Biliary Tract Cancer
Conditions
Keywords
Cholangiocarcinoma, Gallbladder cancer
Brief summary
The purpose of this research study is to determine the safety and efficacy of CPI-613 (devimistat) in the treatment of advanced biliary tract cancer when used in combination with standard of care chemotherapy (gemcitabine plus cisplatin) compared to gemcitabine plus cisplatin alone. This research study has two parts: In the phase 1 portion of this study, patients will receive a combination of CPI-613 and standard of care chemotherapy. Dose levels of CPI-613 will be adjusted to find the best dose, which will be the recommended phase 2 dose level. In the phase 2 portion of this study, patients will be randomized into two arms. Patients in Arm A will receive the combination of the recommended dose level of CPI-613 and standard of care chemotherapy. Patients in Arm B will receive standard of care chemotherapy. At the end of the study, researchers will compare the health outcomes of the patients that received CPI-613 + standard care to the outcomes of patients that received only standard care.
Interventions
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase II: 2:1 Randomization with Bayesian Design Control Arm
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion: * Patients must have a pathologically or cytologically confirmed carcinoma (except neuroendocrine) of the biliary tract (intra-hepatic, extra-hepatic (hilar, distal) or gallbladder) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors of mixed cholangiocarcinoma/hepatocellular carcinoma histology are excluded. * Patients may not have received prior systemic treatment (chemotherapy or targeted therapy) for advanced BTC. Prior peri-operative chemotherapy is permitted provided it was completed \> 6 months from enrollment. * Patients may have received prior radiation, chemoembolization, radioembolization or other local ablative therapies or hepatic resection if completed ≥ 4 weeks prior to enrollment AND if patient has recovered to ≤ grade 1 toxicity. Extrahepatic palliative radiation is permitted if completed ≥ 2 weeks prior to enrollment AND if patient has recovered to ≤ grade 1 toxicity * Patients must have radiographically measurable disease (as per RECISTv1.1) in at least one site not previously treated with radiation or liver directed therapy (including bland, chemo- or radio-embolization, or ablation) either within the liver or in a metastatic site. * Must be ≥ 18 years of age. * Must have an ECOG performance status of 0-1. * Ability to understand and willingness to sign IRB-approved informed consent. * Willing to provide archived tissue, if available, from a previous diagnostic biopsy or surgery. * Must be able to tolerate CT and/or MRI with contrast. * Adequate organ function (per protocol) obtained ≤ 2 weeks prior to enrollment. * Women of child-bearing potential and men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation and for 6 months (for men and women) following completion of study therapy. Exclusions: * Prior history of brain metastasis (unless previously treated, asymptomatic and stable for at least 3 months) or organ transplant. * Underwent a major surgical procedure \< 4 weeks prior to enrollment. * Active second malignancy other than in situ cancer or localized prostate cancer (Gleason score \<8). Patients with history of other malignancy are eligible provided primary treatment of that cancer was completed \> 1 year prior to enrollment and the patient is free of clinical or radiologic evidence of recurrent or progressive malignancy. * Ongoing active, uncontrolled infection (must be afebrile for \> 48 hours off antibiotics) . * Psychiatric illness, other significant medical illness, or social situation which, in the investigator's opinion, would limit compliance or ability to comply with study requirements. * Pregnancy or breastfeeding. (Women must not be pregnant or breastfeeding since study drugs may harm the fetus or child. All females of childbearing potential \[not surgically sterilized and between menarche and 1 year post menopause\] must have a negative screening pregnancy test.) * Active heart disease including symptomatic heart failure (NYHA class 3 or 4), unstable angina pectoris, uncontrolled cardiac arrhythmia or interstitial lung disease. * Prisoners or subjects who are involuntarily incarcerated, or compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness would be excluded. * Prolonged QTcF interval \>480 msec. * Known hypersensitivity to cisplatin, gemcitabine or CPI-613, or its inactive components.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Incidence of Dose-limiting Toxicity | Up to day 22 | Dose limiting toxicities will determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of combination therapy with CPI-613 + gemcitabine and cisplatin. Assessed using the NCI CTCAE v5.0 |
