Abstract
Purpose:
Romidepsin dosing recommendations for patients with malignancy and varying degrees of hepatic dysfunction was lacking at the time of regulatory approval for T-cell lymphoma. We conducted a multicenter phase I clinical trial (ETCTN-9008) via the NCI Organ Dysfunction Working Group to investigate safety, first cycle maximum-tolerated dose (MTD), and pharmacokinetic profile of romidepsin in this setting.
Patients and Methods:
Patients with select advanced solid tumors or hematologic malignancies were stratified according to hepatic function. Romidepsin was administered intravenously on days 1, 8 and 15 of a 28-day cycle and escalation followed a 3+3 design in moderate and severe impairment cohorts. Blood samples for detailed pharmacokinetic analyses were collected after the first dose.
Results:
Thirty-one patients received one dose of romidepsin and were evaluable for pharmacokinetic analyses in normal (n=12), mild (n=8), moderate (n=5) and severe (n=6) cohorts. Adverse events across cohorts were similar, and dose-limiting toxicity occurred in two patients (mild and severe impairment cohorts). The MTD was not determined since the geometric mean area under the curve values of romidepsin in moderate (7mg/m2) and severe (5mg/m2) impairment cohort were 114% and 116% of the normal cohort (14 mg/m2).
Conclusion:
Data from the ETCTN-9008 trial led to changes in the romidepsin labeling to reflect starting dose adjustment for patients with cancer and moderate and severe hepatic impairment, with no adjustment for mild hepatic impairment.
Keywords: Advanced malignancy, liver dysfunction, romidepsin
Introduction
Histone deacetylase (HDAC) inhibitors are a class of epigenetic modifiers which have been found in preclinical tumor models to induce cell cycle arrest and differentiation, induce cell death, reduce angiogenesis and modulate the immune system (1,2).
Romidepsin is a HDAC inhibitor which targets both class I and II HDAC enzymes, and is approved for use in cutaneous T-cell lymphoma (CTCL) (3,4) and peripheral T-cell lymphoma (PTCL) (5,6). It is a bicyclic depsipeptide with a disulfide bond that is converted by cellular reducing activity to yield a free sulfhydryl moiety, which is thought to bind to the zinc in the HDAC active site pocket (7).
The recommended dose and schedule of romidepsin is 14 mg/m2 intravenously over 4 hours on days 1, 8 and 15 of a 28-day cycle (8). Romidepsin is extensively metabolized in liver and excreted primarily through bile, and as such patients with impaired hepatic function were excluded from early phase trials (9). As a post-marketing requirement, romidepsin dosing in cancer patients with hepatic dysfunction was to be explored in a clinical trial to establish dosing guidelines for these patients to offer an optimum benefit with minimum risk to patients. Due to the propensity for ECG abnormalities pre-clinically and clinically with romidepsin and the HDAC inhibitor class, this trial could not be conducted in healthy volunteers (10–12).
Thus, a National Cancer Institute (NCI) Organ Dysfunction Working Group (ODWG) multicenter phase I clinical trial (ETCTN-9008, NCT01638533) of single agent romidepsin was performed in patients with select advanced solid tumors or hematologic malignancies and varying degrees of hepatic dysfunction. The study was designed to establish the safety and tolerability, maximum-tolerated dose (MTD), and pharmacokinetic profile of romidepsin in this patient cohort.
Patients and Methods
Eligibility criteria
Patients equal to or older than 18 years with histological or cytological confirmed lymphoma, chronic lymphocytic lymphoma (CLL) or select solid tumor malignancies were eligible even if a prior treatment included romidepsin. Patients with relapsed or refractory PTCL or CTCL were eligible without the requirement of having relapsed within 6 months of last treatment, consistent with labelling. Patients with solid tumors must have had recurrent or metastatic, disease, for which standard curative measures were unavailable. Patients with neuroendocrine tumors were excluded due to efficacy and safety concerns (11). Patients with prostate cancer, renal cell cancer, lung cancer, colorectal cancers, soft tissue sarcomas (NCT00112463), glioma and thyroid cancer were excluded in the normal and mild cohorts due to a lack of efficacy but were permitted to enroll in the moderate and severe cohorts (13–18). These patients signed a separate informed consent outlining the lack of efficacy observed in prior studies as above and were consented to the study by a protocol-specified designee who was not their longitudinal oncologist.
Radiologically or clinically evaluable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, life expectancy > 3 months, and adequate hematologic and renal function parameters were required. Use of medications with the potential or ability to affect the activity or pharmacokinetics of romidepsin was not permitted and included those with risk of QTc prolongation/Torsades de Pointes or strong CYP3A4 inhibitors or inducers (9,10). Warfarin was not permitted due to potentiation of anticoagulation by romidepsin. The study was registered at clinicaltrials.gov (NCT01638533), and participants signed a written informed consent approved by the Institutional Review Boards of participating institutions. The study complied with the International Ethical Guidelines for Biomedical Research Involving Human Subjects and the Declaration of Helsinki.
