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Bile Duct CancerPhase 2NCT04566133

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

A Phase 2 study testing Trametinib and Hydroxychloroquine in people with Bile Duct Cancer and Biliary Cancer, run by National Cancer Institute (NCI) at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Trametinib and Hydroxychloroquine
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2 participants
Where
1 siteUnited States
Study dates
15 Feb 2022to 31 Dec 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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)
  • alanine aminotransferase (ALT) or aspartate aminotransferase (AST) less than or equal to 5 x ULN.
  • Creatinine OR Measured or calculated creatinine clearance (CrCl) (eGFR may also be used in place of CrCl)*** : < 1.5x institution upper limit of normal OR greater than or equal to 30 mL/min/1.73 m^2 for participant with creatinine levels greater than or equal to 1.5 X institutional ULN
  • Notes:
  • ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);
  • AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase);
  • GFR=glomerular filtration rate; ULN=upper limit of normal.
  • Creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR) should be calculated per institutional standard.
  • Patients must have at least 1 focus of disease that is amenable to mandatory tumor biopsies and be willing to undergo this. Ideally, the biopsied lesion should not be one of the target measurable lesions, although this can be up to the discretion of the investigators.
  • The study drugs are harmful for developing human fetus. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) at the study entry, for the duration of study treatment and up to 4 months after the last dose of the study drug(s). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Patients must be able to understand and be willing to sign a written informed consent.

Who cannot join

  • 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.
  • Any unresolved toxicity NCI Common Terminology Criteria for Adverse Events (CTCAE) v.5 Grade greater than or equal to 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Patients with Grade greater than or equal to 2 neuropathy will be evaluated on a case-by-case basis.
  • 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)
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  • 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
  • Known chronic hepatitis B virus, unless hepatitis B virus (HBV) viral load is undetectable.
  • Known history of hepatitis C virus (HCV) infection, unless completed treatment and cured with undetectable HCV viral load.
  • Known prior severe hypersensitivity to study drugs or any component in its formulations (CTCAE v5.0 grade >= 3).
  • Pregnant women are excluded from this study because study therapy can cause fetal harm. Because there is potential risk for adverse events in nursing infants secondary to treatment of the mother with study therapy, breastfeeding should be discontinued if the mother is treated with study drugs.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: Phase II Study of Combination of Trametinib (MEK Inhibitor) and Hydroxychloroquine (HCQ) (Autophagy Inhibitor) in Patients With KRAS Mutation Refractory Bile Tract Carcinoma (BTC).

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.

Read more

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....

Read the 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.

Keywords
Tumor Regression, Progression Free Survival, New Drug Combination
Medical subject headings
Bile Duct Neoplasms, Biliary Tract Neoplasms, Cholangiocarcinoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TrametinibDrug

    Also called Mekinist

    orally 2 mg once a day

  • HydroxychloroquineDrug

    Also called Plaquenil

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

Study groups in NCT04566133
Study groupRoleWhat they receive
Cohort 1/Arm 1: Trametinib + Hydroxychloroquine (HCQ)ExperimentalTrametinib + hydroxychloroquine (HCQ)
Receives: Drug: Trametinib; Drug: Hydroxychloroquine

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

    Measured: 3 months

Secondary outcomes (4)

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

    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.

    Measured: Every 2 months up to approximately 10 months

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

    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.

    Measured: Every 2 months up to approximately 10 months

  3. Serious Adverse Events Possibly, Probably, and/or Definitely Related to 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.

    Measured: 90 days after treatment

  4. Overall Survival

    Overall survival is defined as the duration of time from start of treatment to death from any cause.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Sep 2020
  2. Study start15 Feb 2022
  3. Primary completion11 May 2022
  4. Study completion31 Dec 2022

Why it stopped: Slow accrual

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
2 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04566133
Sponsor's protocol ID
200152
Other IDs
20-C-0152
Status last verified
Jul 2023
First submitted
25 Sep 2020
Last updated
21 Aug 2023
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Trametinib and Hydroxychloroquine in people with Bile Duct Cancer and Biliary Cancer, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 21 Aug 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 21 Aug 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Median Progression Free Survival (PFS) (time frame: 3 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04566133.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Aug 2023.

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