PARP Inhibitor BMN-673 and Temozolomide or Irinotecan Hydrochloride in Treating Patients With Locally Advanced or Metastatic Solid Tumors

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability and to estimate the maximum tolerated dose (MTD) of
the following combinations in participants with advanced solid tumors: Arm A: BMN 673 (PARP
inhibitor BMN-673) and temozolomide; Arm B: BMN 673 and irinotecan (irinotecan
hydrochloride).

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of BMN 673, temozolomide, and irinotecan when BMN 673 is
given in combination with temozolomide (Arm A) or irinotecan (Arm B). To assess the effects
of temozolomide and irinotecan in Arms A and B respectively on the pharmacokinetics of BMN
673.

II. To evaluate biomarkers that correlate with effect of BMN 673 in combination with
temozolomide or irinotecan.

III. To document any anti-tumor activity.

OUTLINE: This is a dose-escalation study of PARP inhibitor BMN-673. Patients are assigned to
1 of 2 treatment arms.

ARM A: Patients receive PARP inhibitor BMN-673 orally (PO) once daily (QD) on days 1-28 and
temozolomide PO daily on days1-5. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

ARM B: Patients receive PARP inhibitor BNM-673 as in Arm A and irinotecan hydrochloride
intravenously (IV) on days 1 and 15. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 12
months.

Inclusion Criteria:

- Histologically or cytologically documented, unresectable, locally advanced or
metastatic solid tumor for which no standard therapy is recognized or for which
standard therapy has failed

- Measurable disease as defined by Response Evaluation Criteria in Solid Tumors version
1.1 (RECIST, v1.1)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
upper limit of normal (ULN); if liver function abnormalities are due to hepatic
metastasis, then AST and ALT may be =< 5 x ULN

- Total serum bilirubin =< 1.5 x ULN

- Calculated creatinine clearance of >= 40 ml/min; as per Cockcroft-Gault formula

- Hemoglobin >= 9.0 g/dL

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelet count >= 100,000/mm^3

- Able to take oral medications

- Willing and able to provide written, signed informed consent after the nature of the
study has been explained, and prior to any research-related procedures

- Sexually active patients must be willing to use an acceptable method of contraception
such as double barrier contraception during treatment and for 30 days after the last
dose of BMN 673

- Females of childbearing potential must have a negative serum pregnancy test at
screening

Exclusion Criteria:

- Has not recovered (recovery is defined as National Cancer Institute [NCI] Common
Terminology Criteria for Adverse Events [CTCAE version (v)4.03] grade =< 1) from the
acute toxicities of previous therapy, except treatment-related alopecia or laboratory
abnormalities otherwise meeting the inclusion requirements stated in the inclusion
criterion

- Prior treatment with a PARP inhibitor

- Prior allergic reaction or severe intolerance to either irinotecan or temozolomide

- History of central nervous system (CNS) metastasis that are untreated or not stable

- Any antitumor systemic cytotoxic therapies within 28 days prior to enrollment (6 weeks
for nitrosoureas or mitomycin-C); prior high-dose chemotherapy with bone marrow or
stem cell transplant is excluded

- Is known to have human immunodeficiency virus (HIV) or has active hepatitis C virus
(HCV), or active hepatitis B virus (HBV)

- Has had major surgery within 28 days prior to enrollment

- Active gastrointestinal tract disease with malabsorption syndrome

- Requirement for IV alimentation

- Uncontrolled inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)

- Symptomatic congestive heart failure (New York Heart Association > class II), unstable
angina, or unstable cardiac arrhythmia requiring medication (atrial fibrillation is
permitted)

- Use of any investigational product or investigational medical device within 28 days
prior to enrollment

- Concurrent disease or condition that would interfere with study participation or
safety, such as:

- Active, clinically significant infection requiring the use of parenteral
anti-microbial agents, or grade > 2 by NCI CTCAE (v 4.03) within 14 days prior to
enrollment

- Clinically significant bleeding diathesis or coagulopathy, including known
platelet function disorders

- Non-healing wound, ulcer, or bone fracture

- Bone marrow disorder including myelodysplasia