Melanoma Clinical Trial

Testing the Addition of Navitoclax to the Combination of Dabrafenib and Trametinib in People Who Have BRAF Mutant Melanoma

Summary

This phase I/II trial studies the side effects and best dose of dabrafenib, trametinib, and navitoclax and to see how well they work in treating patients with BRAF mutant melanoma or solid tumors that have spread to other parts of the body (metastatic) or cannot be removed by surgery (unresectable). Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Navitoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving navitoclax, dabrafenib, and trametinib may help shrink tumors in patients with melanoma.

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Full Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD), toxicity, and safety profile of navitoclax when given in combination with dabrafenib and trametinib in patients with BRAF-mutant solid tumors. (Phase I) II. To estimate the complete response (CR) rate in patients with BRAF-mutant melanoma treated with dabrafenib, trametinib, and navitoclax as compared to the historical control dabrafenib and trametinib combination (DT). (Phase II) III. To compare the maximal tumor regression in patients with BRAF-mutant melanoma treated with dabrafenib, trametinib versus dabrafenib, trametinib, and navitoclax. (Phase II)

SECONDARY OBJECTIVES:

I. To describe pharmacodynamics effects of treatment with dabrafenib, trametinib, and navitoclax on both serial tumor biopsies and serial blood draws in a small subset of patients treated with BRAF-mutant melanoma. (Phase I) II. To describe the pharmacokinetics of treatment with dabrafenib, trametinib, and navitoclax. (Phase I) III. To compare the progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) in patients with BRAF-mutant melanoma treated with dabrafenib, trametinib, versus dabrafenib, trametinib, and navitoclax. (Phase II) IV. To compare the degree of apoptosis induced in on-treatment biopsies of patients with BRAF-mutant melanoma treated with dabrafenib, trametinib versus dabrafenib, trametinib, and navitoclax. (Phase II) V. To explore other pharmacodynamic effects in on-treatment biopsies of patients with BRAF-mutant melanoma treated with either dabrafenib, trametinib versus dabrafenib, trametinib, and navitoclax including cell proliferation (Ki-67), proteomics (reverse-phase protein microarrays [RPPA]), and B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (BCL-2) family gene expression analysis. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of dabrafenib, trametinib, and navitoclax followed by a randomized phase II study.

PHASE I: Patients receive navitoclax orally (PO) once daily (QD) on days -7 to -1 of cycle 1 only. Patients also receive dabrafenib PO twice daily (BID), trametinib PO QD, and navitoclax PO QD days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 arms.

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

ARM II: Patients receive navitoclax PO QD days -7 to -1 of cycle 1 only. Patients also receive dabrafenib PO BID, trametinib PO QD, and navitoclax PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After the completion of study treatment, patients are followed up for clinical evaluation at 28 days and every 3 months thereafter until disease progression or death, whichever comes first. For survival follow up, patients are followed every 12 months for 3 years.

View Eligibility Criteria

Eligibility Criteria

Inclusion Criteria:

PHASE I SUBJECTS ONLY: Prior therapy is allowed; for patients enrolled in the Phase I portion of the study, patients may have received any number of prior lines of therapy including treatment with a BRAF and/or MEK inhibitor; prior navitoclax use will not be allowed, unless the patient received < 7 days of navitoclax lead-in on this or another study and had to stop for reasons other than toxicity or disease progression

Patients must have histologically confirmed, BRAF-mutant (V600E/K) melanoma (molecularly confirmed using validated, commercially available assay performed in a Clinical Laboratory Improvement Act [CLIA]-approved laboratory) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective

If test at CLIA-certified lab used a non-Food and Drug Administration (FDA) approved method, information about the assay must be provided; (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test)
Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
Prior therapy is allowed; for patients enrolled in the Phase II portion of the study, patients may have received prior immunotherapy (including high-dose IL-2, ipilimumab, nivolumab, and other anti-PD1/PDL1 antibodies) or chemotherapy; however prior navitoclax, BRAF inhibitor and/or MEK inhibitor therapy will not be allowed
Age >= 18 years. Because no dosing or adverse event data are currently available on the use of navitoclax in combination with dabrafenib and trametinib in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
Life expectancy of greater than 3 months
Leukocytes >= 3,000/mcL
Absolute neutrophil count >= 1 x 10^9/L
Hemoglobin >= 9 g/dl (patients may be transfused to this level)
Platelets >= 100,000/mcL
Total bilirubin =< 1.5 x institutional upper limit of normal OR > 1.5 x institutional upper limit of normal allowed if direct bilirubin is within normal range
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 x upper limit of normal (ULN)
Serum creatinine =< 1.5 mg/dL OR creatinine clearance >= 50 mL/min/1.73 m^2
Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO)
Patients must have a corrected QT (QTc) interval of less than 480 msec
The effects of navitoclax, dabrafenib, and trametinib on the developing human fetus are unknown; for this reason, women of child-bearing potential and men with partners of childbearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed due to drug-drug interactions which can render hormonal contraceptives ineffective) prior to study entry, for the duration of study participation, and for 4 months after completion of study drug administration; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately; based on studies in animals, it is also known that dabrafenib may cause damage to the tissue that makes sperm; this may cause sperm to be abnormal in shape and size and could lead to infertility, which may be irreversible; safety and efficacy of the combination of dabrafenib and trametinib in pediatric populations have not been investigated; dabrafenib or trametinib-dabrafenib combination should not be administered to pediatric populations outside clinical trials
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
Ability to understand and the willingness to sign a written informed consent document; if a patient has impaired decision-making capacity, a legally authorized representative, patients will be allowed to participate

Exclusion Criteria:

PHASE I SUBJECTS ONLY: Patients must not have received prior navitoclax, unless the patient received < 7 days of navitoclax lead-in on this or another study and had to stop for reasons other than toxicity or disease progression
Patients who have had immunotherapy, chemotherapy or radiotherapy within 14 days prior to the first dose of navitoclax, or prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks prior to first dose of dabrafenib and/or trametinib; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment; biologics will not be allowed within 30 days prior to, or during, navitoclax administration
Prior navitoclax, BRAF inhibitor, and MEK inhibitor is prohibited; (exceptions for Phase I are described above)
Patients who are receiving any other investigational agents have received any other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study
Patients with treated leptomeningeal or brain metastasis are not eligible unless there is demonstrated stability (documented by imaging) for >= 3 months from any prior treatment of leptomeningeal or brain metastasis. Treatment may include surgery, radiation or systemic therapy. Patients with untreated leptomeningeal or brain metastasis or requiring corticosteroids are not eligible. Subjects on a stable dose of corticosteroids > 1 month or who have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor. Subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks
History of allergic reactions attributed to compounds of similar chemical or biologic composition to navitoclax, dabrafenib, or trametinib, or excipients or to dimethyl sulfoxide (DMSO)
Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with study requirements
Pregnant women are excluded from this study because navitoclax, dabrafenib, and trametinib may have teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study drugs, breastfeeding should be discontinued if the mother is treated with the study drugs
Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy that predict to interact with any of the study drugs are ineligible because of the potential for pharmacokinetic interactions with the study drugs; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated; it is not necessary to conduct HIV testing at screening; patients who are HIV-positive with undetectable viral loads, not on interacting antiretroviral therapy, and have CD4 counts above 300/mm^3 may be eligible after discussion with the principal investigator
History of another malignancy; exception: patients who have been disease-free for 3 years (depending upon tumor type studied or clinical setting, 3 or 5 years can be used; e.g., for advanced melanoma and pancreatic studies 3 years is more appropriate due to aggressiveness of the disease, while 5 years can be more appropriate for prostate or ovarian cancer or adjuvant setting when life expectancy is longer), or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the CTEP medical monitor if unsure whether second malignancies meet the requirements specified above; exception: patients with history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility
History of interstitial lung disease or pneumonitis

History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR):

History of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)
Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure > 21 mmHg

History or evidence of cardiovascular risk including any of the following:

A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec on screening electrocardiography (ECG)
History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)
History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization
History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system
Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy
Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study
Known history of hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible); it is not necessary to conduct HBV and HCV testing at screening
Subject has an underlying condition predisposing them to bleeding or currently exhibits signs of clinically significant bleeding
Subject has a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug
A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency
Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v. 5.0) grade 2 or higher from previous anti-cancer therapy, except alopecia or an endocrine toxicity related to immunotherapy (e.g. thyroiditis/hypothyroidism, adrenal insufficiency, hypophysitis) requiring replacement therapy, at the time of randomization
Due to the expected dose-limiting toxicity of thrombocytopenia, the following concomitant medications are not allowed during navitoclax administration: clopidogrel, ibuprofen, tirofiban, warfarin, and other anticoagulants, drugs, or herbal supplements that affect platelet function are excluded, with the exception of low-dose anticoagulation medications (such as heparin) that are used to maintain the patency of a central intravenous catheter; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor

Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:

Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed)
Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis
Because the composition, pharmacokinetics (PK), and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)
Anticoagulants or antiplatelet agents except for low-dose, aspirin
Preclinical studies indicate that navitoclax is metabolized by CYP3A4, is a moderate inhibitor of CYP2C8, and is a strong inhibitor of CYP2C9; there is also evidence of interactions with dabrafenib; therefore, caution should be exercised when dosing navitoclax concurrently with CYP2C8 and CYP2C9 substrates; common CYP2C8 substrates include paclitaxel, statins, and glitazones, whereas CYP2C9 substrates include phenytoin; when possible, investigators should switch to alternative medications or monitor the patients closely; CYP3A inhibitors such as ketoconazole and clarithromycin are not allowed 7 days prior to the first dose of navitoclax or during navitoclax administration

Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of permeability-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; below are a few examples of the agents:

Strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib may be decreased:

Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine)
Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, s-mephenytoin
Miscellaneous: bosentan, St. John's wort

Strong inhibitors of CYP3A or CYP2C8 since concentrations of dabrafenib may be increased:

Antibiotics: clarithromycin, telithromycin, troleandomycin
Antidepressants: nefazodone
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole
Hyperlipidemia: gemfibrozil
Antiretroviral: ritonavir, saquinavir, atazanavir
Miscellaneous: conivaptan

Study is for people with:

Melanoma

Phase:

Phase 1

Estimated Enrollment:

75

Study ID:

NCT01989585

Recruitment Status:

Active, not recruiting

Sponsor:

National Cancer Institute (NCI)

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There are 46 Locations for this study

See Locations Near You

Mayo Clinic Hospital in Arizona
Phoenix Arizona, 85054, United States
Mayo Clinic in Arizona
Scottsdale Arizona, 85259, United States
Los Angeles County-USC Medical Center
Los Angeles California, 90033, United States
USC / Norris Comprehensive Cancer Center
Los Angeles California, 90033, United States
USC Norris Oncology/Hematology-Newport Beach
Newport Beach California, 92663, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange California, 92868, United States
University of California Davis Comprehensive Cancer Center
Sacramento California, 95817, United States
University of Colorado Hospital
Aurora Colorado, 80045, United States
UM Sylvester Comprehensive Cancer Center at Aventura
Aventura Florida, 33180, United States
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables Florida, 33146, United States
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach Florida, 33442, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami Florida, 33136, United States
UM Sylvester Comprehensive Cancer Center at Kendall
Miami Florida, 33176, United States
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation Florida, 33324, United States
Moffitt Cancer Center - McKinley Campus
Tampa Florida, 33612, United States
Moffitt Cancer Center
Tampa Florida, 33612, United States
Northwestern University
Chicago Illinois, 60611, United States
University of Iowa/Holden Comprehensive Cancer Center
Iowa City Iowa, 52242, United States
University of Kansas Clinical Research Center
Fairway Kansas, 66205, United States
HaysMed University of Kansas Health System
Hays Kansas, 67601, United States
University of Kansas Cancer Center
Kansas City Kansas, 66160, United States
Lawrence Memorial Hospital
Lawrence Kansas, 66044, United States
Olathe Health Cancer Center
Olathe Kansas, 66061, United States
University of Kansas Cancer Center-Overland Park
Overland Park Kansas, 66210, United States
University of Kansas Hospital-Indian Creek Campus
Overland Park Kansas, 66211, United States
Ascension Via Christi - Pittsburg
Pittsburg Kansas, 66762, United States
Salina Regional Health Center
Salina Kansas, 67401, United States
University of Kansas Health System Saint Francis Campus
Topeka Kansas, 66606, United States
University of Kansas Hospital-Westwood Cancer Center
Westwood Kansas, 66205, United States
Massachusetts General Hospital Cancer Center
Boston Massachusetts, 02114, United States
Dana-Farber Cancer Institute
Boston Massachusetts, 02215, United States
Mayo Clinic in Rochester
Rochester Minnesota, 55905, United States
Siteman Cancer Center at West County Hospital
Creve Coeur Missouri, 63141, United States
Truman Medical Centers
Kansas City Missouri, 64108, United States
University of Kansas Cancer Center - North
Kansas City Missouri, 64154, United States
University of Kansas Cancer Center - Lee's Summit
Lee's Summit Missouri, 64064, United States
University of Kansas Cancer Center at North Kansas City Hospital
North Kansas City Missouri, 64116, United States
Washington University School of Medicine
Saint Louis Missouri, 63110, United States
Siteman Cancer Center-South County
Saint Louis Missouri, 63129, United States
Siteman Cancer Center at Christian Hospital
Saint Louis Missouri, 63136, United States
Siteman Cancer Center at Saint Peters Hospital
Saint Peters Missouri, 63376, United States
Rutgers Cancer Institute of New Jersey
New Brunswick New Jersey, 08903, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York New York, 10016, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York New York, 10032, United States
UNC Lineberger Comprehensive Cancer Center
Chapel Hill North Carolina, 27599, United States
Duke University Medical Center
Durham North Carolina, 27710, United States
Ohio State University Comprehensive Cancer Center
Columbus Ohio, 43210, United States
Thomas Jefferson University Hospital
Philadelphia Pennsylvania, 19107, United States
M D Anderson Cancer Center
Houston Texas, 77030, United States

How clear is this clinincal trial information?

Study is for people with:

Melanoma

Phase:

Phase 1

Estimated Enrollment:

75

Study ID:

NCT01989585

Recruitment Status:

Active, not recruiting

Sponsor:


National Cancer Institute (NCI)

How clear is this clinincal trial information?

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