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
Conditions
Brief summary
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
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.
Interventions
Given IV
Sponsors
National Cancer Institute (NCI)
Wake Forest University Health Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From the first dose of 6,8-bis(benzylthio)octanoic acid to death, assessed up to 4 years | Estimated using Kaplan-Meier techniques. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate Defined as Proportion of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) | From the start of the treatment until disease progression, assessed up to 4 year | 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 |
| Progression-free Survival | 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 | 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). |
| Number of Participants With Adverse Events Using the National Cancer Institute Common Terminology Criteria | Up to 1 month completion of study treatment, assessed up to 1 year | Adverse events will be captured using the National Cancer Institute Common Terminology Criteria (NCI CTCAE) version 3.0 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 2,300 mg/m² Patients receive 6,8-bis(benzylthio)octanoic acid IVover 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.
6,8-bis(benzylthio)octanoic acid: Given IV | 4 |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 1,200/3,000 mg/m² Pre-cycle: Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-5, 1 week prior to course 1.
Patients receive 6,8-bis(benzylthio)octanoic acid IVover 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.
6,8-bis(benzylthio)octanoic acid: Given IV | 2 |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 600/3,000 mg/m² Pre-cycle: Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-5, 1 week prior to course 1.
Patients receive 6,8-bis(benzylthio)octanoic acid IVover 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.
6,8-bis(benzylthio)octanoic acid: Given IV | 11 |
| Total | 17 |
Baseline characteristics
| Characteristic | Treatment (6,8-bis[Benzylthio]Octanoic Acid) 2,300 mg/m² | Treatment (6,8-bis[Benzylthio]Octanoic Acid) 1,200/3,000 mg/m² | Treatment (6,8-bis[Benzylthio]Octanoic Acid) 600/3,000 mg/m² | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 5 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 1 Participants | 6 Participants | 11 Participants |
| Age, Continuous | 52 years | 66 years | 62 years | 57 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 2 Participants | 11 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 2 Participants | 9 Participants | 15 Participants |
| Region of Enrollment United States | 4 participants | 2 participants | 11 participants | 17 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 7 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 4 | 2 / 2 | 11 / 11 |
| other Total, other adverse events | 4 / 4 | 2 / 2 | 11 / 11 |
| serious Total, serious adverse events | 0 / 4 | 1 / 2 | 1 / 11 |
Outcome results
Primary
Overall Survival
Estimated using Kaplan-Meier techniques.
Time frame: From the first dose of 6,8-bis(benzylthio)octanoic acid to death, assessed up to 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 2,300 mg/m² | Overall Survival | 4.7 months |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 1,200/3,000 mg/m² | Overall Survival | 1.6 months |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 600/3,000 mg/m² | Overall Survival | 3.94 months |
Secondary
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
Time frame: Up to 1 month completion of study treatment, assessed up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 2,300 mg/m² | Number of Participants With Adverse Events Using the National Cancer Institute Common Terminology Criteria | 4 Participants |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 1,200/3,000 mg/m² | Number of Participants With Adverse Events Using the National Cancer Institute Common Terminology Criteria | 2 Participants |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 600/3,000 mg/m² | Number of Participants With Adverse Events Using the National Cancer Institute Common Terminology Criteria | 11 Participants |
Secondary
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).
Time frame: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 2,300 mg/m² | Progression-free Survival | 1.6 months |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 1,200/3,000 mg/m² | Progression-free Survival | 0 months |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 600/3,000 mg/m² | Progression-free Survival | 2.5 months |
Secondary
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
Time frame: From the start of the treatment until disease progression, assessed up to 4 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 2,300 mg/m² | Response Rate Defined as Proportion of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) | Progression | 4 participants |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 2,300 mg/m² | Response Rate Defined as Proportion of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) | Stable Disease | 0 participants |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 2,300 mg/m² | Response Rate Defined as Proportion of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) | Not Evaluable | 0 participants |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 1,200/3,000 mg/m² | Response Rate Defined as Proportion of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) | Stable Disease | 2 participants |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 1,200/3,000 mg/m² | Response Rate Defined as Proportion of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) | Not Evaluable | 0 participants |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 1,200/3,000 mg/m² | Response Rate Defined as Proportion of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) | Progression | 0 participants |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 600/3,000 mg/m² | Response Rate Defined as Proportion of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) | Not Evaluable | 2 participants |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 600/3,000 mg/m² | Response Rate Defined as Proportion of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) | Progression | 7 participants |
| Treatment (6,8-bis[Benzylthio]Octanoic Acid) 600/3,000 mg/m² | Response Rate Defined as Proportion of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) | Stable Disease | 2 participants |