Clinical Trial Design
This was a single arm multi-institutional study conducted at nine participating sites, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins was the coordinating center. Patients were stratified into four hepatic function cohorts (A: normal, B: mild dysfunction, C: moderate dysfunction, D: severe dysfunction; Table 1). Patients whose degree of hepatic dysfunction changed between registration and initiation of protocol therapy were re-assigned to a different dysfunction cohorts and dose level. Patients in Cohort A were included in this study as control patients and were followed for toxicity.
Table 1.
Romidepsin dose levels based on liver function.
| Dose Level | Normal Function (Cohort A) | Mild Dysfunction (Cohort B) | Moderate Dysfunction (Cohort C) | Severe Dysfunction (Cohort D) |
|---|---|---|---|---|
| (bilirubin ≤ ULN and AST ≤ ULN) | (bilirubin ≤ ULN and AST > ULN or bilirubin > ULN but ≤ 1.5x ULN and any AST) | (bilirubin > 1.5x ULN but ≤ 3x ULN and any AST) | (bilirubin > 3x ULN but ≤ 10x ULN1 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 |
The upper limit was changed from ≤ 10x upper limit of normal (ULN) to up to investigators discretion during the conduct of the trial.
Romidepsin was supplied by the National Cancer Institute’s Division of Cancer Treatment and Diagnosis under a Clinical Trials Agreement (CTA) with Celgene. Romidepsin was administered intravenously (IV) 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 antagonist was administered as premedication to prevent nausea, with granisetron as the preferred agent as it is known to have limited impact on QTc in contrast to other agents (19).
Dose escalation followed a standard 3+3design, with the exception of the normal and mild hepatic function cohort (Table 1). Doses were selected with the hypothesis that each hepatic impairment group would have higher exposure and therefore require an approximate 30% decrement from 14 mg/m2. Mild hepatic impairment was determined to have no effect on romidepsin exposure in a population PK analysis in patients with CTCL and PTCL (20,21). The mild hepatic impairment cohort was included in our study to confirm these prior results with a 14 mg/m2 starting dose. No more than twelve patients were to be enrolled to the normal hepatic function cohort, which served as a pharmacokinetics comparison. Initially, the severe cohort was not to enroll until the first dose level of the moderate cohort completed. The protocol was subsequently amended to allow patients in the severe dysfunction cohort to enroll one patient at a time due to difficulties in accruing in the moderate cohort. Doses in more severe cohorts were not to escalate beyond doses being tested in less severe cohorts. A patient was to be dose reduced to the next lowest dose level if they experienced and recover from a Grade 4 adverse event.
Common Terminology Criteria for Adverse Events (CTCAE, version 4.0) was used to grade treatment-related toxicity. Dose limiting toxicity (DLT) was an adverse event that occurred during Cycle 1 and was probably or definitely related to the study drug and met the following criteria: Grade ≥ 3 non-hematologic toxicity (except allergic reactions, alopecia, grade ≥ 3 diarrhea, nausea or vomiting responsive to supportive care, grade 3 rise in creatinine responsive to fluids within 24 hours, grade ≥ 3 electrolyte toxicity that is corrected to grade 1 or baseline within 48 hours, grade 4 asymptomatic hyperuricemia); Grade 4 neutropenia or thrombocytopenia or any febrile neutropenia; Grade ≥ 2 neurotoxicity. Worsening liver function, as defined by a rise in serum bilirubin not related to tumor progression or stent occlusion, was also considered a DLT if a patient in the mild cohort progressed into the severe dysfunction range for one week, or if a patient in either the moderate or severe cohorts had a >1.5 times increase in bilirubin lasting one week.
Patients were evaluable for safety if they experienced a DLT or received at least two of the three planned doses during the first cycle of therapy and were followed for a minimum of 21 days without DLT. Only DLTs that occurred during the first cycle of treatment were used to guide cohort dose escalation. The MTD was defined as the highest dose at which no more than one instance of DLT was observed among the first six patients treated.
Safety Assessments
Baseline evaluations included routine history and physical examination, complete blood counts, serum chemistries, electrocardiography (ECG) and radiologic evaluations. Liver function tests (AST and total bilirubin) were repeated within 24 hours prior to starting cycle 1 day 1. Results of potassium and magnesium were required to be available prior to administration of study drug and replaced if needed. Additional ECGs were performed at baseline and pre-dose on Cycle 1 Days 1, 8 and 15, and at the beginning of each cycle thereafter prior to romidepsin administration. On Cycle 1 Day 1, additional ECGs were performed at 4, 6 and 8 hours after the initiation of the infusion. If QTc prolongation (> 500 msec) was observed, ECG was performed in triplicate to confirm prolongation and then performed daily until QTc returned to < 500 msec. Responses of measurable lesions were evaluated using RECIST 1.1 criteria after every two cycles (22). All patients were followed for toxicity assessment for 30 days after going off-study or until death, whichever occurred first.