| Phase 2: Overall Response Rate (ORR) | Until last dose of study treatment (up to 2 years) | Objective response assessment will be determined by review of CT or MR scans of the chest, abdomen and pelvis. ORR (Partial Response + Complete Response) will be assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, during active study treatment. All enrolled patients who receive at least 1 cycle of therapy and have their disease re-evaluated will be considered evaluable for response. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival (PFS) | Until last dose of study treatment (up to 2 years) | PFS will be determined from date of first study treatment until the date of radiological or clinical progression (leading to withdrawal from the study) or date of last disease evaluation (for patients without progression). It will be calculated using the product-limit method of Kaplan and Meier. All patients that receive at least one dose of study treatment will be considered evaluable. |
| Median Overall Survival (OS) | Up to 3 years after enrollment | From date of first study treatment until date of last disease evaluation or until death from any cause. Using the product-limit method of Kaplan and Meier. |
| Incidence of Toxicities | Up to 100 days after last dose of study treatment | To evaluate the safety of CPI-613 in combination with gemcitabine and cisplatin in this patient population, assessed using the Common Toxicity Criteria for Adverse Events (CTCAE) v5.0. All patients that receive at least one dose of study treatment will be considered evaluable. Number of patients experiencing the maximum graded toxicity (Grade 2 or higher). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 2, Arm A (Investigational) On Day 1 and Day 8 of each 3-week cycle, patients will receive CPI-613 + gemcitabine and cisplatin. Patients may continue gemcitabine, cisplatin and CPI-613 for up to 2 years in absence of disease progression or unacceptable toxicity.
CPI 613: Given intravenously
Gemcitabine: Given intravenously
Cisplatin: Given intravenously | 37 |
| Phase 2, Arm B (Standard of Care) On Day 1 and Day 8 of each 3-week cycle, patients will receive gemcitabine and cisplatin. Patients may continue gemcitabine and cisplatin for up to 2 years in absence of disease progression or unacceptable toxicity.
Gemcitabine: Given intravenously
Cisplatin: Given intravenously | 18 |
| Phase 1, CPI-613 500 mg/m2 On Day 1 and Day 8 of each 3-week cycle, patients will receive CPI-613 + gemcitabine and cisplatin. Patients may continue gemcitabine, cisplatin and CPI-613 for up to 2 years in absence of disease progression or unacceptable toxicity.
CPI 613: Given intravenously
Gemcitabine: Given intravenously | 1 |
| Phase 1, CPI-613 1000 mg/m2 On Day 1 and Day 8 of each 3-week cycle, patients will receive CPI-613 + gemcitabine and cisplatin. Patients may continue gemcitabine, cisplatin and CPI-613 for up to 2 years in absence of disease progression or unacceptable toxicity.
CPI 613: Given intravenously
Gemcitabine: Given intravenously
Cisplatin: Given intravenously | 1 |
| Phase 1, CPI-613 1500 mg/m2 On Day 1 and Day 8 of each 3-week cycle, patients will receive CPI-613 + gemcitabine and cisplatin. Patients may continue gemcitabine, cisplatin and CPI-613 for up to 2 years in absence of disease progression or unacceptable toxicity.
CPI 613: Given intravenously
Gemcitabine: Given intravenously
Cisplatin: Given intravenously | 2 |
| Phase 1, CPI-613 2000 mg/m2 On Day 1 and Day 8 of each 3-week cycle, patients will receive CPI-613 + gemcitabine and cisplatin. Patients may continue gemcitabine, cisplatin and CPI-613 for up to 2 years in absence of disease progression or unacceptable toxicity.
