Dabrafenib/Trametinib/Navitoclax In Braf Mutant Melanoma

Before the research starts (screening): After signing this consent form, the participant
will be asked to undergo some screening tests or procedures. The purpose is to find out if
the participant can be in the research study. Many of these tests and procedures are likely
to be part of regular cancer care. They may be done even if it turns out that the
participant does not take part in the research study. If the participant has had some of
these tests or procedures recently, they may or may not have to be repeated.

- A medical history which includes questions about the participant's current medications,
and any allergies.

- Performance status, which evaluates how the participant is able to carry on their usual
activities

- Physical exam including vital signs (blood pressure, heart rate and temperature),
height and weight

- Documentation of the participant's BRAF mutation

- MUGA scan or echocardiogram. These exams will allow the doctor to see how well the
participant's heart works.

- A MUGA scan, which is a test in which ultrasound is used to examine the participant's
heart. A radioactive substance, which is detectable with a special camera, is injected
into the participant's blood stream. As the blood fills the heart, the camera is able
to create an animated image of the heart's functioning.

- The echocardiogram is a machine which picks up the echoes of the sound waves the
participant's heart makes and the instrument will create a moving picture of the heart.

- Routine blood tests (about 2 teaspoons) for chemistry, hematology and blood clotting

- Assessment of tumor by CT scan (typically of chest, abdomen, and pelvis), MRI
(Magnetic Resonance Imaging) or X-Ray

- MRI or CT scan of brain

- Electrocardiogram (ECG)

- Pregnancy test for women of childbearing potential

- An examination of the participant's skin will be done by a dermatologist

- Photographs of skin lesions, if any are present

- Eye tests, which will be done by an eye doctor (ophthalmologist)

If these tests show that the participant is eligible to participate in the research study,
the participant will begin the study drug. If the participant does not meet the eligibility
criteria, the participant will not be able to participate in this research study.

After the screening procedures confirm that the participant are eligible to participate in
the research study:

Optional Tumor Biopsies:

A small number of participants enrolled in this study will be asked to undergo multiple
biopsies of one of their tumors. Only tumors that can be easily and safely biopsied in the
clinic will be biopsied. The participant will have the choice to agree or disagree to these
optional biopsies later in Section O. of this consent. If the participant agrees, tumor
biopsies will be taken at multiple time points as noted below.

Lead-In Period:

If the participant takes part in this research study, the participant will take navitoclax
every day for 7 days by itself. This is called the lead-in period. Before the lead-in period
starts, the participant will have the following tests/procedures:

- A medical history which includes questions about the participant's current medications,
and any allergies

- Physical exam including vital signs (blood pressure, heart rate and temperature) and
weight

- Performance status, which evaluates how the participant is able to carry on their usual
activities

- Electrocardiogram (ECG)

- Routine blood tests (about 2 teaspoons) for chemistry and hematology

- Blood sample for BRAF analysis (about 2 tablespoons)

- Tumor biopsy - this is optional

If these tests/procedures were done within 3 days of starting navitoclax, they do not need
to be repeated.

Cycles 1 and On:

After the lead-in period, the participant's blood work will be checked. If the results show
it is safe to continue, then dabrafenib and trametinib will be added to the navitoclax. The
participant will take all three study drugs every day for 28 days. This 28-day period of
time is called a cycle. The participant will be given a study drug diary for every cycle, so
that the participant can record when the participant take the study drugs each day. The
diary will also include special instructions for taking the study drugs.

The investigator are looking for the highest dose of the study drug navitoclax that can be
given without severe or unmanageable side effects. Not everyone who takes part in this
research study will get the same dose of the study drug. The dose the participant get will
depend on the number of participants who have been enrolled in the study before and how well
they have tolerated their doses.

The participant will be asked to come to the clinic on the days listed below for the
following tests and procedures:

Cycle 1, Day 1:

- A medical history which includes questions about their current medications and health

- Physical exam including vital signs (blood pressure, heart rate and temperature) and
weight

- Performance status, which evaluates how the participant's are able to carry on their
usual activities

- Electrocardiogram (ECG)

- Routine blood tests (about 2 teaspoons) for chemistry and hematology

- Pharmacokinetic (PK) blood test (about 1 teaspoon) to monitor how their body absorbs
and breaks down the study drugs. PK blood samples will be taken pre-dose and 1, 2, 4,
6, 8, 24 hours post dose (24 hour post dose sample will be taken on Cycle 1 Day 2).

- Blood sample for BRAF analysis (about 2 tablespoons)

- Tumor biopsy - this is optional

Cycle 1, Day 8:

- Tumor biopsy - this is optional

Cycle 1, Day 15:

- Pharmacokinetic (PK) blood test (about 1 teaspoon) to monitor how their body absorbs
and breaks down the study drugs. PK blood samples will be taken pre-dose and 2, 4, 6,
8, 24 hours post dose (24 hour post dose sample will be taken on Cycle 1 Day 16).

