9Mayo Clinic, Rochester, Minnesota. 10Division of Medical Oncology and romidepsin dosing in patients with cancer with hepatic dysfunction Hematology, Department of Medicine, Princess Margaret Cancer Centre, Uni- was to be explored in a clinical trial to establish dosing guidelines for 11 versity of Toronto, Toronto, Ontario, Canada. Developmental Therapeutics these patients to offer an optimum benefit with minimum risk to Clinic, Division of Cancer Treatment and Diagnosis, National Cancer Institute, patients. Because of the propensity for ECG abnormalities preclinically Bethesda, Maryland. 12Investigational Drug Branch, Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, Bethesda, Maryland. 13Department and clinically with romidepsin and the HDAC inhibitor class, this trial of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Med- could not be conducted in healthy volunteers (10–12). icine, Baltimore, Maryland. Thus, a NCI Organ Dysfunction Working Group (ODWG) multi- Clinical trials.gov Registration ID: NCT01638533. center phase I clinical trial (ETCTN-9008, NCT01638533) of single-agent romidepsin was performed in patients with select advanced solid tumors Current address for P. Haluska: Bristol-Myers Squibb, Lawrenceville, New Jersey; and current address for S. Kummar, Division of Oncology, Department of or hematologic malignancies and varying degrees of hepatic dysfunction. Medicine, Stanford University, Palo Alto, California. The study was designed to establish the safety and tolerability, MTD, and pharmacokinetic profile of romidepsin in this patient cohort. Corresponding Author: Michelle A. Rudek, The Sidney Kimmel Cancer Center at Johns Hopkins, 1650 Orleans St., CRB1 Rm 1M52, Baltimore, MD 21287. Phone: 443-287-6476; E-mail: [email protected] Patients and Methods – Clin Cancer Res 2020;XX:XX XX Eligibility criteria doi: 10.1158/1078-0432.CCR-20-1412 Patients equal to or older than 18 years with histologic or cytologic 2020 American Association for Cancer Research. confirmed lymphoma, chronic lymphocytic lymphoma, or select solid

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complied with the International Ethical Guidelines for Biomedical Translational Relevance Research Involving Human Subjects and the Declaration of Helsinki. Romidepsin is a histone deacetylase (HDAC) inhibitor that targets both class I and II HDAC enzymes, and is approved for Clinical trial design use in cutaneous and peripheral T-cell lymphoma. At the time of This was a single-arm multi-institutional study conducted at nine romidepsin approval, there was limited data supporting its use in participating sites, and the Sidney Kimmel Comprehensive Cancer patients with hepatic impairment. Because of this drugs’ extensive Center at Johns Hopkins (Baltimore, MD) was the coordinating center. metabolism, a postmarketing evaluation was required to explore Patients were stratified into four hepatic function cohorts (A: normal, appropriate dosing for patients with malignancy and varying B: mild dysfunction, C: moderate dysfunction, D: severe degrees of hepatic dysfunction (ETCTN-9008). In this multicenter dysfunction; Table 1). Patients whose degree of hepatic dysfunction phase I clinical trial, an early pharmacokinetic evaluation was changed between registration and initiation of protocol therapy were utilized to stop dose escalation in the moderate and severe cohorts, reassigned to a different dysfunction cohorts and dose level. Patients in due to exposure mirroring the FDA-approved dose in patients with cohort A were included in this study as control patients and were normal hepatic function. These data supported amendment of the followed for toxicity. romidepsin package label with dose adjustment in patients with Romidepsin was supplied by the NCI Division of Cancer Treatment cancer and moderate and severe hepatic impairment, and closer and Diagnosis under a Clinical Trials Agreement with Celgene. monitoring for toxicity. Romidepsin was administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle. Treatment continued until progressive disease or unacceptable toxicity. A 5-HT3 receptor antag- onist was administered as premedication to prevent nausea, with tumor malignancies were eligible even if a prior treatment included granisetron as the preferred agent as it is known to have limited romidepsin. Patients with relapsed or refractory PTCL or CTCL were impact on QTc in contrast to other agents (19). eligible without the requirement of having relapsed within 6 months of Dose escalation followed a standard 3þ3 design, with the exception last treatment, consistent with labeling. Patients with solid tumors of the normal and mild hepatic function cohort (Table 1). Doses were must have had recurrent or metastatic, disease, for which standard selected with the hypothesis that each hepatic impairment group curative measures were unavailable. Patients with neuroendocrine would have higher exposure and therefore require an approximate tumors were excluded because of efficacy and safety concerns (11). 30% decrement from 14 mg/m2. Mild hepatic impairment was deter- Patients with prostate cancer, renal cell cancer, lung cancer, colorectal mined to have no effect on romidepsin exposure in a population cancers, soft-tissue sarcomas (NCT00112463), glioma, and thyroid pharmacokinetic analysis in patients with CTCL and PTCL (20, 21). cancer were excluded in the normal and mild cohorts due to a lack of The mild hepatic impairment cohort was included in our study to efficacy but were permitted to enroll in the moderate and severe confirm these prior results with a 14 mg/m2 starting dose. No more cohorts (13–18). These patients signed a separate informed consent than 12 patients were to be enrolled to the normal hepatic function outlining the lack of efficacy observed in prior studies as above and cohort, which served as a pharmacokinetic comparison. Initially, the were consented to the study by a protocol-specified designee who was severe cohort was not to enroll until the first dose level of the moderate not their longitudinal oncologist. cohort completed. The protocol was subsequently amended to allow Radiologically or clinically evaluable disease, Eastern Cooperative patients in the severe dysfunction cohort to enroll one patient at a time Oncology Group (ECOG) performance status 0–2, life expectancy due to difficulties in accruing in the moderate cohort. Doses in more >3 months, and adequate hematologic and renal function parameters severe cohorts were not to escalate beyond doses being tested in less were required. Use of medications with the potential or ability to affect severe cohorts. A patient was to be dose reduced to the next lowest dose the activity or pharmacokinetics of romidepsin was not permitted and level if they experienced and recover from a grade 4 adverse event. included those with risk of QTc prolongation/Torsades de Pointes or Common Terminology Criteria for Adverse Events (version 4.0) strong CYP3A4 inhibitors or inducers (9, 10). Warfarin was not was used to grade treatment-related toxicity. Dose-limiting toxicity permitted because of potentiation of anticoagulation by romidepsin. (DLT) was an adverse event that occurred during cycle 1 and was The study was registered at clinical trials.gov (NCT01638533), and probably or definitely related to the study drug and met the following participants signed a written informed consent approved by the criteria: grade ≥3 nonhematologic toxicity (except allergic reactions, Institutional Review Boards of participating institutions. The study alopecia, grade ≥3 diarrhea, nausea, or vomiting responsive to

