Navitoclax and Sorafenib Tosylate in Treating Patients With Relapsed or Refractory Solid Tumors

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of the combination of navitoclax and
sorafenib tosylate (sorafenib) in patients with advanced solid tumors. (Dose escalation
cohort) II. To better characterize the toxicity profile of the combination of navitoclax and
sorafenib. (Dose expansion cohort)

SECONDARY OBJECTIVES:

I. To identify any activity of this treatment combination in patients with metastatic cancer.
(Dose escalation cohort) II. To seek preliminary evidence of activity of this treatment
combination in patients with hepatoma. (Dose expansion cohort)

TERTIARY OBJECTIVES:

I. To determine whether the combination of navitoclax and sorafenib induces apoptosis that
can be detected by peripheral blood biomarker analysis. (Dose escalation cohort) II. To
assess peripheral blood biomarkers and pharmacokinetics in a more homogenous population.
(Dose expansion cohort) III. To determine whether treatment is associated with Mcl-1 down
regulation in hepatocellular carcinoma (HCC) at the maximum tolerated dose (MTD). (Dose
expansion cohort) IV. To assess in a preliminary fashion whether pretreatment tumor cell
levels of Mcl-1 predict response to this regimen through serial biopsies. (Dose expansion
cohort)

OUTLINE: This is a dose-escalation study of navitoclax.

Patients receive navitoclax orally (PO) once daily (QD) on days 1-21 (days 1-28 course of 1
only) and sorafenib tosylate PO twice daily (BID) on days 1-21. Courses repeat every 21 days
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

- For Dose Escalation Cohort: Patients must have histologically confirmed malignancy
that is metastatic or unresectable and for which standard curative or palliative
measures do not exist or are no longer effective

- For Dose Expansion Cohort: HCC patients only: HCC confirmed by biopsy OR diagnosed by
clinical and radiologic criteria; all of the following criteria must be met or a
biopsy is required:

- Known cirrhosis or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV)
infection

- Hypervascular liver masses > 2 cm, and either serum alpha-fetoprotein (AFP) > 400
ng/ml

- AFP > three times normal and doubling in value in the antecedent 3 months

- In the expansion cohort, prior treatment with sorafenib as first-line therapy
allowed

- Any number of the following prior therapies is allowed:

- Chemotherapy >= 28 days prior to registration

- Mitomycin C/nitrosoureas >= 42 days prior to registration

- Immunotherapy >= 28 days prior to registration

- Biologic therapy >= 28 days prior to registration

- Targeted therapy >= 28 days prior to registration

- Radiation therapy >= 28 days prior to registration

- Radiation to < 25% of bone marrow

- HCC patients only: prior regional treatments for liver metastasis are permitted
including:

- Selective internal radiation therapy such as brachytherapy, cyber knife,
radiolabeled microsphere embolization, etc.

- Hepatic artery chemoembolization

- Hepatic artery embolization

- Hepatic artery infusional chemotherapy

- Radiofrequency ablation

- NOTE: patients must be >= 4 weeks from treatment and show progressive
measurable/evaluable disease in the liver after regional therapy or must have
measurable disease outside the liver

- HCC patients only: Child Pugh class A or B7 liver disease

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Life expectancy of > 3 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL (patients may be treated with hematopoietic
growth factors to achieve or maintain this level)

- Hemoglobin >= 9.0 g/dL

- International normalized ratio (INR) =< 1.4

- Platelets >= 100,000/mm^3

- Total bilirubin =< 1.5 x ULN (institutional upper limit of normal) (patients with
Gilbert's syndrome may have direct bilirubin > 2.5 x ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN

- Serum creatinine =< 1.5 times the ULN

- Able to swallow and retain oral medication

- Negative serum pregnancy test =< 7 days prior to registration for women of
childbearing potential

- NOTE: 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)

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

- Willing to provide tissue samples for correlative research purposes

Exclusion Criteria:

- Unresolved toxicity of National Cancer Institute Common Terminology Criteria for
Adverse Events, version 4.0 (NCI CTCAE v 4.0) grade 2 or higher from previous
anti-cancer therapy, except alopecia

- Receiving any other investigational agents =< 28 days prior to registration

- Known brain metastases (even if treated)

- Known portal hypertension or history of variceal bleeding

- Inadequately controlled hypertension (systolic blood pressure of > 150 mmHg or
diastolic pressure > 90 mmHg on anti-hypertensive medications)

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to navitoclax or sorafenib

- Current use of anticoagulation; NOTE: use of low-dose anticoagulation medications
(such as heparin) that are used to maintain the patency of a central intravenous
catheter is allowed

- Corrected QT (QTc) interval > 480 msec on baseline electrocardiogram (EKG)

- Documented history of prolonged QTc interval =< 6 months prior to registration

- Receiving any medications that prolong the QTc and have a known risk for Torsades de
pointes; providers should use caution with drugs with possible increased risk for
Torsades de pointes; NOTE: patient will be eligible if they can be taken off these
medications prior to initiation of therapy and no less than 4 half-lives of the
medication

- Current use of certain concomitant medications due to mechanistic-based platelet
toxicities from navitoclax: clopidogrel, ibuprofen, tirofiban and other
anticoagulants, drugs or herbal supplements that effect platelet function; NOTE:
antiplatelet use is prohibited during the use of navitoclax; 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 principal investigator in conjunction with
the medical monitor

- Current use of strong CYP3A inhibitors such as ketoconazole, itraconazole,
voriconazole, posaconazole, nefazodone, and clarithromycin are prohibited; NOTE:
moderate inhibitors of CYP3A4 should be used with caution; navitoclax is a moderate
inhibitor of CYP2C8 and a strong inhibitor of CYP2C9; caution should be exercised when
dosing navitoclax concurrently with CYP2C8 and CYP2C9 substrates; common CYP2C8
substrates include paclitaxel, statins and repaglinide; CYP2C9 substrates include
celecoxib, phenytoin and warfarin; when possible, investigators should switch to
alternative medications or monitor the patients closely

- Concurrent use of strong CYP3A4/5 inducers such as carbamazepine, phenytoin, rifampin,
and St. John's wort are prohibited

- 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

- Any of the following:

- Pregnant women

- Nursing women

- Women of childbearing potential who are unwilling to employ adequate
contraception; NOTE: 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; women of child-bearing potential and men 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 90 days
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)

- 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 90 days following completion of therapy

- Human immunodeficiency virus (HIV)-positive patients on highly active antiretroviral
therapy (HAART) are excluded

- Underlying condition predisposing them to bleeding or currently exhibits signs of
clinically significant bleeding

- Recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding =< 1
year prior to the registration

- History of cardiovascular disease (e.g., myocardial infraction [MI], thrombotic or
thromboembolic event in the last 6 months)