Pancreatic Cancer
Conditions
Keywords
Pancreatic cancer, advanced solid tumors
Brief summary
This was a phase I dose escalation trial designed to determine the maximum tolerated dose (MTD) for the combination of romidepsin (depsipeptide) and gemcitabine. The study was originally planned as a Phase I/II; however only Phase I of the study was conducted.
Interventions
DRUGRomidepsin
7, 10 or 12 mg/m\^2 via intravenous infusion over 4 hours on either Days 1, 8 and 15 or Days 1 and 15 of each 28-day cycle.
DRUGGemcitabine
800 or 1000 mg/m\^2 via intravenous infusion over 30 minutes on either Days 1,8 and 15 or Days 1 and 15 of each 28 day cycle.
Sponsors
Celgene
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* histologically confirmed advanced solid tumors * measurable or evaluable disease * written informed consent * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
Exclusion criteria
* Prior treatment with romidepsin or gemcitabine * Prior chemotherapy treatment within 3 weeks prior to the first day of treatment or prior treatment with an investigational agent within 4 weeks prior to the first day of treatment. Patients must have recovered from all therapy-related toxicities (Common Terminology Criteria grade ≤ 1) * Prior radiotherapy within 4 weeks prior to the first day of treatment. Patients who have not fully recovered or whose acute toxicity related to prior radiotherapy has not returned to baseline are ineligible. * Prior surgery within 3 weeks prior to the first day of treatment, excluding surgical biopsies and port placements * Concomitant use of any other anti-cancer therapy * Concomitant use of any investigational agent * Use of any investigational agent within 4 weeks of study entry * Any known cardiac abnormalities, including congenital long QT syndrome, QTcF interval \>480 milliseconds, myocardial infarction within 12 months of study entry, coronary artery disease (CAD), congestive heart failure (CHF), evidence of cardiac ischemia at screening, known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest, hypertrophic cardiomegaly or restrictive cardiomyopathy chronic hypertension, any cardiac arrhythmia requiring anti-arrhythmic medication * Serum potassium \<3.8 mmol/L or serum magnesium \<2.0 mg/dL (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria) * Concomitant use of drugs that may cause a prolongation of the QTc * Concomitant use of CYP3A4 inhibitors * Clinically significant active infection * Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C * Inadequate bone marrow or other organ function as evidenced by: * Hemoglobin \<9 g/dL (Transfusions and/or erythropoietin are permitted.) * Absolute neutrophil count (ANC) ≤1.5 x 10\^9 cells/L * Platelet count \<100 x 10\^9 cells/L or platelet count \<75 x 10\^9 cells/L if bone marrow disease involvement is documented * Total bilirubin \>2.0 x upper limit of normal (ULN) * Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) \>2.0 x ULN or \>3.0 x ULN in the presence of demonstrable liver metastases * Serum creatinine \>2.0 x ULN * Patients who are pregnant or breast-feeding * Any significant medical or psychiatric condition that might prevent the patient from complying with all study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Dose-limiting Toxicity (DLT) | 28 days | Toxicities were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), V 3.0. A DLT was one of the following, if considered at least possibly related to study treatment: Grade 4 neutropenia for ≥5 days or febrile neutropenia; Grade 4 thrombocytopenia or need for a platelet transfusion; ≥ Grade 3 nausea and/or emesis despite using optimal antiemetic therapy; ≥ Grade 3 diarrhea despite using maximal supportive therapy; Any clinically significant Grade 3 or 4 nonhematologic toxicity; Inability to administer all doses in cycle 1. |
| Number of Participants With Adverse Events (AEs) | From the date of first dose to 30 days after last dose (up to 236 days). | AEs were graded for severity according to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), V 3.0: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe (prevents normal everyday activities); Grade 4: Life-threatening or disabling; Grade 5: Death. A serious AE is associated with events that pose a threat to a patient's life or functioning, require hospitalization, is a congenital anomaly/birth defect or is an important medical event or condition that may jeopardize the patient and may require medical or surgical intervention to prevent one of the above outcomes. |
| Best Overall Response | Disease assessments were performed within 4 weeks of first dose and every 8 weeks thereafter (up to 236 days). | Disease response was determined by the Investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria using computed tomography or magnetic resonance imaging: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions or the appearance of ≥1 new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. |
Countries
United States
Participant flow
Pre-assignment details
Patients were assigned to 1 of 2 dose schedules concurrently on an every-other-patient basis using a 3+3 dosing scheme: Patients in Schedule A received study treatment Days 1, 8, and 15 and those in Schedule B on Days 1 and 15 of every 28-day cycle. Patients were observed for 28 days before enrollment at the next dose level, based on toxicities.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 Participants received romidepsin 10 mg/m\^2 plus gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 every 28 days. | 7 |
| Dose Level 2 Participants received romidepsin 7 mg/m\^2 plus gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 every 28 days. | 7 |