Table 1. Romidepsin dose levels based on liver function.

Normal function Moderate dysfunction Severe dysfunction Dose level (cohort A) Mild dysfunction (cohort B) (cohort C) (cohort D)

(bilirubin ≤ ULN and (bilirubin ≤ ULN and AST > ULN or bilirubin > (bilirubin >1.5 ULN but (bilirubin >3 ULN but AST ≤ ULN) ULN but ≤1.5 ULN and any AST) ≤3 ULN and any AST) ≤10 ULNa and any AST) Level 1 — 10 mg/m2 5 mg/m2 3.5 mg/m2 Level 1 14 mg/m2 14 mg/m2 7 mg/m2 5 mg/m2 Level 2 No escalation No escalation 10 mg/m2 7 mg/m2 Level 3 No escalation No escalation 14 mg/m2 10 mg/m2 Level 4 No escalation No escalation No escalation 14 mg/m2

aThe upper limit was changed from ≤10 upper limit of normal (ULN) to up to investigators discretion during the conduct of the trial.

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supportive care, grade 3 rise in creatinine responsive to fluids within (97.7%–111.9%), intraassay precision (5.2%–13.4%), and interassay 24 hours, grade ≥3 electrolyte toxicity that is corrected to grade 1 or precision (3.9%–8.2%) were within FDA guidelines (25). baseline within 48 hours, grade 4 asymptomatic hyperuricemia); grade Pharmacokinetic parameters were calculated from individual romi- 4 neutropenia or thrombocytopenia or any febrile neutropenia; grade depsin concentration–time data using standard noncompartmental ≥2 neurotoxicity. Worsening liver function, as defined by a rise in methods as implemented in Phoenix WinNonlin version 6.3 (Phar- serum bilirubin not related to tumor progression or stent occlusion, sight A Certara Company). Pharmacokinetic parameters were assessed was also considered a DLT if a patient in the mild cohort progressed on each patient regardless of evaluability for safety. All pharmacoki- into the severe dysfunction range for one week, or if a patient in either netic parameters were assessed and deemed reportable if at least 10 the moderate or severe cohorts had a >1.5 times increase in bilirubin nonpretreatment samples were collected. lasting 1 week. Patients were evaluable for safety if they experienced a DLT or Statistical considerations received at least two of the three planned doses during the first cycle of The primary endpoints of this study were (i) to determine the MTD therapy and were followed for a minimum of 21 days without a DLT. and DLT risk of romidepsin in patients with varying degrees of hepatic Only DLTs that occurred during the first cycle of treatment were used dysfunction (mild, moderate, severe) to provide appropriate dosing to guide cohort dose escalation. The MTD was defined as the highest recommendations for romidepsin in such patients and (ii) to charac- dose at which no more than one instance of DLT was observed among terize the pharmacokinetic profile of romidepsin in patients with the first six patients treated. varying degrees of hepatic dysfunction. A secondary endpoint was to document any antitumor activity associated with romidepsin treat- Safety assessments ment of patients enrolled on this study. Analyses were descriptive in Baseline evaluations included routine history and physical nature in this phase I study. We aimed to characterize observed examination, complete blood counts, serum chemistries, ECG, and toxicities by dose level within each category of liver dysfunction, and radiologic evaluations. Liver function tests [aspartate aminotrans- describe clinical activity across cancer types. ferase (AST) and total bilirubin] were repeated within 24 hours The dose-escalation rules were adapted from the 3 þ 3designto prior to starting cycle 1 day 1. Results of potassium and magnesium eliminate waiting periods between dose levels, as the clinical stability of were required to be available prior to administration of study drug patients with impaired hepatic function is frequently limited. The plan and replaced if needed. Additional ECGs were performed at base- was for a minimum of 2 and maximum of 12 patients accrued in cohorts line and predose on cycle 1 days 1, 8, and 15, and at the beginning of B–D at each dose level. Cohort A was to accrue at least 12 patients. each cycle thereafter prior to romidepsin administration. On cycle Pharmacokinetic parameters were summarized using descriptive 1 day 1, additional ECGs were performed at 4, 6, and 8 hours after statistics. Differences between the pharmacokinetic parameters of the initiation of the infusion. If QTc prolongation (>500 ms) was romidepsin between varying degrees of liver dysfunction were eval- observed, ECG was performed in triplicate to confirm prolongation uated statistically by use of the Kruskal–Wallis test. All statistical tests and then performed daily until QTc returned to <500 ms. Responses were performed using either R (ver. 3.6.2) or JMP Statistical Discovery of measurable lesions were evaluated using RECIST 1.1 criteria after software (version 7; SAS Institute). Statistical significance was set to the every two cycles (22). All patients were followed for toxicity level 0.05. assessment for 30 days after going off-study or until death, which- ever occurred first. Results Pharmacokinetic evaluations Patient characteristics Blood samples for pharmacokinetic analysis were collected in From August 2012 to August 2017, 38 patients were enrolled in the heparinized tubes prior to drug administration and up to 48 hours study. Seven subjects were not eligible and/or not treated in the study after initiation of the infusion. Blood samples were centrifuged at due to late determination of ineligibility (n ¼ 4), consent withdrawal 1,000 g for 10 minutes within 1 hour to obtain plasma. The plasma (n ¼ 1), disease progression before treatment (n ¼ 1), and other reason was stored at 70C until analysis. (n ¼ 1). The trial remained open to accrue the remaining moderate Concentrations of romidepsin were determined using a validated impairment patient until November 2018 when the FDA accepted data LC/MS-MS method at the Analytical Pharmacology Core Laboratory at in the interim clinical study report to support the dosing recommen- the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins dations (26). Median age was 62 (range, 18–79), 45% female and the (Baltimore, MD; refs. 23, 24). Romidepsin was quantified over the range median number of prior treatments was three (range, 0–10). The most of 0.1 to 100 ng/mL with dilutions of up to 1:100 vol/vol being accurate. common tumor types enrolled were colorectal cancer and pancreatic/ Romidepsin was extracted from 200 mL of plasma using ethyl acetate hepatobiliary. Colorectal cancer, which was initially excluded, (600 mL) following the addition of the internal standard harmine (5 accounted for 40% and 50% of the moderate and severe cohorts, ng/mL in 40 mL acetonitrile). Eluents were evaporated to dryness and respectively. Additional demographic data are shown in Table 2. reconstituted with 200 mL of methanol/water (30:70, vol/vol). Chro- matographic separation was achieved with a Phenomenex Luna CN Treatment and efficacy (50 mm 3.0 mm, 3 mm, 100A) followed by a Phenomenex HyperClone Thirty-one patients received at least one dose of romidepsin: normal BDS C8 column (50 mm 2.0 mm, 5 mm, 130A) and a 0.1% formic acid (n ¼ 12), mild (n ¼ 8), moderate (n ¼ 5), and severe (n ¼ 6) cohorts. All in methanol/water gradient over a 7-minute total analytical run time. A of these had evaluable plasma concentration data and were evaluable for blank solvent was injected in between each sample, including calibrators both safety and pharmacokinetic analyses. Twenty-three subjects who and quality control samples, to prevent carryover. An AB Sciex 5500 received at least two of the three planned doses in cycle 1, or who triple quadrupole mass spectrometer operated in positive electrospray experienced a DLT, were evaluable for determination of the DLT. ionization mode was used for the detection of romidepsin and its The median duration of treatment across all cohorts was 50 days internal standard. During the conduct of the trial, the accuracy (range, 1–355), with a median number of doses of four (range, 1–30).

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Table 2. Patient characteristics by dose level.

Liver dysfunction cohorts, n (%) Characteristics Normal (A) Mild (B) Moderate (C) Severe (D) Total