- Blood sample for BRAF analysis (about 2 tablespoons)

- A medical history which includes questions about their current medications and health

Cycles 2+, Day 1:

- A medical history which includes questions about their current medications and health

- Physical exam including vital signs (blood pressure, heart rate and temperature) and
weight

- Performance status, which evaluates how the participant's are able to carry on their
usual activities

- Electrocardiogram (ECG)

- Routine blood tests (about 2 teaspoons) for chemistry and hematology

- Pharmacokinetic (PK) blood test (about 1 teaspoon) to monitor how their body absorbs
and breaks down the study drugs. PK blood samples will be taken pre-dose for cycles 2,
4, 8 and 12 only.

- Blood sample for BRAF analysis (about 2 tablespoons)

- Tumor scans: The investigator will assess the participant's tumor by CT, MRI, or other
appropriate measure prior to every odd cycle (cycles 3, 5, etc.). Photographs of skin
lesions will be taken, if applicable.

- MUGA scan or echocardiogram. The investigator will see how the participant's heart is
working approximately 1 and 3 months after starting therapy, and then every three
months.

- Eye tests, which will be done by an eye doctor (ophthalmologist) - this will be done 1
month after starting therapy and then only if the participant develop vision changes.

- An examination of the participant's skin will be done by a dermatologist - this will be
done every even cycle (cycles 2, 4, 6, etc.)

End of Treatment:

- A medical history which includes questions about their current health and medications

- Physical exam including vital signs (blood pressure, heart rate and temperature) and
weight

- Performance status, which evaluates how the participant is able to carry on with their
usual activities

- Routine blood tests (about 2 teaspoons) for chemistry and hematology

- Tumor scans: The investigator will assess their tumor by CT, MRI, or other appropriate
measure prior to every odd cycle (cycles 3, 5, etc.). Photographs of skin lesions will
be taken, if applicable.

- Tumor biopsy - this is optional

- Blood sample for BRAF analysis (about 2 tablespoons)

Planned Follow-up:

The investigator will ask the participant to come to the clinic for a final visit 4 weeks
after their last study dose. At the visit, the participant will have the following tests and
procedures:

- A medical history which includes questions about their current health and medications

After the final study visit, the investigator would like to keep track of their medical
condition. If the participant stopped the study treatment for any reason other than the
participant's disease getting worse, the investigator will follow the participant until the
disease progresses. If the participant stopped the study treatment because their disease got
worse, the investigator will follow the participant for the rest of their life. The
investigator will do this by reviewing the participant's medical chart. The participant will
not be required to come to the clinic.

***********PHASE 2******** If it is determined that treatment with the triple combination of
of dabrafenib, trametinib, and navitoclax(DTN) at the maximum tolerated dose is well
tolerated, then the phase 2 portion of the trial will be initiated following the
determination of the recommended phase 2 dose (RP2D). Participants with stage IV or
unresectable stage III BRAF-mutant melanoma will be randomized to receive either dabrafenib
and trametinib (DT) or dabrafenib, trametinib, and navitoclax (DTN). The co-primary
objectives of the phase 2 portion of the study will be to determine the complete response
rate of DTN, as compared to historical control, and to compare a shift in the maximal tumor
regression plot (i.e., Waterfall plot) between the two study arms. Secondary objectives will
be to compare progression-free survival (PFS), overall survival (OS), and objective response
rate (ORR) of DT versus DTN. A total of 50 patients will be randomized in equal proportions
to DTN or DT (25 patients per treatment arm)

The following applies to navitoclax dosing:

- There will be a 7-day lead-in of navitoclax

- The lead-in dose of navitoclax is 150 mg daily

- The navitoclax dose to be given in combination with dabrafenib and trametinib following
the 7-day navitoclax lead-in (i.e. on Day 1 of cycle 1) in the phase II study will be
defined following determination of the recommended Phase 2 dose (RP2D).

- Navitoclax will not commence on Day 1 of cycle 1 if any of the following scenarios
occur:

- Platelet count is < 50K

- Patients has evidence of any clinically significant bleeding, defined as grade 2 or
higher hemorrhage regardless of platelet count

- In the event that navitoclax does not commence on Day 1 of cycle 1 in the phase 2
portion of the study, a discussion will occur between investigators and the industry
sponsors regarding whether it is appropriate for this participant to continue on study
a lower than planned dose or to be removed for study and be replaced by another
participant.

Inclusion Criteria:

For phase 1: Patients must have histologically confirmed, BRAF-mutant (V600E/K) malignancy
(molecularly confirmed using Cobas assay or a comparable, FDA-approved assay) that is
metastatic or unresectable and for which standard curative measures do not exist or are no
longer effective.

For phase 2: Patients must have histologically confirmed, BRAF-mutant (V600E/K) melanoma
(molecularly confirmed using Cobas assay or a comparable FDA-approved assay) that is
metastatic or unresectable and for which standard curative measures do not exist or are no
longer effective.

