Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors

PRIMARY OBJECTIVES:

I. To determine the dose-limiting toxicities of trametinib in combination with navitoclax,
and the maximal doses at which both drugs can be safely administered together. (Phase Ib) II.
To determine the response rate of the combination of trametinib and navitoclax in subjects
with KRAS or NRAS mutation-positive advanced or metastatic solid tumors in disease-specific
expansion cohorts. (Phase II) III. To confirm the safety and tolerability of trametinib and
navitoclax in combination at the recommended phase 2 dose (RP2D) determined in the Phase 1b
portion. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetics of both drugs administered together. (Phase Ib) II. To
assess for evidence of response to therapy. (Phase Ib) III. To evaluate the pharmacodynamic
response to therapy in tumor biopsies. (Phase Ib) IV. To evaluate the pharmacodynamic
response to therapy in tumor biopsies (first 15 patients enrolled overall). (Phase II)

OUTLINE: This is a phase Ib, dose-escalation study followed by a phase II study.

Patients receive trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
If unacceptable toxicity is observed, patients may receive trametinib PO QD on days 1-14.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients must have histologically- or cytologically-confirmed diagnosis of KRAS or
NRAS mutation-positive malignancy that is metastatic or unresectable and for which
standard curative measures do not exist or are no longer effective; patients must have
activating mutations affecting codons 12, 13, 61, or 146 as determined in a Clinical
Laboratory Improvement Amendments (CLIA)-certified lab to be eligible for this study

- Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST), 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 by chest x-ray or as >= 10 mm with computed tomography
(CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam

- Participants must have received at least one line of prior systemic chemotherapy and
must have experienced documented radiographic progression or intolerance on this
therapy

- Paired pre-treatment and post-treatment biopsies are required for all patients on Part
1 and first 15 patients in Part 2; participants must have available archival tumor
tissue (at least 20 unstained slides); if archival tissue is not available or is found
not to contain tumor tissue, a fresh biopsy is required; if a patient is having a
tumor biopsy, less than 20 unstained slides are acceptable with approval of the
principal investigator (PI); biopsies will only be performed in a given patient if
they are not deemed to involve unacceptable risk based on the sites of disease and
other concurrent medical conditions

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Life expectancy of greater than 3 months

- Able to swallow and retain orally-administered medication and does not have any
clinically significant gastrointestinal abnormalities that may alter absorption such
as malabsorption syndrome or major resection of the stomach or bowels

- All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
Events version 4 (CTCAE v 4) grade =< 1 (except alopecia) at the time of enrollment;
this requirement to return to =< grade 1 does not apply to immune checkpoint inhibitor
related endocrinopathies (e.g. thyroiditis, hypophysitis, etc.) that necessitate
hormone replacement therapy including, but not limited to levothyroxine, cortisol, and
testosterone; CTCAE v5.0 will be utilized beginning April 1, 2018

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count (ANC) >= 1,200/mcL (subjects may be treated with
hematopoietic growth factors to achieve or maintain this level)

- Hemoglobin >= 9 g/dL

- Platelets >= 100 x 10^9/L

- Albumin >= 2.5 g/dL

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (patients with
Gilbert's syndrome may have serum bilirubin > 1.5 × ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
institutional ULN

- Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault
formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min

- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
time (PTT) =< 1.2 x institutional ULN

- Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by
echocardiogram (ECHO) or multi gated acquisition scan (MUGA)

- Women of child-bearing potential and men with a female partner of child bearing
potential must agree to use adequate contraception using one of the methods listed
below prior to study entry, for the duration of study participation, and up to 4
months following completion of therapy:

- Total abstinence from sexual intercourse (minimum one complete menstrual cycle
prior to study drug administration)

- Vasectomized male subject or vasectomized partner of female subjects

- Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at
least 3 months prior to study drug administration; if the subject is currently
using a hormonal contraceptive, she should also use a barrier method during this
study and for 1 month after study completion

- Intrauterine device (IUD)

- Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide
(contraceptive sponge, jellies or creams)

- Men with a female partner of childbearing potential must have either had a prior
vasectomy or agree to use effective contraception; additionally, male subjects
(including those who are vasectomized) whose partners are pregnant or might be
pregnant must agree to use condoms for the duration of the study and for 4 months
following completion of therapy

- Women of childbearing potential must have a negative serum pregnancy test within 7
days prior to initiation of treatment; women will be considered not of childbearing
potential if they are surgically sterile (bilateral oophorectomy or hysterectomy)
and/or post-menopausal (amenorrheic for at least 12 months); 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; the potential hazard to
the fetus should be explained to the patient and partner (as applicable)

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

Exclusion Criteria:

- 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 or
any carcinoma in situ and/or patients with indolent second malignancies, are eligible;
consult the Cancer Therapy Evaluation Program (CTEP) medical monitor if unsure whether
second malignancies meet the requirements

- History of interstitial lung disease or pneumonitis

- Any major surgery, extensive radiotherapy (> 15 days of treatment), chemotherapy with
delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to first
dose of study treatment and/or daily or weekly chemotherapy without the potential for
delayed toxicity within 14 days prior to first dose of study treatment

- Use of 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 drug(s) and during the study

- Patients with known brain metastases should be excluded from this clinical trial;
exception: patients with brain metastases will be allowed on study if they have
clinically controlled neurologic symptoms, defined as surgical excision and/or
radiation therapy followed by 21 days of stable neurologic function and no evidence of
central nervous system (CNS) disease progression as determined by computed tomography
(CT) or magnetic resonance imaging (MRI) within 21 days prior to the first dose of
study drug

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO), or to
compounds of similar chemical or biologic composition to navitoclax

- 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

- 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)

- The following concomitant medications are not allowed during navitoclax
administration: warfarin, clopidogrel (Plavix), ibuprofen, tirofiban (Aggrastat),
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

- Caution should be exercised when dosing navitoclax concurrently with cytochrome P450,
family 2, subfamily C, polypeptide 8 (CYP2C8) and cytochrome P450, family 2, subfamily
C, polypeptide 9 (CYP2C9) substrates; common CYP2C8 substrates include paclitaxel,
statins, and glitazones, whereas CYP2C9 substrates include phenytoin and warfarin;
when possible, investigators should switch to alternative medications or monitor the
patients closely (particularly in the case of medications that have a narrow
therapeutic window such as warfarin; use of warfarin is specifically prohibited while
on study); 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; 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; patient
instructions and information of possible drug interactions will be given to all
patients upon enrollment in this study

- History or current evidence/risk of retinal vein occlusion (RVO)

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

- Left ventricle ejection fraction (LVEF) < LLN

- 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
enrollment 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

- Known cardiac metastases

- Patients with intra-cardiac defibrillators

- Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with
chronic or cleared HBV and HCV infection are eligible); patients with human
immunodeficiency virus (HIV) are not eligible if on anti-retroviral medications

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- 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., myocardial
infarction [MI], thrombotic or thromboembolic event in the last 6 months)

- Pregnant women or nursing mothers