Number of patients 12 8 5 6 31 Median (range) age 63.5 (42–73) 59.5 (30–79) 62 (58–70) 49 (18–66) 62 (18–79) Sex Male 8 (67) 2 (25) 4 (80) 3 (50) 17 (55) Female 4 (33) 6 (75) 1 (20) 3 (50) 14 (45) Median (range) 2.00 (1.55–2.30) 1.57 (1.53–1.87) 1.74 (1.69–2.41) 1.91 (1.41–2.66) 1.84 (1.41–2.66) BSA (m2) Race White 8 (67) 4 (50) 3 (60) 5 (83) 20 (65) Asian 2 (17) 1 (13) 0 (0) 0 (0) 3 (10) Black 2 (17) 3 (38) 1 (20) 1 (17) 7 (23) Native American 0 (0) 0 (0) 1 (20) 0 (0) 1 (3) ECOGa 0 5 (42) 1 (12.5) 0 (0) 0 (0) 6 (19) 1 7 (58) 6 (75) 2 (40) 4 (67) 19 (62) 2 0 (0) 1 (12.5) 3 (60) 2 (33) 6 (19) Tumor type Solid tumor 11 (92) 8 (100) 4 (80) 6 (100) 29 (94) Adenoid cystic 1 (8) 1 (13) 0 (0) 1 (17) 3 (10) Breast 1 (8) 1 (13) 0 (0) 0 (0) 2 (6) Colorectal 0 (0) 0 (0) 2 (40) 3 (50) 5 (16) Genitourinary 2 (17) 0 (0) 0 (0) 0 (0) 2 (6) Gynecologic 1 (8) 0 (0) 0 (0) 0 (0) 1 (3) Head and neck 3 (25) 0 (0) 0 (0) 0 (0) 3 (10) Hepatocellular 0 (0) 2 (25) 2 (40) 0 (0) 4 (13) Mesothelioma 1 (8) 0 (0) 0 (0) 0 (0) 1 (3) Pancreatic/biliary 0 (0) 3 (38) 0 (0) 2 (33) 5 (16) Skin 2 (17) 0 (0) 0 (0) 0 (0) 2 (6) Tonsil 0 (0) 1 (13) 0 (0) 0 (0) 1 (3) Lymphoma 1 (8) 0 (0) 1 (20) 0 (0) 2 (6) Aspartate aminotransferase (U/L) 25.5 (14–34) 91 (32–146) 100 (44–135) 113.5 (45–136) 44 (14–146) Median (range) Total bilirubin (mg/dL) 0.3 (0.1–0.8) 0.6 (0.1–1.7) 3.4 (2.4–4.2) 6.8 (4.5–34.6) 0.8 (0.1–34.6) Median number of prior therapies (range) 4 (1–6) 2.5 (0–8) 1 (0–4) 3 (2–10) 3 (0–10)

aECOG, Eastern Cooperative Oncology Group performance score.

The median treatment duration was shorter in the moderate and severe moderate and severe cohorts reflected that of the normal cohort cohorts (22 and 16.5 days, respectively) compared with the normal and (approved dose). mild cohorts (117.5 and 44.5 days). Eleven subjects discontinued the Table 3 summarizes the treatment-emergent adverse event (TEAE) study before the end of cycle 1 due to death (n ¼ 5), occurrence of an during cycle 1 that were treatment related. The most frequent all-grade adverse event (n ¼ 3), disease progression (n ¼ 2), and consent TEAEs (>35% of patients) occurring across cohorts were nausea (68%), withdrawal (n ¼ 1). We observed stable disease in 12 patients as the decreased white blood cell counts (55%), thrombocytopenia (52%), best clinical response to romidepsin in this heavily pretreated popu- fatigue (42%), and vomiting (42%). Grade 3 and 4 TEAEs during cycle lation with liver dysfunction. 1 that were treatment related were less than or equal to 19%. ECG changes (QT, ST-T changes) were documented in seven patients (23%) Safety and DLTs with the majority (n ¼ 4) occurring in the normal cohort. There were no Patients with normal liver function (n ¼ 12; 12 evaluable for safety) cases of torsades de pointes or other treatment-emergent arrhythmia. and mild hepatic impairment (n ¼ 8; 6 evaluable for safety) tolerated 14 mg/m2 romidepsin relatively well, with one patient in the mild Pharmacokinetics cohort experiencing a DLT (grade 3 fatigue). Accrual to these cohorts Romidepsin pharmacokinetic data were available for 31 patients was completed as planned. Patients with moderate hepatic dysfunction (Table 4). Geometric mean plasma concentration–time profiles were (n ¼ 5; 3 evaluable for safety) were treated with 7 mg/m2 romidepsin similar when romidepsin was administered to patients with normal (dose level 1) without DLT. Accrual to this dose level could not be hepatic function (14 mg/m2), mild hepatic impairment (14 mg/m2), completed despite maximal recruitment efforts over 6 years. Patients moderate hepatic impairment (7 mg/m2), and severe hepatic impair- with severe hepatic dysfunction (n ¼ 6; 2 evaluable for safety) were ment (5 mg/m2)asshowninFig. 1. Romidepsin plasma concentrations treated at 5 mg/m2 romidepsin (dose level 1), with one patient increased rapidly and reached a plateau at approximately 1-hour post- experiencing a DLT (also grade 3 fatigue). No further dose escalation infusion initiation (first sample collected). Then, after the end of the was attempted in the moderate and severe cohorts due to pharmaco- infusion, concentrations declined in an apparent multiphasic manner. kinetic results demonstrating that exposure for dose level 1 of the Concentrations were still quantifiable at the 48-hour time point.

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Table 3. TEAE related to romidepsin during cycle 1.