Pharmacokinetic evaluations
Blood samples for pharmacokinetics analysis were collected in heparinized tubes prior to drug administration and up to 48 hours after initiation of the infusion. Blood samples were centrifuged at 1000×g for 10 minutes within 1 hour to obtain plasma. The plasma was stored at −70°C until analysis.
Concentrations of romidepsin were determined using a validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) method at the Analytical Pharmacology Core Laboratory at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (23,24). Romidepsin was quantified over the range of 0.1 to 100 ng/mL with dilutions of up to 1:100 v/v being accurate. Romidepsin was extracted from 200 μL of plasma using ethyl acetate (600 μL) following the addition of the internal standard harmine (5 ng/mL in 40 μL acetonitrile). Eluents were evaporated to dryness and reconstituted with 200 μL of methanol/water (30:70, v/v). Chromatographic separation was achieved with a Phenomenex® Luna CN (50 mm × 3.0 mm, 3 μm, 100A) followed by a Phenomenex® HyperClone BDS C8 column (50 mm x2.0 mm, 5μm, 130A) and a 0.1% formic acid in methanol/water gradient over a 7 minute total analytical run time. A blank solvent was injected in between each sample, including calibrators and quality control samples, to prevent carryover. An AB Sciex 5500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for the detection of romidepsin and its internal standard. During the conduct of the trial, the accuracy (97.7–111.9%), intra-assay precision (5.2–13.4%), and inter-assay precision (3.9–8.2%) were within FDA guidelines (25).
Pharmacokinetic parameters were calculated from individual romidepsin concentration-time data using standard noncompartmental methods as implemented in Phoenix WinNonlin version 6.3 (Pharsight A Certara® Company, Cary, North Carolina). Pharmacokinetic parameters were assessed on each patient regardless of evaluability for safety. All pharmacokinetic parameters were assessed and deemed reportable if at least 10 non-pretreatment samples were collected.
Statistical Considerations
The primary endpoints of this study were; a) to determine the MTD and DLT risk of romidepsin in patients with varying degrees of hepatic dysfunction (mild, moderate, severe) in order to provide appropriate dosing recommendations for romidepsin in such patients and b) to characterize the pharmacokinetic profile of romidepsin in patients with varying degrees of hepatic dysfunction. A secondary endpoint was to document any antitumor activity associated with romidepsin treatment of patients enrolled on this study. Analyses were descriptive in nature in this phase I study. We aimed to characterize observed toxicities by dose level within each category of liver dysfunction, and describe clinical activity across cancer types.
The dose escalation rules were adapted from the 3+3 design to eliminate waiting periods between dose levels, as the clinical stability of patients with impaired hepatic function is frequently limited. The plan was for a minimum of two and maximum of 12 patients accrued in cohorts B-D at each dose level. Cohort A was to accrue at least 12 patients.
Pharmacokinetic parameters were summarized using descriptive statistics. Differences between the pharmacokinetic parameters of romidepsin between varying degrees of liver dysfunction were evaluated statistically by use of the Kruskal-Wallis test. All statistical tests were performed using either R (ver. 3.6.2) or JMP Statistical Discovery software (version 7; SAS® Institute, Cary, NC). Statistical significance was set to the level 0.05.
Results
Patient Characteristics
From August 2012 to August 2017, thirty-eight patients were enrolled in the study. Seven subjects were not eligible and/or not treated in the study due to late determination of ineligibility (n=4), consent withdrawal (n=1), disease progression before treatment (n=1) and other reason (n=1). The trial remained open to accrue the remaining moderate impairment patient until November 2018 when the FDA accepted data in the interim clinical study report to support the dosing recommendations (26). Median age was 62 (range 18–79), 45% female and the median number of prior treatments was three (range, 0–10). The most common tumor types enrolled were colorectal cancer and pancreatic/hepatobiliary. Colorectal cancer, which was initially excluded, accounted for 40% and 50% of the moderate and severe cohorts, respectively. Additional demographic data is shown in Table 2.
Table 2.
Patient characteristics by dose level
| Characteristics | Liver Dysfunction Cohorts, n (%) | ||||
|---|---|---|---|---|---|
| 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) BSA (m2) | 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) |
| 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) |
| ECOG1 | |||||
| 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) |
| Gynecological | 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) Median (range) | 25.5 (14–34) | 91 (32–146) | 100 (44–135) | 113.5 (45–136) | 44 (14–146) |
| 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) |
ECOG, Eastern Cooperative Oncology Group Performance Score
Treatment and Efficacy
Thirty-one patients received at least one dose of romidepsin: normal (n=12), mild (n=8), moderate (n=5) and severe (n=6) cohorts. All of these had evaluable plasma concentration data and were evaluable for both safety and pharmacokinetic analyses. Twenty-three subjects who received at least two of the three planned doses in cycle 1, or who experienced a DLT, were evaluable for determination of the DLT.
