Navitoclax and Vistusertib in Treating Patients With Relapsed Small Cell Lung Cancer and Other Solid Tumors

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of the combination of navitoclax and vistusertib
in patients with advanced solid tumors. (Phase I) II. To determine the maximum tolerated dose
(MTD), dose limiting toxicities (DLT), and recommended phase 2 doses (RP2D) of navitoclax and
vistusertib. (Phase I) III. To determine the objective response rate (ORR), defined as
complete plus partial response, of the combination of navitoclax and vistusertib in patients
with recurrent small cell lung cancer (SCLC). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of navitoclax and vistusertib when administered together.
(Phase I) II. To observe and record anti-tumor activity. (Phase I) III. To confirm the safety
and tolerability of navitoclax and vistusertib at the RP2D. (Phase II) IV. To estimate
progression free survival (PFS) and overall survival (OS) of the combination of navitoclax
and vistusertib at the RP2D. (Phase II) V. To estimate disease control rate (DCR) of the
combination of navitoclax and vistusertib at the RP2D. (Phase II)

TERTIARY OBJECTIVES:

I. To assess pharmacodynamic changes in levels of phosphorylated 4EBP1 (p4EBP1) the ratio of
p4EBP1 to total (p4EBP1/4EBP1) in paired pre-treatment and on-treatment biopsies at the RP2D.
(Phase II) II. To correlate changes in BAX and MCL-1 with response. (Phase II) III. To
estimate the baseline inter-patient variability in p4EBP1, pS6, BAX, and MCL-1. (Phase II)
IV. To explore exposure-response relationships between navitoclax and vistusertib exposure
and the pharmacodynamic endpoints (safety, efficacy, and laboratory correlatives). (Phase II)

OUTLINE: This is a phase I, dose-escalation study of navitoclax followed by a phase II study.

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

After completion of study treatment, patients are followed up for 30 days and then every 12
weeks.

Inclusion Criteria:

- PHASE 1 SPECIFIC ELIGIBILITY CRITERIA

- 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

- PHASE 2 SPECIFIC ELIGIBILITY CRITERIA

- Patients must have histologically or cytologically confirmed small cell lung cancer
whose disease has relapsed or progressed after >= 1 prior therapy, one of which must
have been a platinum doublet; pathology confirmation must be done at Sidney Kimmel
Comprehensive Cancer Center (SKCCC) or at the local participating site

- 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 (>= 2 cm) by chest
x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance
imaging (MRI), or calipers by clinical exam

- Subjects must be willing to undergo 2 sets of core needle biopsies (pre-treatment and
on-treatment), if there are lesions amenable to biopsy; an optional core biopsy will
be requested at progression

- GENERAL ELIGIBILITY CRITERIA

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Life expectancy of greater than 12 weeks

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Hemoglobin >= 9.0 g/dL

- Platelets >= 100,000/mcL

- Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper
limit of normal (ULN)

- Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome may have serum
bilirubin > 1.5 ULN)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN if no demonstrable liver metastases or =< 5 x ULN in the
presence of liver metastases

- Creatinine =< 1.5 x ULN and concurrent creatinine clearance (CrCl) >= 50 mL/min/1.73
m^2 for patients with creatinine (Cr) > 1.5 x ULN

- Proteinuria < 1+ on dipstick testing (if 2+ seen on first test, retest >= 24 hours
later)

- Patients with a history of central nervous system (CNS) metastases must have
documentation of stable or improved status based on brain imaging for at least 2 weeks
after completion of definitive treatment and within 2 weeks prior to first dose of
study drug, off or on a stable dose of corticosteroids

- Patients must have completed chemotherapy, biological or radiotherapy >= 3 weeks prior
to entering the study

- Patients must have recovered to =< grade 1 adverse events or to =< grade 2 alopecia
and sensory neuropathy due to prior treatment

- Patients must be able to understand and the willingness to sign a written informed
consent document

- Patients must be able to swallow pills

- Women of child-bearing potential and men must agree to use adequate contraception
prior to study entry, for the duration of study participation, and up to 90 days
following completion of therapy; for women this should include one highly effective
method of contraception and one barrier method as defined below

- Highly effective methods include:

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

- Vasectomized partner;

