Dabrafenib, Trametinib, and Navitoclax in Treating Patients With BRAF Mutant Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

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 course 1
only. Patients also receive dabrafenib PO twice daily (BID), trametinib PO QD, and navitoclax
PO QD days 1-28. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

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

ARM I: Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28. Courses 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 course 1 only. Patients also
receive dabrafenib PO BID, trametinib PO QD, and navitoclax PO QD on days 1-28. Courses
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.

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

- 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) 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

- 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; breastfeeding should be discontinued if
the mother is treated with the study drugs

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible; 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

- 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

- 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, 81 mg aspirin

- Caution should be exercised when dosing navitoclax concurrently with cytochrome P450,
family 2, subfamily C, peptide 8 (CYP2C8) and cytochrome P450, family 2, subfamily C,
peptide 9 (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; cytochrome P450, family 3, subfamily A (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:

- 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

- Antibiotics: clarithromycin, telithromycin, troleandomycin

- Antidepressants: nefazodone

- Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole

- Hyperlipidemia: gemfibrozil

- Antiretroviral: ritonavir, saquinavir, atazanavir

- Miscellaneous: conivaptan