Clinical Trials /

Binimetinib and Hydroxychloroquine in Treating Patients With KRAS Mutant Metastatic Pancreatic Cancer

NCT04132505

Description:

This phase I trial studies the best dose of hydroxychloroquine when given together with binimetinib in treating patients with KRAS gene mutated pancreatic cancer that has spread to other places in the body (metastatic). Binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Hydroxychloroquine may prevent autophagy, a normal process in which a cell destroys proteins and other substances which may lead to cell death. Autophagy may prevent normal cells from developing into tumor cells, but it may also protect tumor cells by destroying anticancer drugs or substances taken up by them. Giving hydroxychloroquine together with binimetinib may work better in treating patients with pancreatic cancer compared to binimetinib alone.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Binimetinib and Hydroxychloroquine in Treating Patients With KRAS Mutant Metastatic Pancreatic Cancer
  • Official Title: Binimetinib Plus Hydroxychloroquine in KRAS Mutant Pancreatic Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2019-0191
  • SECONDARY ID: NCI-2019-04991
  • SECONDARY ID: 2019-0191
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04132505

Conditions

  • KRAS Gene Mutation
  • Metastatic Pancreatic Adenocarcinoma
  • Stage IV Pancreatic Cancer AJCC v8

Interventions

DrugSynonymsArms
BinimetinibARRY-162, ARRY-438162, MEK162, MektoviTreatment (binimetinib, hydroxychloroquine)
HydroxychloroquineTreatment (binimetinib, hydroxychloroquine)

Purpose

This phase I trial studies the best dose of hydroxychloroquine when given together with binimetinib in treating patients with KRAS gene mutated pancreatic cancer that has spread to other places in the body (metastatic). Binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Hydroxychloroquine may prevent autophagy, a normal process in which a cell destroys proteins and other substances which may lead to cell death. Autophagy may prevent normal cells from developing into tumor cells, but it may also protect tumor cells by destroying anticancer drugs or substances taken up by them. Giving hydroxychloroquine together with binimetinib may work better in treating patients with pancreatic cancer compared to binimetinib alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose of hydroxychloroquine (HCQ) when combined with a
      fixed dose of binimetinib.

      SECONDARY OBJECTIVES:

      I. To determine the response rate among a pilot cohort of pancreatic cancer patients.

      II. To determine the safety and toxicity profile of the combination of binimetinib and HCQ.

      III. To determine the ability of the combination to halt tumor growth as measured by
      progression free survival.

      IV. To assess the overall survival of patients treated on this regimen.

      EXPLORATORY OBJECTIVES:

      I. To compare the efficacy of treatment to somatic gene mutation profile as acquired by
      standard of care testing.

      II. To assess pre- and post- treatment tissue to determine if markers of autophagy correlate
      with response to treatment.

      III. To assess the effect of this binimetinib/HCQ treatment on changes in muscle and fat mass
      as analyzed by computed tomography (CT) scan (as standard of care treatment).

      OUTLINE: This is a dose-escalation study of hydroxychloroquine.

      Patients receive binimetinib orally (PO) twice daily (BID) and hydroxychloroquine PO BID on
      days 1-14. Cycles repeat every 14 days in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up every 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (binimetinib, hydroxychloroquine)ExperimentalPatients receive binimetinib PO BID and hydroxychloroquine PO BID on days 1-14. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
  • Binimetinib
  • Hydroxychloroquine

Eligibility Criteria

        Inclusion Criteria:

          -  Have histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma
             based on pathology report with radiologically identified metastases that meet Response
             Evaluation Criteria in Solid Tumors (RECIST) criteria.

          -  Be willing and able to provide written informed consent for the trial.

          -  Have at least one measurable lesion by RECIST criteria.

          -  Have had prior treatment with at least one line of therapy for metastatic disease.

          -  Have had tumor mutation profiling from any Clinical Laboratory Improvement Act (CLIA)
             certified laboratory demonstrating a KRAS mutation. Liquid biopsy demonstrating KRAS
             mutation will be considered acceptable.

          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             performance scale.

          -  Absolute neutrophil count (ANC) >= 1500/uL (specimens must be collected within 10 days
             prior to the start of trial treatment).

          -  Platelets >= 100,000/uL (specimens must be collected within 10 days prior to the start
             of trial treatment).

          -  Hemoglobin >= 9.0 g/dL (specimens must be collected within 10 days prior to the start
             of trial treatment).