The median duration of treatment across all cohorts was 50 days (range 1–355), with a median number of doses of four (range 1–30). The median treatment duration was shorter in the moderate and severe cohorts (22 and 16.5 days, respectively) compared to the normal and mild cohorts (117.5 and 44.5 days). Eleven subjects discontinued the study before the end of Cycle 1 due to death (n = 5), occurrence of an adverse event (n = 3), disease progression (n = 2), and consent withdrawal (n = 1). We observed stable disease in 12 patients as the best clinical response to romidepsin in this heavily pre-treated population with liver dysfunction.
Safety and Dose-limiting Toxicities
Patients with normal liver function (n=12; 12 evaluable for safety) and mild hepatic impairment (n=8; six evaluable for safety) tolerated 14 mg/m2 romidepsin relatively well, with one patient in the mild cohort experiencing a DLT (grade 3 fatigue). Accrual to these cohorts was completed as planned. Patients with moderate hepatic dysfunction (n=5; three evaluable for safety) were treated with 7 mg/m2 romidepsin (dose level 1) without DLT. Accrual to this dose level could not be completed despite maximal recruitment efforts over six years. Patients with severe hepatic dysfunction (n=6; two evaluable for safety) were treated at 5mg/m2 romidepsin (dose level 1), with one patient experiencing a DLT (also grade 3 fatigue). No further dose escalation was attempted in the moderate and severe cohorts due to pharmacokinetic results demonstrating that exposure for dose level 1 of the moderate and severe cohorts reflected that of the normal cohort (approved dose).
Table 3 summarizes the treatment-emergent adverse events during Cycle 1that were treatment-related. The most frequent all grade treatment-emergent adverse events (> 35% of patients) occurring across cohorts were nausea (68%), decreased white blood cell counts (55%), thrombocytopenia (52%), fatigue (42%), and vomiting (42%). Grade 3 and 4 treatment-emergent adverse events during cycle 1 that were treatment-related were less than or equal to 19%. ECG changes (QT, ST-T changes) were documented in seven patients (23%) with the majority (n=4) occurring in the normal cohort. There were no cases of Torsades de Pointes or other treatment-emergent arrhythmia.
Table 3.
Treatment-emergent adverse events (TEAE) related to romidepsin during Cycle 1
| Toxicity | Liver Dysfunction Cohorts, n (%) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Normal (A) (n=12) | Mild (B) (n=8) | Moderate (C) (n=5) | Severe (D) (n=6) | Total (n=31) | ||||||
| Any Grade | Grade 3 or 4 | Any Grade | Grade 3 or 4 | Any Grade | Grade 3 or 4 | Any Grade | Grade 3 or 4 | Any Grade | Grade 3 or 4 | |
| Abdominal pain | - | - | - | - | - | |||||
| Abdominal distension | - | - | - | - | - | |||||
| Anemia | - | - | - | 1 (17%) | 1 (3%) | |||||
| Anorexia | - | - | - | - | - | |||||
| Alkaline phosphatase increased | - | - | - | - | - | |||||
| aPTT increased | - | - | - | - | - | |||||
| Aspartate aminotransferase increased | - | - | - | - | - | |||||
| Asthenia | - | - | - | - | - | |||||
| Bradycardia | - | - | - | - | - | |||||
| Creatinine increased | - | - | - | - | - | |||||
| Diarrhea | - | - | - | - | - | |||||
| Dizziness | - | - | - | - | - | |||||
| Dry mouth | - | - | - | - | - | |||||
| Dry skin | - | - | - | - | - | |||||
| Dysgeusia | - | - | - | - | - | |||||
| Dyspepsia | - | - | - | - | - | |||||
| Fatigue | - | 1 (13%) | - | 1 (17%) | 2 (6%) | |||||
| Flu-like symptoms (malaise) | - | - | - | - | - | |||||
| Gastric haemorrhage | - | - | - | 1 (17%) | 1 (3%) | |||||
| Generalized pain | - | - | - | - | - | |||||
| Glossodynia | - | - | - | - | - | |||||
| Headache | - | - | - | - | - | |||||
| Hypercalcemia | - | - | - | - | - | |||||
| Hyperuricemia | - | - | - | - | - | |||||
| Hypoalbuminemia | - | - | - | - | - | |||||
| Hypocalcemia | - | - | - | - | - | |||||
| Hypoglycemia | - | - | - | - | - | |||||
| Hypokalemia | - | - | - | - | - | |||||
| Hypomagnesmia | - | - | - | - | - | |||||
| Hyponatremia | - | - | - | - | - | |||||
| Hypotension | - | - | 1 (20%) | - | 1 (3%) | |||||
| Infections | - | - | 1 (20%) | - | 1 (3%) | |||||
| Muscle cramping | - | - | - | - | - | |||||
| Nausea | - | - | - | 2 (33%) | 2 (6%) | |||||
| Peripheral neuropathy | - | - | - | - | - | |||||
| Photophobia | - | - | - | - | - | |||||
| QTc prolongation | - | - | - | - | - | |||||
| Tachycardia | - | - | - | - | - | |||||
| Thrombocytopenia | - | - | 1 (20%) | - | 1 (3%) | |||||
| Vomiting | - | - | - | - | - | |||||
