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

• ClinicalTrials.gov Identifier: NCT01766219
• Recruitment Status: Completed
• First Posted: January 11, 2013
• Results First Posted: May 15, 2019
• Last Update Posted: May 15, 2019
• Sponsor: Wake Forest University Health Sciences
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Wake Forest University Health Sciences

Study Description

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

Condition or disease	Intervention/treatment	Phase
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	Drug: 6,8-bis(benzylthio)octanoic acid	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 17 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Open-Label Clinical Trial of CPI-613 in Patients With Advanced Bile Duct Cancers
• Study Start Date: May 2013
• Actual Primary Completion Date: April 2018
• Actual Study Completion Date: May 18, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1: (6,8-bis[benzylthio]octanoic acid) 2,300 mg/m²; 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; Given IV; Other Names: alpha-lipoic acid analogue CPI-613; CPI-613
Experimental: Arm 2: (6,8-bis[benzylthio]octanoic acid) 1,200/3,00 mg/m²; 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; Given IV; Other Names: alpha-lipoic acid analogue CPI-613; CPI-613
Experimental: Arm 3 (6,8-bis[benzylthio]octanoic acid) 600/3,000 mg/m²; 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; Given IV; Other Names: alpha-lipoic acid analogue CPI-613; CPI-613

Outcome Measures

Primary Outcome Measures :

1. Overall Survival [ Time Frame: From the first dose of 6,8-bis(benzylthio)octanoic acid to death, assessed up to 4 years ]
   Estimated using Kaplan-Meier techniques.

Secondary Outcome Measures :

1. Response Rate Defined as Proportion of Patients With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) [ Time Frame: 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
2. Progression-free Survival [ 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 ]
   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).
3. Number of Participants With Adverse Events Using the National Cancer Institute Common Terminology Criteria [ Time Frame: 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, North Carolina

Comprehensive Cancer Center of Wake Forest University

Winston-Salem, North Carolina, United States, 27157

Sponsors and Collaborators

Wake Forest University Health Sciences

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Caio Rocha Lima, MD; Wake Forest University Health Sciences

  Study Documents (Full-Text)

Documents provided by Wake Forest University Health Sciences:

Study Protocol and Statistical Analysis Plan  [PDF] July 16, 2018

More Information

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT01766219
• Other Study ID Numbers: IRB00022533; NCI-2013-00063 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); P30CA012197 ( U.S. NIH Grant/Contract ); CCCWFU 59212 ( Other Identifier: Wake Forest University Health Sciences )
• First Posted: January 11, 2013
• Results First Posted: May 15, 2019
• Last Update Posted: May 15, 2019
• Last Verified: April 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Liver Neoplasms; Cholangiocarcinoma; Bile Duct Neoplasms; Recurrence; Disease Attributes; Pathologic Processes; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Liver Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Biliary Tract Neoplasms; Bile Duct Diseases; Biliary Tract Diseases; Thioctic Acid; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs; Vitamin B Complex; Vitamins; Micronutrients