          -  Creatinine OR measured or calculated creatinine clearance (glomerular filtration rate
             [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x
             upper limit of normal (ULN) OR >= 50 mL/min for subjects with creatinine level > 1.5 x
             ULN (specimens must be collected within 10 days prior to the start of trial
             treatment).

          -  Total bilirubin =< 1.5 x ULN (specimens must be collected within 10 days prior to the
             start of trial treatment).

          -  Indirect bilirubin =< ULN (specimens must be collected within 10 days prior to the
             start of trial treatment).

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]), and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             ULN (=< 5 x ULN for subjects with liver metastases) (specimens must be collected
             within 10 days prior to the start of trial treatment).

          -  Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for subjects with liver metastases)
             (specimens must be collected within 10 days prior to the start of trial treatment).

          -  Serum albumin > 3.3 mg/dl (specimens must be collected within 10 days prior to the
             start of trial treatment).

          -  International normalized ratio (INR) OR prothrombin time (PT), activated partial
             thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant
             therapy as long as PT or aPTT is within therapeutic range of intended use of
             anticoagulants (specimens must be collected within 10 days prior to the start of trial
             treatment).

          -  Female subjects of childbearing potential must have a negative urine or serum
             pregnancy test prior to the start of treatment.

          -  The participant is deemed by the investigator to have the ability to be compliant with
             scheduled visits, treatment plan, and study procedures.

          -  Male and female subjects of childbearing potential must agree to use an adequate
             method of contraception starting with the first dose of trial therapy through 30 days
             after the last dose of trial therapy. Note: Abstinence is acceptable if this is the
             usual lifestyle and preferred contraception for the subject. Acceptable methods of
             contraception are listed in the protocol text.

        Exclusion Criteria:

          -  Has pancreatic tumor other than adenocarcinoma, including: acinar cell carcinoma,
             pancreaticoblastoma, malignant cystic neoplasms, endocrine neoplasms, squamous cell
             carcinoma, ampulla of Vater, periampullary, duodenal, or common bile duct
             malignancies. Poorly differentiated carcinoma may be included at the discretion of the
             investigator if histologic features suggest the possibility of adenocarcinoma.

          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational treatment within 2 weeks prior to the anticipated
             first dose of study treatment.

          -  Received anticancer therapy including chemotherapy, immunotherapy, or antineoplastic
             biologic drugs (e.g. erlotinib) within 14 days of the anticipated start of study
             treatment.

          -  Have undergone major surgery (e.g. inpatient procedures) =< 6 weeks prior to the start
             of study treatment or who have not recovered from side effects of earlier such
             procedures.

          -  Have undergone radiation within 7 days prior to the start of treatment.

          -  Patient has not recovered to =< grade 1 from toxic effects of prior therapy before
             starting study treatment. Note that alopecia, neuropathy, myalgias, and endocrinopathy
             are exceptions to this criteria.

          -  Impaired cardiovascular function or clinically significant cardiovascular disease
             including, but not limited to, any of the following:

               -  History of acute coronary syndromes (including myocardial infarction, unstable
                  angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6
                  months prior to screening;

               -  Congestive heart failure requiring treatment (New York Heart Association grade >=
                  2);

               -  Left ventricular ejection fraction (LVEF) < 50% as determined by multigated
                  acquisition scan (MUGA) or echocardiography (ECHO);

               -  Uncontrolled hypertension defined as persistent systolic blood pressure >= 150
                  mmHg or diastolic blood pressure >= 100 mmHg despite current therapy;

               -  History or presence of clinically significant cardiac arrhythmias (including
                  resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal
                  supraventricular tachycardia);

               -  Triplicate average baseline corrected QT (QTc) interval >= 480 ms.

          -  Impairment of gastrointestinal function or disease which may significantly alter the
             absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or
             diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal
             absorption), or recent (=< 3 months) history of a partial or complete bowel
             obstruction, or other conditions that will interfere significantly with the absorption
             of oral drugs.

          -  Had a solid organ or hematologic transplant.

          -  Concurrent neuromuscular disorder that is associated with elevated creatine kinase
             (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral
             sclerosis, spinal muscular atrophy).

          -  Has required treatment for other malignancies within 1 year prior to first dose of
             study treatment, with the exception of curatively treated basal cell carcinoma of the
             skin, squamous cell carcinoma of the skin and/or curatively resected tumors of low
             invasive potential (e.g., in situ cervical and/or breast cancers).

          -  Has a history of central nervous system (CNS) metastases and/or carcinomatous
             meningitis.

