Clinical Trials /

Testing Dabrafenib and Trametinib With or Without Hydroxychloroquine in Stage IIIC or IV BRAF V600E/K Melanoma

NCT04527549

Description:

This phase II trial investigates how well adding hydroxychloroquine to the standard treatment of dabrafenib and trametinib works to overcome resistance and delay disease progression in treating patients with stage IIIC or IV BRAF V600E/K melanoma. Hydroxychloroquine may cause cell death in tumor cells that rely on a process called "autophagy" for survival. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine together with dabrafenib and trametinib may work better than dabrafenib and trametinib alone to shrink and stabilize the cancer.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing Dabrafenib and Trametinib With or Without Hydroxychloroquine in Stage IIIC or IV BRAF V600E/K Melanoma
  • Official Title: The BAMM2 (BRAF, Autophagy, MEK Inhibition in Melanoma) Study: A Randomized Double Blind Phase II Study of Dabrafenib and Trametinib With or Without Hydroxychloroquine in Advanced BRAF V600E/K Melanoma

Clinical Trial IDs

  • ORG STUDY ID: EA6191
  • SECONDARY ID: NCI-2020-04552
  • SECONDARY ID: EA6191
  • SECONDARY ID: EA6191
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT04527549

Conditions

  • Clinical Stage IV Cutaneous Melanoma AJCC v8
  • Locally Advanced Melanoma
  • Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
  • Pathologic Stage IV Cutaneous Melanoma AJCC v8
  • Unresectable Melanoma

Interventions

DrugSynonymsArms
Dabrafenib MesylateDabrafenib Methanesulfonate, GSK2118436 Methane Sulfonate Salt, GSK2118436B, TafinlarArm A (dabrafenib, trametinib, hydroxychloroquine)
Hydroxychloroquine SulfatePlaquenilArm A (dabrafenib, trametinib, hydroxychloroquine)
Placebo AdministrationArm B (dabrafenib, trametinib, placebo)
Trametinib Dimethyl SulfoxideArm A (dabrafenib, trametinib, hydroxychloroquine)

Purpose

This phase II trial investigates how well adding hydroxychloroquine to the standard treatment of dabrafenib and trametinib works to overcome resistance and delay disease progression in treating patients with stage IIIC or IV BRAF V600E/K melanoma. Hydroxychloroquine may cause cell death in tumor cells that rely on a process called "autophagy" for survival. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine together with dabrafenib and trametinib may work better than dabrafenib and trametinib alone to shrink and stabilize the cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the rate of one year progression-free survival (PFS) when hydroxychloroquine
      sulfate (hydroxychloroquine) or placebo is added to dabrafenib mesylate (dabrafenib) and
      trametinib dimethyl sulfoxide (trametinib) in advanced BRAFV600E/K melanoma.

      SECONDARY OBJECTIVES:

      I. To compare the PFS of both arms. II. To evaluate the best overall response rate by
      treatment arm. III. To evaluate the complete response (CR) rate by treatment arm. IV. To
      evaluate the adverse event rate by treatment arm. V. To evaluate overall survival (OS) by
      treatment arm.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive dabrafenib mesylate orally (PO) twice daily (BID), trametinib
      dimethyl sulfoxide PO once daily (QD), and hydroxychloroquine sulfate PO BID on days 1-28.
      Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive dabrafenib mesylate PO BID, trametinib dimethyl sulfoxide PO QD, and
      placebo PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (dabrafenib, trametinib, hydroxychloroquine)ExperimentalPatients receive dabrafenib mesylate PO BID, trametinib dimethyl sulfoxide PO QD, and hydroxychloroquine sulfate PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Dabrafenib Mesylate
  • Hydroxychloroquine Sulfate
  • Trametinib Dimethyl Sulfoxide
Arm B (dabrafenib, trametinib, placebo)Active ComparatorPatients receive dabrafenib mesylate PO BID, trametinib dimethyl sulfoxide PO QD, and placebo PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Dabrafenib Mesylate
  • Placebo Administration
  • Trametinib Dimethyl Sulfoxide

Eligibility Criteria

        Inclusion Criteria:

          -  Patient must have locally advanced unresectable stage IIIC or stage IV melanoma

          -  Patient must have BRAF V600E or BRAF V600K tumor genotype based on a Clinical
             Laboratory Improvement Act (CLIA) approved assay

          -  Patient must have measurable disease by Response Evaluation Criteria in Solid Tumors
             (RECIST) 1.1. Baseline measurements of sites of disease must be obtained within 3
             weeks prior to study randomization