Liver dysfunction cohorts, n (%) Normal (A) Mild (B) Moderate (C) Severe (D) Total (n ¼ 12) (n ¼ 8) (n ¼ 5) (n ¼ 6) (n ¼ 31) Any Grade 3 Any Grade 3 Any Grade 3 Any Grade 3 Any Grade 3 Toxicity grade or 4 grade or 4 grade or 4 grade or 4 grade or 4

Abdominal pain ——1 (13%) —————1 (3%) — Abdominal distension ——1 (13%) —————1 (3%) — Anemia 4 (33%) — 2 (25%) — 2 (40%) — 1 (17%) 1 (17%) 9 (29%) 1 (3%) Anorexia 5 (42%) — 3 (38%) ———3 (50%) — 11 (35%) — Alkaline phosphatase increased ————1 (20%) ———1 (3%) — aPTT increased ——1 (13%) —————1 (3%) — Aspartate aminotransferase increased 1 (8%) ———————1 (3%) — Asthenia 1 (8%) ———1 (20%) — 1 (17%) — 3 (10%) — Bradycardia 1 (8%) ———————1 (3%) — Creatinine increased 2 (17%) ———————2 (6%) — Diarrhea 1 (8%) ———1 (20%) ———2 (6%) — Dizziness 1 (8%) ———1 (20%) ———2 (6%) — Dry mouth ————1 (20%) ———1 (3%) — Dry skin ————1 (20%) ———1 (3%) — Dysgeusia 1 (8%) — 1 (13%) ———1 (17%) — 3 (10%) — Dyspepsia 1 (8%) ———————1 (3%) — Fatigue 6 (50%) — 3 (38%) 1 (13%) 2 (40%) — 2 (33%) 1 (17%) 13 (42%) 2 (6%) Flu-like symptoms (malaise) 2 (17%) —————1 (17%) — 3 (10%) — Gastric hemorrhage ——————1 (17%) 1 (17%) 1 (3%) 1 (3%) Generalized pain ————1 (20%) ———1 (3%) — Glossodynia ————1 (20%) ———1 (3%) — Headache 3 (25%) —————1 (17%) — 4 (13%) — Hypercalcemia 1 (8%) ———————1 (3%) — Hyperuricemia ——1 (13%) —————1 (3%) — Hypoalbuminemia 2 (17%) — 1 (13%) —————3 (10%) — Hypocalcemia 1 (8%) ———————1 (3%) — Hypoglycemia 1 (8%) ———————1 (3%) — Hypokalemia 1 (8%) ———————1 (3%) — Hypomagnesmia ————1 (20%) ———1 (3%) — Hyponatremia 3 (25%) ———1 (20%) ———4 (13%) — Hypotension ————1 (20%) 1 (20%) ——1 (3%) 1 (3%) Infections 1 (8%) ———2 (40%) 1 (20%) 1 (17%) — 4 (13%) 1 (3%) Muscle cramping ——1 (13%) —————1 (3%) — Nausea 9 (75%) — 6 (75%) — 2 (40%) — 4 (67%) 2 (33%) 21 (68%) 2 (6%) Peripheral neuropathy 2 (17%) ———————2 (6%) — Photophobia 1 (8%) ———————1 (3%) — QTc prolongation 4 (33%) — 2 (25%) — 1 (20%) ———7 (23%) — Tachycardia 1 (8%) — 1 (13%) —————2 (6%) — Thrombocytopenia 7 (58%) — 6 (75%) — 3 (60%) 1 (20%) ——16 (52%) 1 (3%) Vomiting 4 (33%) — 5 (63%) — 1 (20%) — 3 (50%) — 13 (42%) — WBC decrease 9 (75%) 3 (25%) 4 (50%) 1 (13%) 3 (60%) 2 (40%) 1 (17%) 1 (17%) 17 (55%) 7 (23%) Weight loss 1 (8%) ———————1 (3%) —

2 Variability in maximum concentration (Cmax) and area under the and AUCINF values after administration of 7 mg/m romidepsin in – fi plasma concentration time curve extrapolated to in nity (AUCINF) patients with moderate hepatic impairment were 96% and 114% of the values were similaracrossthe cohorts. There was a statistically significant corresponding geometric mean values after administration of 14 mg/m2 difference between hepatic function and dose-normalized Cmax (Cmax/D; romidepsin in patients with normal hepatic function. The geometric ¼ ¼ 2 P 0.002), dose-normalized AUCINF (AUCINF/D; P 0.002), terminal mean Cmax and AUCINF values after administration of 5 mg/m rom- ¼ ¼ half-life (T1/2; P 0.035), and systemic clearance (Cl; P 0.002) using idepsin in patients with severe hepatic impairment were approximately – the Kruskal Wallis test. Unnormalized Cmax and AUCINF were not 95% and 116% of the corresponding geometric mean values after significantly different among the cohorts, and neither was volume of administration of 14 mg/m2 romidepsin in patients with normal hepatic distribution. The geometric mean Cmax and AUCINF values after admin- function, respectively. Consistent with AUCINF results, compared with istration of 14 mg/m2 romidepsin in patients with mild hepatic the normal hepatic function cohort, romidepsin clearance decreased impairment were approximately 115% and 144% of the corresponding with worsening hepatic function. The clearance in the mild and mod- geometric mean values after administration of the same dose in patients erate hepatic clearance is in the same range as the prior population with normal hepatic function, respectively. The geometric mean Cmax pharmacokinetic analysis (21). The two patients who had DLTs were

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Table 4. Romidepsin plasma pharmacokinetic parameters.