- Medroxyprogesterone acetate depot injection;

- Placement of a copper-banded intrauterine device (IUD) or intrauterine
system (IUS);

- Bilateral tubal ligation;

- Barrier methods include:

- Condom;

- Occlusive cap (e.g. diaphragm or cervical/vault caps) with spermicide

- Please note: use of other oral, injected or implanted hormonal methods of
contraception cannot be considered highly effective as it is currently unknown
whether vistusertib may reduce their effectiveness; periodic abstinence, the
rhythm method, and the withdrawal method are not acceptable methods of
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 90 days following completion of therapy

- Women of childbearing potential must have a negative urine 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; 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 for 90 days after
completion of navitoclax and/or vistusertib administration

Exclusion Criteria:

- PHASE 2 SPECIFIC EXCLUSION CRITERIA

- Prior treatment with a TORC1, dual TORC1/2 inhibitor, or BCL-2/xL inhibitor

- Patients with active malignancies other than SCLC or patients with prior curatively
treated malignancy at high risk of relapse during the study period with the exception
of localized squamous or basal cell skin cancers

- PHASE 1 AND GENERAL EXCLUSION CRITERIA

- Major surgery within 21 days of starting protocol treatment

- Patients who are receiving any other investigational agents

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

- Patients receiving anticoagulation or anti-platelet therapy are excluded due to the
risk of thrombocytopenia with navitoclax

- Excluded agents include heparin or low molecular weight heparin, warfarin,
clopidogrel, ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDS),
tirofiban, and other anticoagulants, drugs, or herbal supplements that affect
platelet function

- Administration of heparin to keep subject's infusion lines patent is allowed;
low-dose anticoagulation medications that are used to maintain the patency of a
central intravenous catheter are allowed

- 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 once daily [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

- Patients with an underlying condition predisposing them to bleeding or currently
exhibiting signs of clinically significant bleeding

- Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated
bleeding within 1 year prior to the first dose of study drug

- Patients with a significant history of cardiovascular disease or procedures within the
preceding 6 months (e.g., myocardial infarction [MI], coronary artery bypass graft
placement, angioplasty, vascular stent, angina pectoris, ventricular arrhythmias
requiring continuous therapy, congestive heart failure New York Heart Association
[NYHA] grade >= 2, thrombotic or thromboembolic event)

- Any of the following cardiac criteria:

- Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470
msec obtained from 3 electrocardiograms

- Congenital or family history of long or short QT syndrome, Brugada syndrome,
known history of QTc prolongation or torsades de pointes within 12 months of
entering the study

- Abnormal echocardiogram at baseline (left ventricular ejection fraction [LVEF] <
40% and shortening fraction [SF] < 15%)

- Drugs which have an increased risk for QTc prolongation should be avoided

- Patients with uncontrolled type 1 or type 2 diabetes; patients with an elevated risk
of hyperglycemia should be excluded from study

- Patients currently receiving medications or herbal supplements of the classes below
are ineligible; patients are eligible if they stop use of these compounds at least 1
week prior to receiving any treatment on this protocol

- Potent inhibitors or inducers of CYP3A4 /5 (CYP3A4 inhibitors such as
ketoconazole and clarithromycin are not allowed 7 days prior to the first dose of
navitoclax and during navitoclax administration)

- Strong or moderate inhibitors of Pgp or BRCP1

- Sensitive substrates of CYP2C9 (i.e. phenytoin and warfarin)

- Substrates of certain drug transporters (OATP1B1, OATP1B3, MATE1 or MATE2K)

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with navitoclax and vistusertib

- Patients positive for human immunodeficiency virus (HIV) are not excluded from this
study, but HIV-positive patients must have:

- A stable regimen of highly active anti-retroviral therapy (HAART) that does not
include strong or moderate CYP3A4 inducers or inhibitors

- No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections

- A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
polymerase chain reaction (PCR)-based test

- Any hematopoietic growth factors (e.g., filgrastim [granulocyte colony-stimulating
factor; G-CSF], sargramostim [granulocyte-macrophage colony-stimulating factor;
GM-CSF]) within 14 days prior to receiving study treatment

- 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

- Patients who have received a live, attenuated vaccines within 4 weeks of first dose of
drug