| WBC decrease | 3 (25%) | 1 (13%) | 2 (40%) | 1 (17%) | 7 (23%) | |||||
| Weight loss | - | - | - | - | - | |||||
Pharmacokinetics
Romidepsin pharmacokinetic data was available for 31 patients (Table 4). Mean plasma concentration-time profiles were similar when romidepsin was administered to patients with normal hepatic function (14 mg/m2), mild hepatic impairment (14 mg/m2), moderate hepatic impairment (7mg/m2) and severe hepatic impairment (5mg/m2) as shown in Figure 1. Romidepsin plasma concentrations increased rapidly and reached a plateau at approximately 1-hour post infusion initiation (first sample collected). Then, after the end of the infusion, concentrations declined in an apparent multiphasic manner. Concentrations were still quantifiable at the 48-hour time point. Variability in maximum concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUCINF) values were similar across the cohorts. There was a statistically significant difference between hepatic function and dose-normalized Cmax (Cmax/D p=0.002), dose-normalized AUCINF (AUCINF/D p=0.002), terminal half-life (T1/2; p=0.035), and systemic clearance (Cl; p=0.002) using the Kruskal–Wallis test. Unnormalized Cmax and AUCINF were not significantly different among the cohorts, and neither was volume of distribution. The geometric mean Cmax and AUCINF values after administration of 14 mg/m2 romidepsin in patients with mild hepatic impairment were approximately 115% and 144% of the corresponding geometric mean values after administration of the same dose in patients with normal hepatic function, respectively. The geometric mean Cmax and AUCINF values after administration of 7 mg/m2 romidepsin in patients with moderate hepatic impairment were 96% and 114% of the corresponding geometric mean values after administration of 14 mg/m2 romidepsin in patients with normal hepatic function. The geometric mean Cmax and AUCINF values after administration of 5 mg/m2 romidepsin in patients with severe hepatic impairment were approximately 95% and 116% of the corresponding geometric mean values after administration of 14 mg/m2 romidepsin in patients with normal hepatic function, respectively. Consistent with AUCINF results, compared to the normal hepatic function cohort, romidepsin clearance decreased with worsening hepatic function. The clearance in the mild and moderate hepatic clearance are in the same range as the prior population PK analysis (21). The two patients who had DLTs were in the same range for dose-normalized exposure (Cmax/D (32.1 and 40.5 ng/mL/mg), AUCINF/D (146.6 and 192.4 ng*hr/mL/mg)), or clearance (5.2 or 6.8 L/hr)) compared to patients who did not experience a DLT (range for Cmax/D (7.3–84.6 ng/mL/mg), AUCINF/D (29.9–507.4 ng*hr/mL/mg), or clearance (2.0–33.4 L/hr)).
Table 4.
Romidepsin plasma pharmacokinetic parameters
| Normal Cohort A (n) | Mild Cohort B (n) | Moderate Cohort C (n) | Severe Cohort D (n) | |
|---|---|---|---|---|
| Cmax (ng/mL) | 428±151 (12) | 494±198 (8) | 411±230 (5) | 405±116 (6) |
| AUCINF (ng*hr/mL) | 1692±653 (10) | 2443±738 (7) | 1921±1040 (5) | 1957±876 (6) |
| T1/2 (hr) | 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/hr) | 16.2±8.7 (10) | 9.6±2.7 (7) | 6.9±3.5 (5) | 4.8±2.8 (6) |
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
Figure 1.
Geometric mean and standard deviation concentration–time profile of romidepsin on day 1 on a linear (a) or semi-log plot (b).
Discussion
Romidepsin remains an important therapeutic option in the management of patients with CTCL and PTCL who have received at least one prior line of chemotherapy. It is not indicated for use in any solid tumors to date. Hepatic dysfunction can complicate the presentation and management of patients with malignancy, due to the presence of liver metastases or drug-induced toxicity. Exploring appropriate dosing for 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). Due to potential risks of cardiac toxicity, the post-marketing requirement from the FDA recommended that the drug-drug interaction, QT 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 14mg/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 14mg/m2. Romidepsin exposure in normal hepatic cohort patients is similar to the romidepsin alone arm of the drug-drug interaction trial (23). Due to 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 six evaluable patients in each cohort. Based on 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 investigator’s discretion and any AST). Indeed, it was a well-selected starting dose for each cohort, which allowed for the completion of the trial based on pharmacokinetic data alone.
Significant challenges with conducting hepatic dysfunction studies have been previously noted with several trials not being completed as originally designed (31). We identified additional sites over the study duration in an attempt to enhance accrual rates. Several amendments to the clinical trial protocol were also performed to improve the slow enrolment in the moderate and severe cohorts. These included modifications of inclusion criteria including: reduction in platelet eligibility requirements revised for patients with lymphoma and chronic lymphocytic leukemia from ≥ 75 to ≥ 30 × 109 cells/L, allowance of elevated bilirubin > 3 ULN and up to investigator’s discretion for the severe cohort, and allowance of enrollment of patients with cancers that may not respond to treatment. The severe cohort enrollment criteria was also modified to allow for accrual one patient at a time, without waiting for results from the moderate cohort which was itself experiencing slow accrual. Finally, communication with disease groups at the sites and involvement of Medical Science Liaisons were employed to raise awareness of the study. Despite these efforts, a sixth moderate hepatic impairment patient could not be identified in 6 years.
Of particular relevance in our study is the ethics surrounding enrollment of patients in phase I studies with limited or unknown chance for therapeutic efficacy (34). Patients with select tumor types were originally excluded from the study due to published phase II data supporting lack of efficacy of romidepsin in these tumor types as noted above (13–18). After careful consideration with the study team and sponsor, and an awareness that patients with impaired hepatic function and progressive malignancy have few standard or investigational therapeutic options despite a desire often for additional lines of therapy, and amendment subsequently permitted patients with these tumor types to enroll in the moderate and severe cohorts with appropriate consent. This consent process involved education regarding the available data and alternative options including best supportive care, by an investigator not involved with that patients longitudinal care, nor the principal study investigator (RMC). If we had not allowed this provision to allow colorectal patients, it appears that the trial may not have completed the co-primary goal to characterize the pharmacokinetic profile of romidepsin in patients with varying degrees of hepatic dysfunction.
In conclusion, we have identified important information regarding the pharmacokinetic profile of romidepsin in patients with advanced malignancy and moderate and severe hepatic impairment, which now 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), and close collaboration between clinical investigators, pharmacokinetic experts and industry partners are required for the success of such endeavors.
Translational Relevance.
Romidepsin is a histone deacetylase (HDAC) inhibitor which targets both class I and II HDAC enzymes, and is approved for use in cutaneous and peripheral T-cell lymphoma. At the time of romidepsin approval, there was limited data supporting its’ use in patients with hepatic impairment. Due to this drugs’ extensive metabolism, a post-marketing evaluation was required to explore appropriate dosing for patients with malignancy and varying degrees of hepatic dysfunction (ETCTN-9008). In this multicenter phase I clinical trial, an early pharmacokinetic evaluation was utilized to stop dose escalation in the moderate and severe cohorts, due to exposure mirroring the FDA approved dose in patients with normal hepatic function. These data supported amendment of the romidepsin package label with dose adjustment in patients with cancer and moderate and severe hepatic impairment, and closer monitoring for toxicity.
Acknowledgements:
We thank the patients who volunteered to participate in this study, NCI CTEP, Celgene Corporation, and the research teams and physicians at participating sites. This study was funded by the National Cancer Institute Experimental Therapeutics Clinical Trials Network (grants U01CA062487, U01CA062502, U01CA062505, U01CA069912, U01CA070095, U01CA132123, UM1CA186644, UM1CA186686, UM1CA186689, UM1CA186691, UM1CA186717, and U24CA247648). The project described was also supported by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 TR 001079), the Shared Instrument Grant (S10RR026824-01), the Clinical Protocol and Data Management facilities (P30 CA006973), and the Biostatistics Shared Resource of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (P30 CA006973). Grant Number UL1 TR 001079 is from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH, and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins ICTR, NCATS or NIH. The Cancer Therapy Evaluation Program supplied romidepsin. Support also provided by Celgene Corporation to supplement pharmacokinetic analysis.