Normal Mild Moderate Severe Cohort A (n) Cohort B (n) Cohort C (n) Cohort D (n)

Cmax (ng/mL) 428 151 (12) 494 198 (8) 411 230 (5) 405 116 (6) AUCINF (ng hour/mL) 1,692 653 (10) 2,443 738 (7) 1,921 1,040 (5) 1,957 876 (6) T1/2 (hour) 11.13 2.10 (10) 13.55 1.41 (7) 14.08 3.88 (5) 14.52 4.25 (6) V (L) 20.7 12.5 (10) 17.1 2.5 (7) 19.0 6.4 (5) 15.4 5.1 (6) Cl (L/hour) 16.2 8.7 (10) 9.6 2.7 (7) 6.9 3.5 (5) 4.8 2.8 (6)

Note: Data are presented as the geometric mean SD (n).

Abbreviations: AUCINF, area under the plasma concentration–time curve extrapolated to inﬁnity; Cl, systemic clearance; Cmax, maximum concentration; T1/2, terminal half-life; V, volume of distribution.

in the same range for dose-normalized exposure [Cmax/D (32.1 and prior line of chemotherapy. It is not indicated for use in any solid tumors 40.5 ng/mL/mg), AUCINF/D (146.6 and 192.4 ng hour/mL/mg)], or to date. Hepatic dysfunction can complicate the presentation and clearance (5.2 or 6.8 L/hour) compared with patients who did not management of patients with malignancy, due to the presence of liver – experience a DLT [range for Cmax/D (7.3 84.6 ng/mL/mg), AUCINF/D metastases or drug-induced toxicity. Exploring appropriate dosing for (29.9–507.4 nghour/mL/mg), or clearance (2.0–33.4 L/hour)]. patients with malignancy and varying degrees of hepatic dysfunction is thus important when new drugs are approved for use especially when they are extensively metabolized, which is the case with romidepsin (9). Discussion Because of potential risks of cardiac toxicity, the postmarketing require- Romidepsin remains an important therapeutic option in the management from the FDA recommended that the drug–drug interaction, QT ment of patients with CTCL and PTCL who have received at least one prolongation, and hepatic impairment trials be conducted in patients with cancer rather than healthy volunteers (10–12, 27). The NCI ODWG was selected as a platform for investigation of romidepsin dosing in patients with hepatic dysfunction due to the experience of its clinical sites and investigators in conducting organ dysfunction clinical trials in patients with advanced cancer (28–33). This study confirmed the previously well-characterized adverse events associated with romidepsin including gastrointestinal disturbances, fatigue, and hematologic toxicity (3–6). No new safety signals were identified. The safety profile of romidepsin in patients with mild, moderate, and severe hepatic dysfunction receiving 14, 7, and 5 mg/m2, respectively, was similar to that observed in the normal cohort who received the FDA-approved dose of 14 mg/m2. The importance of early review of pharmacokinetic analysis during trial conduct where safety could be of concern due to increase exposure due to altered romidepsin elimination is highlighted by our results. The pharmacokinetic profile of romidepsin during cycle 1 in patients with mild, moderate, and severe hepatic dysfunction receiving 14, 7, and 5 mg/m2, respectively, was similar to that observed in the normal cohort who received the FDA-approved dose of 14 mg/m2. Romidep- sin exposure in normal hepatic cohort patients is similar to the romidepsin alone arm of the drug–drug interaction trial (23). Because of availability of these results, and recruitment challenges experienced despite the multicenter nature of the clinical trial, no further dose escalation was recommended in the moderate and severe cohorts and the study was closed to accrual despite not achieving 6 evaluable patients in each cohort. On the basis of this data, the romidepsin product information was amended to recommend starting dose adjustment patients with cancer and moderate and severe hepatic impairment, as well as closer monitoring for toxicity (26). A 50% reduction from the standard dosing (7 mg/m2) administered on days 1, 8, and 15 of a 28-day cycle is now recommended for patients with moderate hepatic impairment [bilirubin >1.5 to ≤3 upper limit normal (ULN) and any AST]. A 64% reduction (5 mg/m2) is recommended for patients with severe hepatic impairment (bilirubin >3 ULN and up to ’ Figure 1. investigator s discretion and any AST). Indeed, it was a well-selected Geometric mean and SD concentration–time profile of romidepsin on day 1 on a starting dose for each cohort, which allowed for the completion of the linear (A) or semilog plot (B). trial based on pharmacokinetic data alone.