          -  Patient must have been treated with prior immune checkpoint inhibitor therapy (anti
             PD-1 antibody, anti-CTLA-4 antibody or a combination regimen including either or both
             agents) either in the adjuvant or metastatic setting. Patient may have received
             investigational agents in combination with standard therapy, as long as it was
             adhering to the timeframes

               -  Patient must have discontinued active immunotherapy (IL-2, interferon,
                  anti-CTLA-4 antibody, anti-PD-1 antibody etc.) or chemotherapy at least 4 weeks
                  prior to randomization

               -  Patient must have discontinued any oral targeted therapy at least 2 weeks prior
                  to randomization

               -  Patients must not receive any other investigational anticancer therapy during the
                  period on study or the 4 weeks prior to randomization

          -  Patient may have been treated with prior adjuvant therapy including combined BRAF and
             MEK inhibitor therapy. Patients will be eligible if they tolerated this therapy and
             did not discontinue the therapy due to toxicity AND >= 6 months have elapsed since the
             end of adjuvant BRAF and MEK inhibition. If patients received BRAF and MEK inhibitor
             therapy in the metastatic setting, they are not eligible

          -  Patient may have been treated with prior chemotherapy or radiation therapy

          -  Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
             or 1

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

          -  Women of childbearing potential and sexually active males must not expect to conceive
             or father children by using accepted and effective method(s) of contraception or
             abstaining from sexual intercourse for the duration of their participation in the
             study and for 4 months after the last dose of protocol treatment

          -  Patient must have recovered from clinically significant reversible toxicities from
             previous treatment prior to randomization. Abnormal laboratory values may be grade 1,
             as long as they meet the eligibility criteria

          -  Patient must be able to swallow and retain oral medication and must not have any
             clinically significant gastrointestinal abnormalities that may alter absorption such
             as malabsorption syndrome or major resection of the stomach or bowels

          -  Patient must have the ability to understand and the willingness to sign a written
             informed consent document. Patients with impaired decision-making capacity (IDMC) who
             have a legally authorized representative (LAR) or caregiver and/or family member
             available will also be considered eligible

          -  Absolute neutrophil count >= 1,500/mcL (obtained =< 14 days prior to protocol
             randomization)

          -  Platelets >= 100,000/mcL (obtained =< 14 days prior to protocol randomization)

          -  Total bilirubin =< institutional upper limit of normal (ULN) (obtained =< 14 days
             prior to protocol randomization)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3.0 x institutional ULN (obtained =< 14 days prior to protocol randomization)

          -  Creatinine =< 1.5 x institutional ULN (obtained =< 14 days prior to protocol
             randomization)

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patient with asymptomatic new or progressive brain metastases (active brain
             metastases) are eligible if the treating physician determines that CNS specific
             treatment is not required

               -  NOTE: Patient with treated brain metastases are eligible. No brain imaging is
                  required, however, 1 week must elapse after gamma knife therapy. Patient treated
                  with whole brain radiation that have been stable for 2 months are eligible.
                  Patient are excluded if they have leptomeningeal disease or metastases causing
                  spinal cord compression that are symptomatic or untreated or not stable
                  (documented by imaging) for at least 3 months or requiring corticosteroids.
                  Patients on a stable dose of corticosteroids for at least 1 month or who have
                  been off of corticosteroids for at least 1 week are eligible

        Exclusion Criteria:

          -  Patients who are known to be experiencing an objective partial response to
             immunotherapy at the time of study enrollment are not eligible

          -  Women must not be pregnant or breast-feeding due to the potential harm to an unborn
             fetus and possible risk for adverse events in nursing infants with the treatment
             regimens being used. All females of childbearing potential must have a blood test or
             urine study within 14 days prior to randomization to rule out pregnancy. A female of
             childbearing potential is defined as any woman, regardless of sexual orientation or
             whether they have undergone tubal ligation, who meets the following criteria: 1) has
             achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
             oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer
             therapy does not rule out childbearing potential) for at least 24 consecutive months
             (i.e., has had menses at any time in the preceding 24 consecutive months)

          -  Patient must not have a history of interstitial lung disease (ILD) or chronic
             pneumonitis

               -  NOTE: If there is radiographic evidence of ILD that is clinically insignificant
                  and asymptomatic, the patient would be eligible