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 CT scan, MRI, or calipers by clinical exam. See Section 11 for
the evaluation of measurable disease.

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. 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 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.

ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A).

Life expectancy of greater than 3 months.

Patients must have normal organ and marrow function as defined below:

- leukocytes ≥3,000/mcL

- absolute neutrophil count ≥1,200/mcL

- 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

- AST(SGOT)/ALT(SGPT)≤ 2.5 x institutional upper limit of normal

- PT/INR and PTT < 1.3 x ULN

- creatinine within normal institutional limits OR

- creatinine clearance≥50 mL/min/1.73 m2 for patients with creatinine levels above
institutional normal.

Patients must have a 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 must agree to use
adequate contraception prior to study entry, for the duration of study participation, and
for 4 months after completion of study drug administration. Because estradiol is a main
CYP3CA substrate and dabrafenib is a strong inducer, hormonal contraceptives may not be
effective. Additional contraceptive measures should be in place such as barrier method of
birth control and abstinence. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her treating
physician immediately. Men treated or enrolled on this protocol must also agree to use
adequate contraception prior to the study, for the duration of study participation, and 4
months after completion of study drug administration.

Ability to understand and the willingness to sign a written informed consent document.

Able to swallow and retain oral medication.

Exclusion Criteria:

- Patients who have had immunotherapy, chemotherapy or radiotherapy within 4 weeks (6
weeks for nitrosoureas or mitomycin C) prior to entering the study.

Patients must not have received prior navitoclax. In the phase II portion of the study,
prior BRAF inhibitor and/or MEK inhibitor will be prohibited.

Patients who are receiving any other investigational agents.

Patients must have no clinical evidence of brain metastasis. Patients with prior
resection, stereotactic radiosurgery, or whole brain radiation for brain metastasis are
eligible, provided that disease is asymptomatic, corticosteroids are not needed, and that
imaging is stable for a least 4 weeks prior to enrollment in the study.

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.

HIV-positive patients on combination antiretroviral therapy are ineligible because of the
potential for pharmacokinetic interactions with the study drugs. In addition, these
patients are at increased risk of lethal infections when treated with marrow-suppressive
therapy. Appropriate studies will be undertaken in patients receiving combination
antiretroviral therapy when indicated.

History of another malignancy.

Exception: Patients who have been disease-free for 3 years, or patients with a history of
completely resected non-melanoma skin cancer and/or patients with indolent secondary
malignancies, are eligible. Subjects with any malignancy with confirmed activating RAS
mutation are excluded. Prospective RAS testing is not required. However, if the results of
previous RAS testing are known, they must be used in assessing eligibility. Consult the
CTEP Medical Monitor if unsure whether second malignancies meet the requirements specified
above.

History of interstitial lung disease or pneumonitis.

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, 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, 81 mg aspirin

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 mm Hg.

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

- LVEF
- A QT interval corrected for heart rate using the Bazett's formula QTcB ≥480 msec.

- 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.

Active Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (patients with
chronic or cleared HBV and HCV infection are eligible).

Anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal (with
the exception of hormones for thyroid conditions or estrogen replacement therapy [ERT]),
and other investigational agents will not be allowed within 14 days prior to the first
dose of navitoclax, and 21 days prior to first dose of dabrafenib and trametinib.
Additionally, participants must have recovered to less than grade 2 clinically significant
adverse effect(s)/toxicity(ies) of the previous therapy. Biologics will not be allowed
within 30 days prior to, or during, navitoclax administration.

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/mm3) 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.

Preclinical studies indicate that navitoclax is metabolized by CYP3A4, is a moderate
inhibitor of CYP2C8, and is a strong inhibitor of CYP2C9. 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.

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.

Subject has a significant history of cardiovascular disease (e.g., MI, thrombotic or
thromboembolic event in the last 6 months).

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
P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be
excluded. Below are a few examples of the agents.

Prohibited - Strong inducers/inhibitors of CYP3A, CYP2C8, Pgp, and Bcrp since
concentrations of dabrafenib can be decreased/increased.

Strong CYP3A/2C8/Pgp/Bcrp Inhibitor/Inducer

- Antibiotics- clarithromycin, telithromycin, rifamycin class agents (e.g., rifampin,
rifabutin, rifapentine), troleandomycin

- Antifungals- itraconazole, ketoconazole, posaconazole, voriconazole

- Antidepressants- nefazodone

- Hyperlipidemia- gemfibrozil

- Miscellaneous- carbamazepine, Phenobarbital, amiodarone, phenytoin, S- mephenytoin,

- Immunosuppressive agents- cyclosporine

Because the lists of these agents are constantly changing, it is important to regularly
consult a frequently-updated list such as
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the
Physicians' Desk Reference may also provide this information. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be prescribed or
if the patient is considering a new over-the-counter medicine or herbal product. Appendix
C is a patient information sheet that can be used for this specific protocol and presented
to the patient.

A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Any participant who has ingested grapefruit juice within three days of commencing therapy.