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

Phase 2

Terminated

Conditions: Biliary Cancer
Cholangiocarcinoma
Biliary Tract Neoplasms
Bile Duct Cancer

Interventions: Drug: Trametinib
Drug: Hydroxychloroquine

Registration Number: NCT04566133

Lead Sponsor: National Cancer Institute (NCI)

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....

Detailed Description: Background:

* Among the new cases of bile tract carcinoma (BTC) that are diagnosed every year in the United States, there are approximately 6,500 cases of gallbladder carcinoma, 3,000 cases of extrahepatic cholangiocarcinoma, and 3,000 cases of intrahepatic cholangiocarcinoma.

* Current treatment options for patients with cholangiocarcinoma are limited and take no account of the known biological and genetic heterogeneity in these diseases. Median survival for advanced disease remains poor at approximately 1 year.

* Activating kirsten rat sarcoma (KRAS) mutations are frequently detected in all subtypes of BTC and can be found in up to 40% of BTC, predominantly in perihilar and distal cholangiocarcinoma (CCA). However, pharmacological inhibition of mutated KRAS has demonstrated little clinical benefit in general.

* Trametinib is a reversible, highly selective allosteric inhibitor of mitogen-activated extracellular signal regulated kinases methyl ethyl ketone 1 (MEK1) and methyl ethyl ketone 2 (MEK2). Tumor cells with KRAS mutations commonly have hyperactivated extracellular signal-related kinase (ERK) pathways in which activated MEK is a critical component. However, tumors are able to overcome MEK signaling inhibition by trametinib through upregulation of autophagy pathway.

* Hydroxychloroquine (HCQ) inhibits lysosomal acidification and prevents the degradation of autophagosomes, to suppress autophagy.

* Trametinib has been approved by FDA for the treatment of melanoma as a single agent or for the treatment of other cancers if tumors carry BRAF mutation. Hydroxychloroquine is approved for the treatment of malaria, lupus erythematosus and acute or chronic rheumatoid arthritis.

* Preclinical studies have shown that combined treatment of trametinib plus HCQ elicited striking tumor regression in animal model.

Objective:

-To determine whether the 5-month progression free survival (PFS) of the trametinib plus hydroxychloroquine (HCQ) combination in subjects with refractory bile tract carcinoma (BTC) with KRAS mutation exceeds 25%.

Eligibility:

* Histopathological confirmation of BTC or carcinoma highly suggestive of a diagnosis of BTC.

* Tumor must have KRAS mutation.

* Patients must have disease that is not amenable to potentially curative resection, transplantation or ablation.

* Age greater than or equal to 18 years

* Patients must have measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

* At least two weeks washout period from previous therapy

* Eastern Cooperative Oncology Group (ECOG) less than or equal to 2

* Adequate renal, hepatic and bone marrow function

Design:

-The study is open-labeled phase 2 study. It is designed to enroll total 30 patients with refractory BTC, to test the hypothesis that treatment with a combination of HCQ and trametinib prevents cancer progression/recurrence. We propose that this combination will have relative safety profile and antitumor efficacy in BTC patients with KRAS mutation.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 2

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort 1/Arm 1: Trametinib + Hydroxychloroquine (HCQ)	Trametinib	Trametinib + hydroxychloroquine (HCQ)
Cohort 1/Arm 1: Trametinib + Hydroxychloroquine (HCQ)	Hydroxychloroquine	Trametinib + hydroxychloroquine (HCQ)

Primary Outcome Measures

Name	Time	Method
Median Progression Free Survival (PFS)	3 months	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).

Secondary Outcome Measures

Name	Time	Method
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	Response is defined as a Complete Response (CR) + Partial Response (PR) in participants with refractory BTC with KRAS mutation treated with the combination of trametinib plus HCQ. Response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR) is disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. Any pathological lymph nodes must have reduction in short axis to \<10 mm. Partial Response (PR) is at least a 30% decrease in the sum of target lesions, taking as reference the baseline sum diameters.
Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment	90 days after treatment	Adverse events were assessed by the by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
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	Response is defined as a Complete Response (CR) + Partial Response (PR) in participants with refractory BTC with KRAS mutation treated with the combination of trametinib plus HCQ. Response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR) is disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. Any pathological lymph nodes must have reduction in short axis to \<10 mm. Partial Response (PR) is at least a 30% decrease in the sum of target lesions, taking as reference the baseline sum diameters.
Overall Survival	duration of time from the start of treatment to death from any cause, approximately 10 months	Overall survival is defined as the duration of time from start of treatment to death from any cause.