          -  History or current evidence of retinal vein occlusion (RVO) or current risk factors
             for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
             or hypercoagulability syndromes); history of retinal degenerative disease.

          -  Has an active infection requiring systemic therapy.

          -  Chronic use of steroids for pain or emesis management.

          -  Has known ophthalmologic disease that, in the opinion of investigators, would pose an
             increased risk of visual disturbances during the study. This includes a history or
             current evidence of retinal vein occlusion (RVO) or current risk factors for RVO
             (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or
             hypercoagulability syndromes); history of retinal degenerative disease. The routine
             use of eyeglasses does not in itself disqualify patient participation.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the screening visit through 30 days
             after the last dose of trial treatment.

          -  Has a known history of human immunodeficiency virus (HIV) infection (HIV 1/2
             antibodies) (No HIV screening is required for patients with no known diagnosis).

          -  Has a history of the following liver diseases:

               -  Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive),

               -  Hepatitis C (defined as detectable hepatitis C virus [HCV] ribonucleic acid
                  [RNA]),

               -  Primary biliary cholangitis,

               -  Primary sclerosing cholangitis,

               -  History of immune mediated cholangitis.

               -  Of note, patients with a history of bacterial cholangitis are eligible if the
                  infection has been fully resolved prior to the screening visit. An exception is
                  made for hepatitis C patients who have undergone treatment and who have negative
                  serologic testing for at least one year.

          -  Has a known history of active TB (Mycobacterium Tuberculosis).

          -  Is unable to tolerate a contrast enhanced computed tomography (CT) or magnetic
             resonance imaging (MRI) for staging/restaging purposes.

          -  In the estimation of the treating physician or primary investigator, have had a
             clinical deterioration of their ECOG performance within the month prior to enrollment.
             Evidence for such deterioration shall be documented in the patient's medical record.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator. Evidence for
             such abnormalities/conditions will be documented in the patient's medical record.

          -  Has a history of thromboembolic or cerebrovascular events =< 12 weeks prior to the
             first dose of study treatment. Examples include transient ischemic attacks,
             cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive)
             deep vein thrombosis or pulmonary emboli. Note: Patients with either deep vein
             thrombosis or pulmonary emboli that does not result in hemodynamic instability are
             allowed to enroll as long as they are on a stable dose of anticoagulants for at least
             4 weeks. Also note: Patients with thromboembolic events related to indwelling
             catheters or other procedures may be enrolled. Finally: patients with stable
             mesenteric thrombosis that predate study assessment (eg portal vein thrombus) may be
             enrolled.

          -  Has a history of active bleeding requiring transfusion within a 3 month period prior
             to screening. (Transfusions attributed to chemotherapy related anemia do not meet this
             exclusion criterion.)

          -  Known cases of drug-induced hepatobiliary toxicities (other than a radiological
             finding of fatty liver).

          -  Has had prior treatment with a MEK or ERK inhibitor.

          -  Partial or complete bowel obstruction.

          -  Impaired gastrointestinal function that may significantly alter the absorption of
             binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome,
             small bowel resection with decreased intestinal absorption) or baseline diarrhea >=
             grade 1.

          -  Use of digoxin, mefloquine, cyclosporine, methotrexate, fexofenadine, quinidine,
             talinolol, vinblastine, coumestrol, daidzein, dantrolene, estrone-3-sulfate,
             genistein, prazosin, sulfasalazine, or antiepileptics if used for seizures (ok to use
             the latter if part of a pain regimen). Prior loperamide use for diarrhea is permitted
             at enrollment but should be changed to diphenoxylate / atropine before initiation of
             treatment.

          -  Has a history of psoriatic arthritis requiring systemic treatment.

          -  Has a history of porphyria.

          -  (Expansion phase only) Inability to safely undergo tumor biopsies (e.g. requirement
             for antiplatelet therapy).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:Up to 30 days
Safety Issue:
Description:Will employ the Bayesian optimal interval (BOIN) design to find the MTD.

Secondary Outcome Measures

Measure:Response rate
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Incidence of adverse events
Time Frame:Up to 1 year
Safety Issue:
Description:Toxicity will be assessed using common toxicity criteria version 5.
Measure:Progression free survival
Time Frame:Up to 1 year
Safety Issue:
Description:To determine the ability of the combination to halt tumor growth
Measure:Overall survival
Time Frame:Up to 1 year
Safety Issue:
Description:To assess the overall survival of patients treated on this regimen

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated