Dabrafenib, Trametinib, and Navitoclax in Treating Patients With BRAF Mutant Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
Dabrafenib, Trametinib, and Navitoclax in Treating Patients With BRAF Mutant Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
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, trametinib, and navitoclax may stop the growth of tumor
 cells by blocking some of the enzymes needed for cell growth.
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 28 days, and then every
 12 months for 3 years.
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

 -  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 must have no clinical evidence of leptomeningeal or brain metastasis causing
 spinal cord compression that are symptomatic or untreated or not stable for >= 3
 months (must be documented by imaging) or requiring corticosteroids; 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

 -  Miscellane