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Significant challenges with conducting hepatic dysfunction studies grants from Astellas (research support), Five Prime Therapeutics (research support), have been previously noted with several trials not being completed as Regeneron (research support), Tizona (research support), and Transgene (research originally designed (31). We identified additional sites over the study support) outside the submitted work. A. Dowlati reports other from Seattle Genetics (advisory board), Ipsen (advisory board), Astra Zeneca (advisory board), Bristol duration in an attempt to enhance accrual rates. Several amendments Myers Squibb (advisory board), and Takeda (adviosry board) outside the submitted to the clinical trial protocol were also performed to improve the slow work. O.B. Alese reports research funding (institution) from Taiho Oncology, Ipsen enrolment in the moderate and severe cohorts. These included mod- Pharmaceuticals, Tesaro Inc., Bristol Myers Squibb, PCI Biotech AS, ASCO, Calithera ifications of inclusion criteria including: reduction in platelet eligibility Biosciences, Inc., SynCore Biotechnology Co., Ltd and consulting/advisory role from requirements revised for patients with lymphoma and chronic lym- Exelixis, Conjupro BioTherapeutics, R-Pharm US LLC, Ipsen Pharmaceuticals. R.D. phocytic leukemia from ≥75 to ≥30 109 cells/L, allowance of elevated Harvey reports grants from Celgene (research funding to my institution that supports > ’ my salary) outside the submitted work. P. Haluska reports that he is currently bilirubin 3 ULN and up to investigator s discretion for the severe employee and stockholder of Bristol Myers Squibb. L.L. Siu reports grants from NCI cohort, and allowance of enrollment of patients with cancers that may (UM1-CA186644) during the conduct of the study; personal fees from Merck not respond to treatment. The severe cohort enrollment criteria was (consultation/scientific advisory board), Pfizer (consultation/scientific advisory also modified to allow for accrual one patient at a time, without waiting board), Celgene (consultation/scientific advisory board), AstraZeneca (consulta- fi fi for results from the moderate cohort that was itself experiencing tion/scienti c advisory board), Morphosys (consultation/scienti c advisory board), fi fi slow accrual. Finally, communication with disease groups at the sites GeneSeeq (consultation/scienti c advisory board), Loxo (consultation/scienti c advisory board), Oncorus (consultation/scientific advisory board), Symphogen (con- and involvement of Medical Science Liaisons were employed to raise sultation/scientific advisory board), Seattle Genetics (consultation/scientific advisory awareness of the study. Despite these efforts, a sixth moderate hepatic board), GlaxoSmithKine (consultation/scientific advisory board), Voronoi (consul- impairment patient could not be identified in 6 years. tation/scientific advisory board), Treadwell Therapeutics (consultation/scientific Of particular relevance in our study is the ethics surrounding advisory board), Arvinas (consultation/scientific advisory board), Navire (consulta- fi fi enrollment of patients in phase I studies with limited or unknown tion/scienti c advisory board), Relay (consultation/scienti c advisory board), Rubius fi fi chance for therapeutic efficacy (34). Patients with select tumor types (consultation/scienti c advisory board), Novartis (consultation/scienti c advisory board); other from Novartis (clinical trials support for institution), Bristol-Myers- were originally excluded from the study due to published phase II data Squibb (clinical trials support for institution), Pfizer (clinical trials support for supporting lack of efficacy of romidepsin in these tumor types as noted institution), Boerhinger-Ingelheim (clinical trials support for institution), Roche above (13–18). After careful consideration with the study team and (clinical trials support for institution), Karyopharm (clinical trials support for sponsor, and an awareness that patients with impaired hepatic func- institution), AstraZeneca (clinical trials support for institution), Merck (clinical trials tion and progressive malignancy have few standard or investigational support for institution), Celgene (clinical trials support for institution), Astellas therapeutic options despite a desire often for additional lines of (clinical trials support for institution), Bayer (clinical trials support for institution), Abbvie (clinical trials support for institution), Amgen (clinical trials support for therapy, and amendment subsequently permitted patients with these institution), Symphogen (clinical trials support for institution), Intensity Therapeu- tumor types to enroll in the moderate and severe cohorts with tics (clinical trials support for institution), Mirati Therapeutics (clinical trials support appropriate consent. This consent process involved