| Dose Level 5 Participants received romidepsin 10 mg/m\^2 plus gemcitabine 800 mg/m\^2 on Days 1 and 15 every 28 days. | 10 |
| Dose Level 6 Participants received romidepsin 10 mg/m\^2 plus gemcitabine 1000 mg/m\^2 on Days 1 and 15 every 28 days. | 6 |
| Dose Level 8 Participants received romidepsin 12 mg/m\^2 plus gemcitabine 800 mg/m\^2 on Days 1 and 15 every 28 days. | 6 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 1 |
| Overall Study | Disease Progression | 3 | 3 | 3 | 4 | 4 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Other | 0 | 0 | 3 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 2 | 1 | 1 | 0 |
| Overall Study | Symptomatic Deterioration | 0 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Dose Level 1 | Dose Level 2 | Dose Level 5 | Dose Level 6 | Dose Level 8 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 58.9 years STANDARD_DEVIATION 11.25 | 53.4 years STANDARD_DEVIATION 11.04 | 62.6 years STANDARD_DEVIATION 10.86 | 57.3 years STANDARD_DEVIATION 15.54 | 57.0 years STANDARD_DEVIATION 13.37 | 58.3 years STANDARD_DEVIATION 11.98 |
| Body Surface Area (BSA) | 1.9 m^2 STANDARD_DEVIATION 0.28 | 1.8 m^2 STANDARD_DEVIATION 0.29 | 1.8 m^2 STANDARD_DEVIATION 0.19 | 1.7 m^2 STANDARD_DEVIATION 0.23 | 1.7 m^2 STANDARD_DEVIATION 0.35 | 1.8 m^2 STANDARD_DEVIATION 0.27 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 7 Participants | 10 Participants | 6 Participants | 6 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 169.3 cm STANDARD_DEVIATION 9.52 | 163.7 cm STANDARD_DEVIATION 8.13 | 170.9 cm STANDARD_DEVIATION 10.33 | 159.6 cm STANDARD_DEVIATION 4.09 | 164.9 cm STANDARD_DEVIATION 8.71 | 166.3 cm STANDARD_DEVIATION 9.21 |
| Race/Ethnicity, Customized Black | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Pakistani | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 6 participants | 6 participants | 10 participants | 6 participants | 6 participants | 34 participants |
| Region of Enrollment United States | 7 participants | 7 participants | 10 participants | 6 participants | 6 participants | 36 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 4 Participants | 6 Participants | 5 Participants | 25 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 6 Participants | 0 Participants | 1 Participants | 11 Participants |
| Weight | 79.8 kg STANDARD_DEVIATION 20.54 | 77.6 kg STANDARD_DEVIATION 25.21 | 73.1 kg STANDARD_DEVIATION 12.58 | 69.0 kg STANDARD_DEVIATION 26.84 | 61.7 kg STANDARD_DEVIATION 27.56 | 72.7 kg STANDARD_DEVIATION 21.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 7 | 7 / 7 | 10 / 10 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 3 / 7 | 2 / 7 | 4 / 10 | 1 / 6 | 2 / 6 |
Outcome results
Primary
Best Overall Response
Disease response was determined by the Investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria using computed tomography or magnetic resonance imaging: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions or the appearance of ≥1 new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time frame: Disease assessments were performed within 4 weeks of first dose and every 8 weeks thereafter (up to 236 days).
Population: The Efficacy Evaluable (EE) population consisted of all patients who completed at least 2 consecutive cycles of treatment, had at least 1 post-Baseline efficacy assessment performed, and did not have any major protocol violations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Level 1 | Best Overall Response | Stable disease | 5 participants |
| Dose Level 1 | Best Overall Response | Complete Response | 0 participants |
| Dose Level 1 | Best Overall Response | Partial Response | 0 participants |
| Dose Level 1 | Best Overall Response | Progressive disease | 1 participants |
| Dose Level 2 | Best Overall Response | Partial Response | 1 participants |
| Dose Level 2 | Best Overall Response | Stable disease | 4 participants |
| Dose Level 2 | Best Overall Response | Progressive disease | 2 participants |
| Dose Level 2 | Best Overall Response | Complete Response | 0 participants |
| Dose Level 5 | Best Overall Response | Stable disease | 3 participants |
| Dose Level 5 | Best Overall Response | Complete Response | 0 participants |
| Dose Level 5 | Best Overall Response | Progressive disease | 4 participants |
| Dose Level 5 | Best Overall Response | Partial Response | 0 participants |
| Dose Level 6 | Best Overall Response | Stable disease | 1 participants |
| Dose Level 6 | Best Overall Response | Complete Response | 0 participants |
| Dose Level 6 | Best Overall Response | Progressive disease | 3 participants |
| Dose Level 6 | Best Overall Response | Partial Response | 0 participants |
| Dose Level 8 | Best Overall Response | Complete Response | 0 participants |
| Dose Level 8 | Best Overall Response | Progressive disease | 1 participants |
| Dose Level 8 | Best Overall Response | Partial Response | 1 participants |
| Dose Level 8 | Best Overall Response | Stable disease | 1 participants |
Primary
Number of Participants With a Dose-limiting Toxicity (DLT)
Toxicities were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), V 3.0. A DLT was one of the following, if considered at least possibly related to study treatment: Grade 4 neutropenia for ≥5 days or febrile neutropenia; Grade 4 thrombocytopenia or need for a platelet transfusion; ≥ Grade 3 nausea and/or emesis despite using optimal antiemetic therapy; ≥ Grade 3 diarrhea despite using maximal supportive therapy; Any clinically significant Grade 3 or 4 nonhematologic toxicity; Inability to administer all doses in cycle 1.