CPI 613: Given intravenously
Gemcitabine: Given intravenously
Cisplatin: Given intravenously | 16 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 5 | 0 | 0 | 0 | 0 |
| Overall Study | Alternative Therapy | 3 | 0 | 1 | 0 | 0 | 2 |
| Overall Study | Physician Decision | 3 | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Sponsor Termination | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 5 | 0 | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Total | Phase 2, Arm B (Standard of Care) | Phase 1, CPI-613 500 mg/m2 | Phase 1, CPI-613 1000 mg/m2 | Phase 2, Arm A (Investigational) | Phase 1, CPI-613 1500 mg/m2 | Phase 1, CPI-613 2000 mg/m2 |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 50 Participants | 14 Participants | 1 Participants | 1 Participants | 24 Participants | 0 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 4 Participants | 0 Participants | 0 Participants | 13 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 3 Participants | 0 Participants | 0 Participants | 5 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 15 Participants | 1 Participants | 1 Participants | 32 Participants | 1 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 66 Participants | 15 Participants | 1 Participants | 1 Participants | 34 Participants | 2 Participants | 13 Participants |
| Region of Enrollment United States | 75 participants | 18 participants | 1 participants | 1 participants | 37 participants | 2 participants | 16 participants |
| Sex: Female, Male Female | 37 Participants | 12 Participants | 1 Participants | 0 Participants | 16 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 38 Participants | 6 Participants | 0 Participants | 1 Participants | 21 Participants | 0 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 25 / 37 | 7 / 18 | 0 / 1 | 1 / 1 | 2 / 2 | 12 / 16 |
| other Total, other adverse events | 35 / 37 | 15 / 18 | 1 / 1 | 1 / 1 | 2 / 2 | 16 / 16 |
| serious Total, serious adverse events | 13 / 37 | 9 / 18 | 0 / 1 | 1 / 1 | 2 / 2 | 11 / 16 |
Outcome results
Primary
Phase 1: Incidence of Dose-limiting Toxicity
Dose limiting toxicities will determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of combination therapy with CPI-613 + gemcitabine and cisplatin. Assessed using the NCI CTCAE v5.0
Time frame: Up to day 22
Population: only applies to Phase 1 patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 2, Arm A (Investigational) | Phase 1: Incidence of Dose-limiting Toxicity | 0 Participants |
| Phase 2, Arm B (Standard of Care) | Phase 1: Incidence of Dose-limiting Toxicity | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Phase 1: Incidence of Dose-limiting Toxicity | 0 Participants |
| Phase 1, CPI-613 1000 mg/m2 | Phase 1: Incidence of Dose-limiting Toxicity | 0 Participants |
| Phase 1, CPI-613 1500 mg/m2 | Phase 1: Incidence of Dose-limiting Toxicity | 0 Participants |
| Phase 1, CPI-613 2000 mg/m2 | Phase 1: Incidence of Dose-limiting Toxicity | 1 Participants |
Primary
Phase 2: Overall Response Rate (ORR)
Objective response assessment will be determined by review of CT or MR scans of the chest, abdomen and pelvis. ORR (Partial Response + Complete Response) will be assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, during active study treatment. All enrolled patients who receive at least 1 cycle of therapy and have their disease re-evaluated will be considered evaluable for response. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.)
Time frame: Until last dose of study treatment (up to 2 years)
Population: Phase 2, Arm A- 37 patients were randomized to Arm A treatment, with 36 patients receiving treatment. Per protocol the 16 patients in the Phase 1 portion of the study were included, for a total of 52 patients in the investigational arm. All 52 subjects were considered for evaluability. Two subjects were found to be unevaluable.~Phase 2, Arm B- 18 patients were randomized to Arm B treatment, with 16 patients receiving treatment.Three subjects were found to be unevaluable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 2, Arm A (Investigational) | Phase 2: Overall Response Rate (ORR) | 15 Participants |
| Phase 2, Arm B (Standard of Care) | Phase 2: Overall Response Rate (ORR) | 6 Participants |
| Phase 1, CPI-613 500 mg/m2 | Phase 2: Overall Response Rate (ORR) | 0 Participants |
| Phase 1, CPI-613 1000 mg/m2 | Phase 2: Overall Response Rate (ORR) | 0 Participants |
| Phase 1, CPI-613 1500 mg/m2 | Phase 2: Overall Response Rate (ORR) | 0 Participants |
| Phase 1, CPI-613 2000 mg/m2 | Phase 2: Overall Response Rate (ORR) | 0 Participants |
Secondary
Incidence of Toxicities
To evaluate the safety of CPI-613 in combination with gemcitabine and cisplatin in this patient population, assessed using the Common Toxicity Criteria for Adverse Events (CTCAE) v5.0. All patients that receive at least one dose of study treatment will be considered evaluable. Number of patients experiencing the maximum graded toxicity (Grade 2 or higher).
Time frame: Up to 100 days after last dose of study treatment
Population: Phase 2, Arm A- 37 patients were randomized to Arm A treatment, with 36 patients receiving treatment. Per protocol the 16 patients receiving the RP2D of Devimistat in the Phase 1 portion of the study were included, for a total of 52 patients. This combination was done per protocol.~Phase 2, Arm B- 18 patients were randomized to Arm B treatment, with 16 patients receiving treatment. For 16 receiving study treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Gastroesophageal relux disease- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Urinary Tract Infection- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | hypersalivation- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Aspartate aminotransferase increased- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | generalize muscle weakness- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hematuria- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Lymphocyte count decreased- Grade 4 | 0 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hiccups- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Bacteremia- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hot flashes- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Fatigue- Grade 3 | 3 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hypercalcemia- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Biliary tract Infection- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hyperglycemia- Grade 2 | 2 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Neutrophil count decreased- Grade 3 | 18 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hypertension- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Blood transfusion- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hypertension- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Abdominal pain- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hypoalbuminemia- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Blood bilirubin increased- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hypokalemia- Grade 2 | 3 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | White Blood Cell Decreased- Grade 2 | 3 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hypomagnesemia- Grade 2 | 3 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | chest tightness- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hypomagnesemia- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Alanine aminotransferase increased- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hyponatremia- Grade 3 | 2 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Cholecystitis- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Infection- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Platelet count decreased- Grade 3 | 5 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Infusion Related Reaction- Grade 2 | 3 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Constipation- Grade 2 | 3 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Lymphocyte count decreased- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Alopecia- Grade 2 | 2 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Nausea- Grade 2 | 8 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Creatinine increased- Grade 2 | 3 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Neutrophil count decreased- Grade 2 | 2 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | White Blood Cell Decreased- Grade 3 | 4 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Neutrophil count decreased- Grade 4 | 2 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Diarrhea- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Pancreatitis- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Anemia- Grade 2 | 4 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Peripheral Motor Neuropathy- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Diarrhea- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Platelet count decreased- Grade 2 | 3 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Platelet count decreased- Grade 4 | 2 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Generalized Edema- Grade 2 | 0 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Sepsis- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Dysgeusia- Grade 2 | 2 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Stroke- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Anemia- Grade 3 | 10 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Pulmonary Embolism- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Enterocolitis- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Vomiting- Grade 2 | 2 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Peripheral Sensory Neuropathy- Grade 2 | 3 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Fatigue- Grade 2 | 15 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Alanine aminotransferase increased- Grade 3 | 0 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Anorexia- Grade 2 | 3 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Aspartate aminotransferase increased- Grade 3 | 0 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Febrile Neutropenia- Grade 3 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Fever- Grade 2 | 0 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Hypomagnesemia- Grade 4 | 0 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Liver Abscess- Grade 3 | 0 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Flu like symptoms- Grade 2 | 1 Participants |
| Phase 2, Arm B (Standard of Care) | Incidence of Toxicities | Anorexia- Grade 3 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Lymphocyte count decreased- Grade 4 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Neutrophil count decreased- Grade 3 | 8 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Peripheral Motor Neuropathy- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Platelet count decreased- Grade 2 | 2 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Platelet count decreased- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Urinary Tract Infection- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | White Blood Cell Decreased- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Generalized Edema- Grade 2 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hypomagnesemia- Grade 4 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Fatigue- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Abdominal pain- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Alanine aminotransferase increased- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Alopecia- Grade 2 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Anemia- Grade 2 | 2 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Anemia- Grade 3 | 7 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Anorexia- Grade 2 | 4 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Anorexia- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Aspartate aminotransferase increased- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Bacteremia- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Biliary tract Infection- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Blood transfusion- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Blood bilirubin increased- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | chest tightness- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Cholecystitis- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Constipation- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Creatinine increased- Grade 2 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Diarrhea- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Diarrhea- Grade 3 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Dysgeusia- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Enterocolitis- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Fatigue- Grade 2 | 3 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Febrile Neutropenia- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Flu like symptoms- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Gastroesophageal relux disease- Grade 2 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | hypersalivation- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hematuria- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hiccups- Grade 2 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hot flashes- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hypercalcemia- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hyperglycemia- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hypertension- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hypertension- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hypoalbuminemia- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hypokalemia- Grade 2 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hypomagnesemia- Grade 2 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hypomagnesemia- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Hyponatremia- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Infection- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Infusion Related Reaction- Grade 2 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Lymphocyte count decreased- Grade 3 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Nausea- Grade 2 | 2 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Neutrophil count decreased- Grade 2 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Neutrophil count decreased- Grade 4 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Pancreatitis- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Peripheral Sensory Neuropathy- Grade 2 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Platelet count decreased- Grade 4 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Sepsis- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Stroke- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Pulmonary Embolism- Grade 3 | 0 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Vomiting- Grade 2 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | White Blood Cell Decreased- Grade 3 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Alanine aminotransferase increased- Grade 3 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Aspartate aminotransferase increased- Grade 3 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Fever- Grade 2 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | Liver Abscess- Grade 3 | 1 Participants |
| Phase 1, CPI-613 500 mg/m2 | Incidence of Toxicities | generalize muscle weakness- Grade 2 | 0 Participants |
Secondary
Median Overall Survival (OS)
From date of first study treatment until date of last disease evaluation or until death from any cause. Using the product-limit method of Kaplan and Meier.
Time frame: Up to 3 years after enrollment
Population: Phase 2, Arm A- 37 patients were randomized to Arm A treatment, with 36 patients receiving treatment. Per protocol the 16 patients in the Phase 1 portion of the study were included, for a total of 52 patients in the investigational arm. All 52 subjects were considered for evaluability. Two subjects were found to be unevaluable.~Phase 2, Arm B- 18 patients were randomized to Arm B treatment, with 16 patients receiving treatment. Three subjects were found to be unevaluable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2, Arm A (Investigational) | Median Overall Survival (OS) | 15.6 months |
| Phase 2, Arm B (Standard of Care) | Median Overall Survival (OS) | 22.2 months |
Secondary
Median Progression Free Survival (PFS)
PFS will be determined from date of first study treatment until the date of radiological or clinical progression (leading to withdrawal from the study) or date of last disease evaluation (for patients without progression). It will be calculated using the product-limit method of Kaplan and Meier. All patients that receive at least one dose of study treatment will be considered evaluable.
Time frame: Until last dose of study treatment (up to 2 years)
Population: Phase 2, Arm A- 37 patients were randomized to Arm A treatment, with 36 patients receiving treatment. Per protocol the 16 patients in the Phase 1 portion of the study were included, for a total of 52 patients in the investigational arm. All 52 subjects were considered for evaluability. Two subjects were found to be unevaluable.~Phase 2, Arm B- 18 patients were randomized to Arm B treatment, with 16 patients receiving treatment. Three subjects were found to be unevaluable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2, Arm A (Investigational) | Median Progression Free Survival (PFS) | 8.7 months |
| Phase 2, Arm B (Standard of Care) | Median Progression Free Survival (PFS) | 9.6 months |