education regard- for institution), Shattucks (clinical trials support for institution), Avid (clinical trials ing the available data and alternative options including best supportive support for institution), Agios (spouse: stock ownership), and Treadwell Therapeutics care, by an investigator not involved with that patients longitudinal (spouse: cofounder) outside the submitted work. S. Kummar reports personal fees care, nor the principal study investigator (RMC). If we had not allowed from Bayer (consultant, institutional clinical trial support), Boehringer Ingelheim (consultant), HarbourBiomed (consultant), Genome & Company (consultant), Var- this provision to allow patients with colorectal cancer, it appears that ian (consultant), and Springworks Therapeutics (consultant, institutional clinical trial the trial may not have completed the coprimary goal to characterize the support) outside the submitted work. M. Downs reports grants from Celegene pharmacokinetic profile of romidepsin in patients with varying Corporation during the conduct of the study. G.L. Rosner reports grants from degrees of hepatic dysfunction. Celgene Corporation (the funding was to Johns Hopkins University for pharmaco- In conclusion, we have identified important information regarding logic analysis.) during the conduct of the study. M.A. Rudek reports grants from the pharmacokinetic profile of romidepsin in patients with advanced Celgene Corporation during the conduct of the study; grants from Cullinan, Reno- voRx, and Syndax outside the submitted work. No potential conflicts of interest were malignancy and moderate and severe hepatic impairment, which now disclosed by the other authors. guides more evidenced-based treatment recommendations for these challenging patient cohorts. Multicenter clinical trial networks such as those led by the NCI Cancer Therapy Evaluation Program (CTEP), Authors’ Contributions and close collaboration between clinical investigators, pharmacoki- R.M. Connolly: Conceptualization, resources, data curation, formal analysis, netic experts, and industry partners are required for the success of such supervision, validation, methodology, writing-original draft, project administration, writing-review and editing. E. Laille: Conceptualization, resources, endeavors. data curation, supervision, validation, investigation, methodology, writing-review and editing. U. Vaishampayan: Resources, writing-review and editing. V. Chung: Disclosure of Potential Conflicts of Interest Resources, writing-review and editing. K. Kelly: Resources, writing-review and R.M. Connolly reports research funding to institution for clinical trials from editing. A. Dowlati: Resources, writing-review and editing. O.B. Alese: Resources, Novartis, Merck, Macrogenics, Puma Biotechnology, Genentech. R.M. Connolly writing-review and editing. R.D. Harvey: Resources, writing-original draft, writing- reports travel grant from Genentech. U. Vaishampayan reports grants and personal review and editing. P. Haluska: Resources, writing-review and editing. L.L. Siu: fees from BMS during the conduct of the study; grants and personal fees from Exelixis, Resources, writing-review and editing. S. Kummar: Resources, writing-review and Bayer, Astellas; and personal fees from Sanofi outside the submitted work. V. Chung editing. R. Piekarz: Conceptualization, resources, funding acquisition, project reports personal fees from Ipsen (speaker for Onivyde), Celgene (speaker for administration, writing-review and editing. S.P. Ivy: Conceptualization, resources, Abraxane), Apeiron (advisory board), Westwood Biosciences (advisory board), and funding acquisition, project administration, writing-review and editing. Perthera (consultant) outside the submitted work. K. Kelly reports personal fees from N.M. Anders: Methodology, writing-original draft, writing-review and editing. AstraZenveca (consultancy/advisory board), EMD Serono (consultancy/advisory M. Downs: Data curation, investigation, writing-review and editing. board, research support), (consultancy/advisory board), Merck (consultancy/advi- A. O’Connor: Data curation, investigation, writing-review and editing. sory board), Novartis (consultancy/advisory board), Pfizer (consultancy/advisory A. Scardina: Resources, data curation, investigation, writing-review and editing. board), Regeneron (consultancy/advisory board), Symphogen (consultancy/advisory J. Saunders: Formal analysis, validation, writing-review and editing. G.L. Rosner: board), and Inviata; grants and personal fees from AbbVie (consultancy/advisory Conceptualization, formal analysis, validation, writing-review and editing. board, Research support), Bristol-Myers Squibb (consultancy/advisory board, M.A. Carducci: Conceptualization, resources, supervision, funding acquisition, research support), Genentech/Roche (consultancy/advisory board, research support); project administration, writing-review and editing. M.A. Rudek:

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Connolly et al.

Conceptualization, resources, formal analysis, supervision, funding acquisition, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (P30 validation, methodology, writing-original draft, project administration, writing- CA006973). Grant number UL1 TR 001079 is from the National Center for review and editing. Advancing Translational Sciences (NCATS), a component of the NIH, and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors Acknowledgments and do not necessarily represent the ofﬁcial view of the Johns Hopkins ICTR, NCATS, We thank the patients who volunteered to participate in this study, NCI CTEP, or NIH. The Cancer Therapy Evaluation Program supplied romidepsin. Support was Celgene Corporation, and the research teams and physicians at participating sites. also provided by Celgene Corporation to supplement pharmacokinetic analysis. This study was funded by the NCI Experimental Therapeutics Clinical Trials Network (grants U01CA062487, U01CA062502, U01CA062505, U01CA069912, The costs of publication of this article were defrayed in part by the payment of page U01CA070095, U01CA132123, UM1CA186644, UM1CA186686, UM1CA186689, charges. This article must therefore be hereby marked advertisement in accordance UM1CA186691, UM1CA186717, and U24CA247648). The project described was with 18 U.S.C. Section 1734 solely to indicate this fact. also supported by the Analytical Pharmacology Core of the Sidney Kimmel Com- prehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 TR 001079), the Shared Instrument Grant (S10RR026824-01), the Clinical Protocol and Received June 7, 2020; revised June 30, 2020; accepted August 4, 2020; Data Management facilities (P30 CA006973), and the Biostatistics Shared Resource of published ﬁrst August 14, 2020.

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Phase I and Pharmacokinetic Study of Romidepsin in Patients with Cancer and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study

Roisin M. Connolly, Eric Laille, Ulka Vaishampayan, et al.

Clin Cancer Res Published OnlineFirst August 14, 2020.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-20-1412

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