CPI-613 in Treating Patients With Advanced or Metastatic Bile Duct Cancer That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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This pilot clinical trial studies 6,8-bis(benzylthio)octanoic acid in treating patients with advanced or metastatic cholangiocarcinoma that cannot be removed by surgery. 6,8-Bis(benzylthio)octanoic acid may stop the growth of cholangiocarcinoma by blocking blood flow to the tumor

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the safety and efficacy of CPI-613 (6,8-bis[benzylthio]octanoic acid) in patients with advanced unresectable cholangiocarcinoma who have failed available therapies. OUTLINE: Pre-cycle: Patients receive 6,8-bis(benzylthio)octanoic acid intravenously (IV) over 2 hours on days 1-5, 1 week prior to course 1. Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1 and 4 of weeks 1-3. Treatment repeats every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients responding to treatment may receive up to 4 more courses of treatment. After completion of study treatment, patients are followed up bimonthly.

Official Title
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A Pilot Open-Label Clinical Trial of CPI-613 in Patients With Advanced Bile Duct Cancers

Conditions
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Adult Primary Cholangiocellular Carcinoma, Advanced Adult Primary Liver Cancer, Cholangiocarcinoma of the Extrahepatic Bile Duct, Cholangiocarcinoma of the Gallbladder, Localized Unresectable Adult Primary Liver Cancer, Metastatic Extrahepatic Bile Duct Cancer, Recurrent Adult Primary Liver Cancer, Recurrent Extrahepatic Bile Duct Cancer, Unresectable Extrahepatic Bile Duct Cancer

Intervention / Treatment
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* Drug: 6,8-bis(benzylthio)octanoic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically and cytologically proven cholangiocarcinoma of any type (including intrahepatic cholangiocarcinoma, extrahepatic primary cholangiocarcinoma, hilar cholangiocarcinomas, cholangiocarcinomas located in the gall bladder or hepatic capsule effraction, and carcinoma of the Ampulla of Vater, etc.) that is not amenable to surgery, radiation, or combined modality therapy with curative intent, and has failed or is not eligible for available chemotherapies such as gemcitabine with or without platinum Local, locally-advanced, or metastatic disease documented as having shown progression on a scan (e.g., computed tomography [CT], magnetic resonance imaging [MRI]) Measurable tumor according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria with at least one unidimensionally measurable target lesion No evidence of biliary duct obstruction, unless obstruction is controlled by local treatment or, in whom the biliary tree can be decompressed by endoscopic or percutaneous stenting with subsequent reduction in bilirubin to below 1.5 x upper level of normal (ULN) No acute toxic effects from previous treatment superior to grade 1 at the start of the study Eastern Cooperative Oncology Group (ECOG) performance status being 0-3 Expected survival > 3 months Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use accepted contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive or double barrier device) during the study, and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation Fertile men must practice effective contraceptive methods during the study, unless documentation of infertility exists Granulocyte count >= 1500/mm^3 White blood cell (WBC) >= 3500 cells/mm^3 or >= 3.5 bil/L Platelet count >=100,000 cells/mm^3 or >=100 bil/L Absolute neutrophil count (ANC) >=1500 cells/mm^3 or >=1.5 bil/L Hemoglobin >= 9 g/dL or >= 90 g/L Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) =< 3 x upper normal limit (UNL), alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 3 x UNL (=< 5 x UNL if liver metastases present) Bilirubin =< 1.5 x UNL Serum creatinine =< 2.0 mg/dL or 177 µmol/L International normalized ratio or INR must be =< 1.5 No evidence of active infection and no serious infection within the past month Mentally competent, ability to understand and willingness to sign the informed consent form Exclusion Criteria: Patients receiving any other standard or investigational treatment for their cancer, or any other investigational agent for any indication within the past 2 weeks prior to initiation of CPI-613 treatment Serious medical illness that would potentially increase patients' risk for toxicity Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease) Pregnant women, or women of child-bearing potential not using reliable means of contraception (because the teratogenic potential of CPI-613 is unknown) Lactating females Fertile men unwilling to practice contraceptive methods during the study period Life expectancy less than 3 months Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients Unwilling or unable to follow protocol requirements Dyspnea with moderate exertion; patients with clinically significant pleural or pericardial effusions Active heart disease including but not limited to symptomatic congestive heart failure, symptomatic coronary artery disease, symptomatic angina pectoris, symptomatic myocardial infarction, or symptomatic congestive heart failure; also patients with a history of myocardial infarction that is < 1 year prior to registration, or patients with previous congestive heart failure (< 1 year prior to registration) requiring pharmacologic support or with left ventricular ejection fraction < 50%) A history of additional risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome) Evidence of active infection, or serious infection within the past month Patients with known human immunodeficiency virus (HIV) infection Patients who have received cancer immunotherapy of any type within the past 2 weeks prior to initiation of CPI-613 treatment Requirement for immediate palliative treatment of any kind including surgery Patients that have received a chemotherapy regimen with stem cell support in the previous 6 months Prior illicit drug addiction Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of the patient

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: (6,8-bis[benzylthio]octanoic acid) 2,300 mg/m²<br>Participants will not be treated with CPI-613 during pre-Cycle 1 and will only be treated with 3 weeks on/1 week off at 2,300 mg/m² as a starting dose. If none of these 3 participants develop a dose-limiting toxicity through Cycle 1, the dose for the 3-weeks-on-1-week-off treatment cycles will be 3,000 mg/m² in all subsequent participants in this trial. Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1 and 4 of weeks 1-3. Treatment repeats every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients responding to treatment may receive up to 4 more courses of treatment. | Drug: 6,8-bis(benzylthio)octanoic acid<br>* Given IV<br>* Other names: CPI-613;|
| Experimental: Arm 2: (6,8-bis[benzylthio]octanoic acid) 1,200/3,00 mg/m²<br>Participants will received pre-cycle 1 week dose at 1200 mg/m² and dosing will escalate to 3,000 mg/m² for the three weeks on, one week off cycle. Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1 and 4 of weeks 1-3. Treatment repeats every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients responding to treatment may receive up to 4 more courses of treatment. | Drug: 6,8-bis(benzylthio)octanoic acid<br>* Given IV<br>* Other names: CPI-613;|
| Experimental: Arm 3 (6,8-bis[benzylthio]octanoic acid) 600/3,000 mg/m²<br>Participants will received pre-cycle 1 week dose at 600 mg/m² and dosing will escalate to 3,000 mg/m² for the three weeks on, one week off cycle. Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1 and 4 of weeks 1-3. Treatment repeats every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients responding to treatment may receive up to 4 more courses of treatment. | Drug: 6,8-bis(benzylthio)octanoic acid<br>* Given IV<br>* Other names: CPI-613;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Estimated using Kaplan-Meier techniques. | From the first dose of 6,8-bis(benzylthio)octanoic acid to death, assessed up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate Defined as Proportion of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) | Using the RECIST version 1.1 as defined by patient with 95% confidence interval will be included. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study | From the start of the treatment until disease progression, assessed up to 4 year | 
| Progression-free Survival | Estimated using Kaplan-Meier techniques as well as RECIST 1.1. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression). | From the first dose of 6,8-bis(benzylthio)octanoic acid to disease progression (DP) or death due to any cause, assessed up to 4 years | 
| Number of Participants With Adverse Events Using the National Cancer Institute Common Terminology Criteria | Adverse events will be captured using the National Cancer Institute Common Terminology Criteria (NCI CTCAE) version 3.0 | Up to 1 month completion of study treatment, assessed up to 1 year |