Time frame: 28 days
Population: Safety population - all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1 | Number of Participants With a Dose-limiting Toxicity (DLT) | 3 participants |
| Dose Level 2 | Number of Participants With a Dose-limiting Toxicity (DLT) | 1 participants |
| Dose Level 5 | Number of Participants With a Dose-limiting Toxicity (DLT) | 0 participants |
| Dose Level 6 | Number of Participants With a Dose-limiting Toxicity (DLT) | 2 participants |
| Dose Level 8 | Number of Participants With a Dose-limiting Toxicity (DLT) | 0 participants |
Primary
Number of Participants With Adverse Events (AEs)
AEs were graded for severity according to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), V 3.0: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe (prevents normal everyday activities); Grade 4: Life-threatening or disabling; Grade 5: Death. A serious AE is associated with events that pose a threat to a patient's life or functioning, require hospitalization, is a congenital anomaly/birth defect or is an important medical event or condition that may jeopardize the patient and may require medical or surgical intervention to prevent one of the above outcomes.
Time frame: From the date of first dose to 30 days after last dose (up to 236 days).
Population: Safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Level 1 | Number of Participants With Adverse Events (AEs) | Any adverse event | 7 participants |
| Dose Level 1 | Number of Participants With Adverse Events (AEs) | ≥Grade 3 adverse event | 7 participants |
| Dose Level 1 | Number of Participants With Adverse Events (AEs) | Grade 4 adverse event | 1 participants |
| Dose Level 1 | Number of Participants With Adverse Events (AEs) | Serious adverse event | 3 participants |
| Dose Level 1 | Number of Participants With Adverse Events (AEs) | Adverse event leading to discontinuation | 0 participants |
| Dose Level 1 | Number of Participants With Adverse Events (AEs) | Adverse event leading to death | 0 participants |
| Dose Level 2 | Number of Participants With Adverse Events (AEs) | Adverse event leading to discontinuation | 0 participants |
| Dose Level 2 | Number of Participants With Adverse Events (AEs) | Adverse event leading to death | 0 participants |
| Dose Level 2 | Number of Participants With Adverse Events (AEs) | Any adverse event | 7 participants |
| Dose Level 2 | Number of Participants With Adverse Events (AEs) | Grade 4 adverse event | 2 participants |
| Dose Level 2 | Number of Participants With Adverse Events (AEs) | Serious adverse event | 2 participants |
| Dose Level 2 | Number of Participants With Adverse Events (AEs) | ≥Grade 3 adverse event | 5 participants |
| Dose Level 5 | Number of Participants With Adverse Events (AEs) | Serious adverse event | 4 participants |
| Dose Level 5 | Number of Participants With Adverse Events (AEs) | Adverse event leading to discontinuation | 1 participants |
| Dose Level 5 | Number of Participants With Adverse Events (AEs) | Any adverse event | 10 participants |
| Dose Level 5 | Number of Participants With Adverse Events (AEs) | Grade 4 adverse event | 3 participants |
| Dose Level 5 | Number of Participants With Adverse Events (AEs) | ≥Grade 3 adverse event | 5 participants |
| Dose Level 5 | Number of Participants With Adverse Events (AEs) | Adverse event leading to death | 0 participants |
| Dose Level 6 | Number of Participants With Adverse Events (AEs) | Serious adverse event | 1 participants |
| Dose Level 6 | Number of Participants With Adverse Events (AEs) | ≥Grade 3 adverse event | 4 participants |
| Dose Level 6 | Number of Participants With Adverse Events (AEs) | Grade 4 adverse event | 2 participants |
| Dose Level 6 | Number of Participants With Adverse Events (AEs) | Adverse event leading to death | 0 participants |
| Dose Level 6 | Number of Participants With Adverse Events (AEs) | Adverse event leading to discontinuation | 0 participants |
| Dose Level 6 | Number of Participants With Adverse Events (AEs) | Any adverse event | 6 participants |
| Dose Level 8 | Number of Participants With Adverse Events (AEs) | Adverse event leading to discontinuation | 1 participants |
| Dose Level 8 | Number of Participants With Adverse Events (AEs) | Grade 4 adverse event | 1 participants |
| Dose Level 8 | Number of Participants With Adverse Events (AEs) | ≥Grade 3 adverse event | 3 participants |
| Dose Level 8 | Number of Participants With Adverse Events (AEs) | Adverse event leading to death | 1 participants |
| Dose Level 8 | Number of Participants With Adverse Events (AEs) | Serious adverse event | 2 participants |
| Dose Level 8 | Number of Participants With Adverse Events (AEs) | Any adverse event | 6 participants |