Combination of Trametinib (MEK Inhibitor) and Hydroxychloroquine (HCQ) (Autophagy Inhibitor) in Patients With KRAS Mutation Refractory Bile Tract Carcinoma (BTC).

NCT04566133 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: 20015220-C-0152
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Bile duct cancer is cancer of the slender tubes of the biliary tract. These tubes carry bile through the liver. Such cancer tumors often have an abnormal or mutated gene. Researchers think a mix of drugs can slow the progression of gene-mutated cancers of the biliary tract. Objective: To see if using a combination of trametinib and hydroxychloroquine (HCQ) increases the period of time it takes for a person s bile tract carcinoma (BTC) to get worse. Eligibility: Adults age 18 and older with BTC. Design: Participants will be screened with a physical exam, medical history, and cancer history. Their ability to do their normal activities will be assessed. They will have blood and urine tests. They will give a tumor sample. They will have heart tests. They may talk with a heart doctor. They may have an eye exam. They may have a tuberculosis test. They will have computer tomography (CT) scans of the chest, abdomen, and pelvis. They may have magnetic resonance imaging (MRI) scans of the chest, abdomen, pelvis. Participants will repeat some screening tests throughout the study. Participants will take HCQ and trametinib tablets by mouth daily in 28-day cycles. They will have study visits once a month. They will take the drugs until they have bad side effects or the drugs stop working. Participants will have one more tumor biopsy during the treatment. They will have blood taken often. One month after treatment ends, participants will have a safety follow-up visit. Then they will be called or emailed every 6 months for the rest of their life....

Conditions

Bile Duct Cancer; Biliary Cancer; Biliary Tract Neoplasms; Cholangiocarcinoma

Keywords

Tumor Regression; Progression Free Survival; New Drug Combination

Outcome Measures

Primary Outcomes (1)

• Median Progression Free Survival (PFS)

  Participants with refractory bile tract carcinoma (BTC) with KRAS mutation that exceed 25% who receive trametinib plus hydroxychloroquine (HCQ) combination who are able to not have progressive disease at 5 months will be reported along with a 95% confidence interval. Progression was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progression).

  3 months

Secondary Outcomes (4)

• Proportion of Participants With a Response (Complete Response (CR) + Partial Response (PR) Reported With an 80% Confidence Interval

  Every 2 months up to approximately 10 months

• Proportion of Participants With a Response (Complete Response (CR) + Partial Response (PR) Reported With an 95% Confidence Interval

  Every 2 months up to approximately 10 months

• Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment

  90 days after treatment

• Overall Survival

  duration of time from the start of treatment to death from any cause, approximately 10 months

Other Outcomes (1)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  Date treatment consent signed to date off study, assessed for approximately 3 months and 25 days

Study Arms (1)

Cohort 1/Arm 1: Trametinib + Hydroxychloroquine (HCQ)

EXPERIMENTAL

Trametinib + hydroxychloroquine (HCQ)

Drug: Trametinib; Drug: Hydroxychloroquine

Interventions

Trametinib DRUG

orally 2 mg once a day

Also known as: Mekinist

Cohort 1/Arm 1: Trametinib + Hydroxychloroquine (HCQ)

Hydroxychloroquine DRUG

orally 600 mg twice a day-1,200 mg total dose

Also known as: Plaquenil

Cohort 1/Arm 1: Trametinib + Hydroxychloroquine (HCQ)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histopathological confirmation of
• biliary tract carcinoma (BTC) OR carcinoma in the setting of clinical and radiological characteristics which, together with the pathology, are highly suggestive of a diagnosis of BTC
• Note: The term BTC includes intra- or extra- hepatic cholangiocarcinoma (CCA), gallbladder cancer or ampullary cancer.
• The tumor must have Kirsten rat sarcoma (KRAS) mutation(s) of clinical significance, confirmed by National Cancer Institute (NCI) Laboratory of Pathology or by Food and Drug Administration (FDA).
• Patients must have received or been intolerant of at least one line of chemotherapy.
• Patients must have at least 1 measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Patients must have disease that is not amenable to potentially curative resection, ablation or transplantation.
• Age greater than or equal to 18 years.
• Performance status Eastern Cooperative Oncology Group (ECOG) 0-2
• If liver cirrhosis is present, patient must have a Child-Pugh score \<7 (Class A)
• Patients must have adequate organ and marrow function as defined below:
• absolute neutrophil count (ANC) greater than or equal to 1,500/mcL
• platelets greater than or equal to 100,000/mcL
• hemoglobin greater than or equal to 9 g/dL
• total bilirubin if cirrhosis present: Part of Child Pugh requirement. If no cirrhosis: bilirubin should be less than or equal to 1.5 x upper limit of normal (ULN)

You may not qualify if:

• Patients who have had standard-of-care anti-cancer therapy within 2 weeks of treatment initiation or therapy with investigational agents (e.g., chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies or other investigation agents), large field radiotherapy, or major surgery within 4 weeks of treatment initiation.
• Has biliary duct obstruction, unless a treatable, clinically relevant obstruction has been relieved by internal endoscopic drainage/stenting, palliative by-pass surgery or percutaneous drainage prior to treatment initiation.
• Patients with known brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• Patients with signs of liver failure, e.g., clinically significant ascites, encephalopathy, or variceal bleeding within six months before treatment initiation.
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyper viscosity or hypercoagulability syndromes)
• Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
• Cardiovascular disorders: Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias, stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before treatment initiation
• History of glucose-6-phosphate dehydrogenase (G6PD) deficiency
• History of seizures
• Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. Muscular activities, such as strenuous exercise, that can result in significant increases in plasma creatine kinase (CK) levels should be avoided while on study treatment
• Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
• Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection that under the judgment of the principal investigator (PI) may impair absorption of study drugs)
• Any other condition that would, in the Investigator s judgment, contraindicate the patient s participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication (patients may not receive drug through a feeding tube), social/psychological issues, etc.
• Screening corrected QT interval by Fridericia's (QTcF) \> 500 msec
• Known infection with human immunodeficiency virus (HIV), unless patient is on effective anti-retroviral therapy with undetectable viral load within 6 months of treatment initiation

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Bile Duct Neoplasms; Biliary Tract Neoplasms; Cholangiocarcinoma

Interventions

trametinib; Hydroxychloroquine

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Tim F. Greten
• Organization: National Cancer Institute

gretentf@mail.nih.gov

2407606114

Study Officials

• Tim F Greten, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 25, 2020
• First Posted: September 28, 2020
• Study Start: February 15, 2022
• Primary Completion: May 11, 2022
• Study Completion: December 31, 2022
• Last Updated: August 21, 2023
• Results First Posted: August 21, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing Plan (GDS) plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Locations

US (1)