Footnotes
Conflict of Interest Statement: OBA has received research grants to his institution from Bristol-Myers Squibb, Taiho, Ipsen, Calithera and GlaxoSmithKline. MAC reports compensated consultancy for Astellas, Pfizer, and Roche Genentech; and has received research grants to his institution from Astra Zeneca, EMD Serrano, Merck and Pfizer. VC reports compensated consultancy/advisory board participation for Ipsen, Gritstone, Westwood Bioscience, Perthera, and Apeiron; and reports compensated speakers bureau for Celgene and Ipsen. RMC has received research grants to her institution from Novartis, Puma Biotechnology, Merck, Genentech, and Macrogenics. AD reports compensated consultancy/advisory board participation for Takeda, Abbvie, Seattle Genetics, Astra Zeneca, and Bristol Myers Squibb; and has received research grants to his institution from oxo, Bayer, Incuron, Takeda, Regeneron, Tesaro, Amgen, Seattle Genetics, Symphogen, Abbvie, and Ipsen. PH is currently employed by Bristol-Myers Squibb. RDH reports compensated consultancy for Bristol-Myers Squibb, GlaxoSmithKline, and Takeda; and has received research funding to his institution from Abbvie, Aduro, Amgen, Arqule, AstraZeneca, Bayer, Bristol-Myers Squibb, Boston Biomedical, Calithera, Celgene, Corvus, Eli Lilly, Five Prime Therapeutics, Genmab, GlaxoSmithKline, Halozyme, Hematology/Oncology Pharmacy Association, Ignyta, Incyte, Lycera, Meryx, Nektar, Pfizer, Regeneron, Rgenix, Sanofi, Seattle Genetics, Sutro, Syndax, Takeda, Vertex, and Xencor. KK reports compensated consultancy/advisory board participation for AstraZeneca, AbbVie, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Inviata, Merck, Novartis, Pfizer, Regeneron, and Symphogen and has received research funding to her institution from Astellas, AbbVie, Bristol-Myers Squibb, EMD Serono, Five Prime Therapeutics, Genentech, Regeneron, Tizona, and Transgene. SK reports compensated consultancy for Bayer, Corvus Pharmaceuticals, Springworks Therapeutics, Seattle Genetics, HarbourBioMed, Genome & Company, Pathom IQ, and Boehringer Ingelheim. MAR has received research grants to her institution from Celgene Corporation (for this trail and one other), Cullinan, RenovoRx, and Syndax. MAR’s spouse is employed by GlaxoSmithKline. EL is employed by and owns stock ownership in Bristol Myers Squibb (formerly Celgene Corporation). LLS reports compensated consultancy/advisory board participation for Merck, Pfizer, Celgene, AstraZeneca/Medimmune, Morphosys, Roche, GeneSeeq, Loxo, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Treadwell Therapeutics, Arvinas, Tessa and Navire; and reports institutional support for clinical trials conduct from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks and Avid. LLS’s spouse hold stock in Agios and Treadwell Therapeutics. UV reports honoraria and consulting fees from Bristol-Myers Squibb, Exelixis, Bayer, Sanofi and Pfizer; and has received research support to her institution from Astellas, BMS and Exelixis. NMA, MD, SPI, AO’C, RP, GLR, AS, and JS have no disclosures.
References:
- 1.Ceccacci E, Minucci S. Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia. Br J Cancer 2016;114(6):605–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Christmas BJ, Rafie CI, Hopkins AC, Scott BA, Ma HS, Cruz KA, et al. Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs. Cancer Immunol Res 2018;6(12):1561–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 2009;27(32):5410–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 2010;28(29):4485–91. [DOI] [PubMed] [Google Scholar]
- 5.Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 2011;117(22):5827–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 2012;30(6):631–6. [DOI] [PubMed] [Google Scholar]
- 7.Grant C, Rahman F, Piekarz R, Peer C, Frye R, Robey RW, et al. Romidepsin: a new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors. Expert Rev Anticancer Ther 2010;10(7):997–1008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Celgene Corporation. ISTODAX (romidepsin) for injection: prescribing information Summit, NJ: 2009. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022393lbl.pdf. [Google Scholar]
- 9.Shiraga T, Tozuka Z, Ishimura R, Kawamura A, Kagayama A. Identification of cytochrome P450 enzymes involved in the metabolism of FK228, a potent histone deacetylase inhibitor, in human liver microsomes. Biol Pharm Bull 2005;28(1):124–9. [DOI] [PubMed] [Google Scholar]
- 10.Piekarz RL, Frye AR, Wright JJ, Steinberg SM, Liewehr DJ, Rosing DR, et al. Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res 2006;12(12):3762–73. [DOI] [PubMed] [Google Scholar]
- 11.Shah MH, Binkley P, Chan K, Xiao J, Arbogast D, Collamore M, et al. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res 2006;12(13):3997–4003. [DOI] [PubMed] [Google Scholar]
- 12.Molife R, Fong P, Scurr M, Judson I, Kaye S, de Bono J. HDAC inhibitors and cardiac safety. Clin Cancer Res 2007;13(3):1068; author reply −9. [DOI] [PubMed] [Google Scholar]
- 13.Molife LR, Attard G, Fong PC, Karavasilis V, Reid AH, Patterson S, et al. Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC). Ann Oncol 2010;21(1):109–13. [DOI] [PubMed] [Google Scholar]
- 14.Stadler WM, Margolin K, Ferber S, McCulloch W, Thompson JA. A phase II study of depsipeptide in refractory metastatic renal cell cancer. Clin Genitourin Cancer 2006;5(1):57–60. [DOI] [PubMed] [Google Scholar]
- 15.Otterson GA, Hodgson L, Pang H, Vokes EE, Cancer, Leukemia Group B. Phase II study of the histone deacetylase inhibitor Romidepsin in relapsed small cell lung cancer (Cancer and Leukemia Group B 30304). J Thorac Oncol 2010;5(10):1644–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Whitehead RP, Rankin C, Hoff PM, Gold PJ, Billingsley KG, Chapman RA, et al. Phase II trial of romidepsin (NSC-630176) in previously treated colorectal cancer patients with advanced disease: a Southwest Oncology Group study (S0336). Invest New Drugs 2009;27(5):469–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Iwamoto FM, Lamborn KR, Kuhn JG, Wen PY, Yung WK, Gilbert MR, et al. A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American Brain Tumor Consortium Study 03–03. Neuro Oncol 2011;13(5):509–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Sherman EJ, Su YB, Lyall A, Schoder H, Fury MG, Ghossein RA, et al. Evaluation of romidepsin for clinical activity and radioactive iodine reuptake in radioactive iodine-refractory thyroid carcinoma. Thyroid 2013;23(5):593–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Ganjare A, Kulkarni AP. Comparative electrocardiographic effects of intravenous ondansetron and granisetron in patients undergoing surgery for carcinoma breast: A prospective single-blind randomised trial. Indian J Anaesth 2013;57(1):41–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Celgene Corporation. ISTODAX (romidepsin) for injection: prescribing information Summit, NJ: June 2013. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022393s011lbl.pdf. [Google Scholar]
- 21.U. S. Food and Drug Administration Center for Drug Evaluation and Research. ISTODAX (romidepsin) NDA-22393 Clinical Pharmacology and Biopharmaceutics Review, March 2009. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022393s000_ClinPharmR.pdf. Retrieved February 9, 2020.
- 22.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228–47. [DOI] [PubMed] [Google Scholar]
- 23.Laille E, Patel M, Jones SF, Burris HA 3rd, Infante J Lemech C, et al. Evaluation of CYP3A-mediated drug-drug interactions with romidepsin in patients with advanced cancer. J Clin Pharmacol 2015;55(12):1378–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Chen X, Gardner ER, Figg WD. Determination of the cyclic depsipeptide FK228 in human and mouse plasma by liquid chromatography with mass-spectrometric detection. J Chromatogr B Analyt Technol Biomed Life Sci 2008;865(1–2):153–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.U. S. Food and Drug Administration Center for Drug Evaluation and Research. Guidance for industry bioanalytical method validation May, 2001.
- 26.Celgene Corporation. ISTODAX (romidepsin) for injection: prescribing information Summit, NJ: November 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022393s015lbl.pdf. [Google Scholar]
- 27.U. S. Food and Drug Administration Center for Drug Evaluation and Research. ISTODAX (romidepsin) NDA-22393 approval letter, November 5, 2009. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/022393s000ltr.pdf. Retrieved February 9, 2020.
- 28.Ramalingam SS, Kummar S, Sarantopoulos J, Shibata S, LoRusso P, Yerk M, et al. Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study. J Clin Oncol 2010;28(29):4507–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.LoRusso PM, Venkatakrishnan K, Ramanathan RK, Sarantopoulos J, Mulkerin D, Shibata SI, et al. Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction: phase I NCI Organ Dysfunction Working Group Study NCI-6432. Clin Cancer Res 2012;18(10):2954–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Shibata SI, Chung V, Synold TW, Longmate JA, Suttle AB, Ottesen LH, et al. Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study. Clin Cancer Res 2013;19(13):3631–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Takebe N, Beumer JH, Kummar S, Kiesel BF, Dowlati A, O’Sullivan Coyne G, et al. A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction. Br J Clin Pharmacol 2019;85(11):2499–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Synold TW, Takimoto CH, Doroshow JH, Gandara D, Mani S, Remick SC, et al. Dose-escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic function: a National Cancer Institute Organ Dysfunction Working Group study. Clin Cancer Res 2007;13(12):3660–6. [DOI] [PubMed] [Google Scholar]
- 33.Ramanathan RK, Egorin MJ, Takimoto CH, Remick SC, Doroshow JH, LoRusso PA, et al. Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 2008;26(4):563–9. [DOI] [PubMed] [Google Scholar]
- 34.Daugherty CK. Ethical issues in the development of new agents. Invest New Drugs 1999;17(2):145–53. [DOI] [PubMed] [Google Scholar]