          -  Patient must not have porphyria or psoriasis due to risk of disease exacerbation
             unless the disease is well controlled and they are under the care of a specialist for
             the disorder who agrees to monitor the patient for exacerbations

          -  Patient must not have a previously documented retinal vein occlusion

          -  Patient must not have a history or evidence of increased cardiovascular risk
             including:

               -  Left ventricular ejection fraction (LVEF) < institutional lower limit of normal
                  measured within 14 days prior to randomization

               -  A QT interval corrected for heart rate using the Bazett's formula >= 480 msec

               -  Current clinically significant uncontrolled arrhythmias. Exception: Patients with
                  controlled atrial fibrillation for > 30 days prior to randomization are eligible

               -  Acute coronary syndromes (including myocardial infarction and unstable angina),
                  coronary angioplasty, or stenting within 6 months prior to randomization

               -  Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram
                  unless a cardiologist concludes the valve abnormality is not clinically
                  significant. Patients with grade 1 abnormalities (i.e., mild
                  regurgitation/stenosis) are eligible

               -  Patients with known history or current symptoms of cardiac disease, or history of
                  treatment with cardiotoxic agents, should have a clinical risk assessment of
                  cardiac function using the New York Heart Association Functional Classification.
                  To be eligible for this trial, patients should be class 2B or better

          -  Patient with known serious concurrent infection or medical illness, including
             psychiatric disorders, which would jeopardize the ability of the patient to receive
             the treatment outlined in this protocol with reasonable safety are not eligible

          -  Patient must not be receiving concurrent therapy for their tumor (i.e.
             chemotherapeutics or investigational agents). Radiotherapy delivered to palliate pain
             is allowed as long as it is not targeting a lesion that meets RECIST criteria for
             progression. Radiation therapy to the surgical bed with gamma knife radiotherapy while
             on treatment during the first cycle is allowed for small volume surgically resected
             brain metastases. Gamma knife radiotherapy for known active, asymptomatic small volume
             central nervous system (CNS) lesions may be performed during the first cycle while on
             study. Radiotherapy for new CNS lesions identified beyond the first cycle is not
             allowed on study

          -  Patient must not have a known immediate or delayed hypersensitivity reaction or
             idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl
             sulfoxide (DMSO)

          -  Patient must not have received cytochrome P450 enzyme -inducing anticonvulsant drugs
             (extended-interval aminoglycoside dosing [EIADs]) (i.e. phenytoin, carbamazepine,
             phenobarbital, primidone or oxcarbazepine) within 4 weeks prior to randomization

          -  Patient must not have a current use of a prohibited medication
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS) rate
Time Frame:From randomization to progression or death (whichever occurs first), assessed at 1 year after completion of treatment
Safety Issue:
Description:Estimated from the Kaplan-Meier curves and compared by treatment arm. A test statistic of the difference in one-year PFS rates divided by the square root or the sum of the variances will be used with a normal approximation. Progression will be evaluated based on international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).

Secondary Outcome Measures

Measure:PFS distribution
Time Frame:From randomization to progression or death (whichever occurs first), assessed at 1 year after completion of treatment
Safety Issue:
Description:Will be estimated using the method of Kaplan-Meier by treatment arm and compared using the log-rank test. In this analysis, all cases with PFS assessed (including cases with censored < one-year) will be included. Progression will be evaluated based on international criteria proposed by the revised RECIST guideline (version 1.1).
Measure:Overall response rate
Time Frame:Up to 1 year after completion of treatment
Safety Issue:
Description:Will be estimated by treatment arm and 95% confidence intervals (CIs) will be provided. Response will be defined by the RECIST guidelines (version 1.1).
Measure:Complete response rate
Time Frame:Up to 1 year after completion of treatment
Safety Issue:
Description:Will be estimated by treatment arm and 95% CIs will be provided. Response will be defined by the RECIST guidelines (version 1.1).
Measure:Overall survival
Time Frame:From randomization to death from any cause, assessed up to 1 year after completion of treatment
Safety Issue:
Description:Overall survival will be described using the method of Kaplan-Meier by treatment arm.
Measure:Incidence of adverse events
Time Frame:Up to 1 year after completion of treatment
Safety Issue:
Description:Will be monitored carefully throughout the study and will be summarized by treatment arm. Adverse events will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).
Measure:Treatment duration
Time Frame:Up to 1 year after completion of treatment
Safety Issue:
Description:Will be estimated by treatment arm.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:ECOG-ACRIN Cancer Research Group

Last Updated

October 23, 2020