Talazoparib, Carboplatin, and Paclitaxel in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of
talazoparib (BMN 673) seven day schedule in combination with carboplatin and paclitaxel.

II. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of
talazoparib (BMN 673) three day schedule in combination with carboplatin and paclitaxel.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity of talazoparib (BMN 673) in combination with
carboplatin and paclitaxel.

II. To determine whether the pharmacokinetic parameters of talazoparib (BMN 673) when given
in combination with carboplatin and paclitaxel correlate with thrombocytopenia.

III. To observe and record anti-tumor activity of talazoparib (BMN 673) alone after the
combination with carboplatin, paclitaxel and talazoparib (BMN 673).

IV. To observe the safety and tolerability of talazoparib (BMN 673) in combination with
paclitaxel and carboplatin and talazoparib (BMN 673) alone after the combination therapy.

EXPLORATORY OBJECTIVES:

I. To serially evaluate pharmacokinetic and pharmacodynamics parameters and use indirect
pharmacokinetic/pharmacodynamics models to correlate with tumor response and resistance to
the combination talazoparib (BMN 673), carboplatin, and paclitaxel therapy.

II. To explore mechanisms of resistance to the combination of talazoparib (BMN 673) with
carboplatin and paclitaxel.

OUTLINE: This is a dose-escalation study of talazoparib. Patients are assigned to 1 of 2
dosing schedules.

SCHEDULE A: Patients receive talazoparib orally (PO) once daily (QD) on days 1-7, paclitaxel
intravenously (IV) over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on
day 1. Treatment repeats every 21 days for 4-6 courses in the absence of disease progression
or unacceptable toxicity.

SCHEDULE B: Patients receive talazoparib PO QD on days 1-3, paclitaxel IV over 1 hour on days
1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days
for 4-6 courses in the absence of disease progression or unacceptable toxicity.

At any time after 4-6 courses of treatment, patients may continue combination study therapy
with talazoparib, carboplatin, and paclitaxel, talazoparib and carboplatin, talazoparib alone
(continuous dosing), or observation without therapy at the discretion of the treating
physician.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients must have histologically confirmed solid malignancy (excluding lymphoma) that
is metastatic or unresectable and for which standard curative measures do not exist or
are no longer effective, and for which: a) there is reasonable expectation of response
to the combination of carboplatin/paclitaxel OR b) BRCA 1/2 germline mutation is
present; due to the longstanding acceptance of BRCA 1 and 2 mutation testing through
Myriad, results from Myriad will be acceptable; if testing for BRCA 1 and 2 germline
mutations is done through another organization, a report from a genetics consult with
a qualified medical professional confirming that the laboratory results show a
recognized germline deleterious BRCA 1 or 2 mutation or rearrangement is required; if
the latter cannot be obtained, principal investigator (PI) or study chair review of
the lab results and confirmation of BRCA mutation or rearrangement will be required OR
c) BRCA 1/2 somatic mutation previously identified using a Clinical Laboratory
Improvement Amendments (CLIA) certified assay

- Patients must have measurable or evaluable disease, as defined by Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 12 weeks

- Absolute neutrophil count >= 1,500/mcL

- Hemoglobin >= 9 g/dL

- Platelets >= 150,000/mcL

- Total bilirubin =< 1.25 x institutional upper limit of normal (ULN), with the
exception of < 2.9 mg/dL for patients with Gilbert's disease

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x ULN; =< 5 x ULN in setting of metastatic liver disease

- Creatinine =< 1.5 x upper limit of normal OR creatinine clearance >= 50 mL/min

- Ability to take oral medications

- Patients with central nervous system (CNS) metastases must be stable after therapy for
CNS metastases (such as surgery, radiotherapy or stereotactic radiosurgery) for at
least 4 weeks and must be off steroid treatment for 2 weeks prior to study enrollment

- The effects of talazoparib (BMN 673) on the developing human fetus are unknown; for
this reason and because other therapeutic agents used in this trial are known to be
teratogenic, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation; 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 talazoparib (BMN
673) administration

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

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) or targeted therapies within 2 weeks prior to entering
the study or those who have not recovered (=< grade 1) from adverse events due to
agents administered with the exception of any grade of alopecia

- No prior carboplatin unless given in neoadjuvant/adjuvant setting for curative intent
and more than 6 months have elapsed since last carboplatin dose; in the case of
relapsed ovarian cancer, patients are eligible if more than 6 months have elapsed
since last carboplatin dose

- Patients who are receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to talazoparib (BMN 673) or other agents used in study

- Peripheral neuropathy of severity greater than grade 1

- The following medications are contraindicated or must be used with caution; because
the lists of these agents are constantly changing, it is important to regularly
consult a frequently-updated medical reference

- Contraindicated:

- Cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) strong and
moderate inhibitors

- CYP2C8 inducers

- Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) strong and
moderate inhibitors

- CYP3A4 inducers

- CYP3A4 sensitive substrates

- Exclusions: the following supportive care medications will be allowed will be
allowed as they are routinely administered with carboplatin and paclitaxel and
have no potential interaction with talazoparib (BMN 673): dexamethasone,
aprepitant, fosaprepitant, and ondansetron); oral pain medications such as
hydrocodone, oxycodone taken on an as needed basis are also permitted

- Transdermal products designed for systemic delivery must be assessed for
interaction potential; topical products not designed to provide systemic delivery
(including inhaled products, ophthalmologic products and transvaginal
preparations) do not need to be considered since they do not have appreciable
systemic absorption

- Other contraindicated medications (per above) are not allowed unless close
monitoring with labs or drug levels or by symptoms with subsequent dose
adjustments is feasible; patients taking these concurrent medications are
ineligible unless they can discontinue or switched to alternative medications
prior to initiation of the study drug (at least 5 half-lives)

- Use with caution:

- CYP2C8 sensitive substrates

- CYP2C8 weak inhibitors

- CYP3A4 non-sensitive substrates

- CYP3A4 weak inhibitors

- These agents may be permitted if discontinuation is not feasible and no
acceptable alternatives are available as determined by the treating physician;
however, caution should be used; consider monitoring with labs or drug levels or
by symptoms and consider dose adjustments of the medication

- 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

- Pregnant women are excluded from this study because talazoparib (BMN 673) is a PARP
inhibitor with the potential for 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 talazoparib (BMN 673), breastfeeding should be
discontinued if the mother is treated with talazoparib (BMN 673); these potential
risks may also apply to other agents used in this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for interactions with study treatment;
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

- No clinically significant bleeding (i.e. gastrointestinal [GI] bleed, intracranial
bleeding) within 6 months or major surgery within 4 weeks; minor surgeries (i.e. port
placement, cataract surgery) are allowed within 2 weeks

- Anticoagulation and anti-platelet therapies are not permitted (this includes coumadin,
low molecular weight heparins, factor Xa inhibitors, aspirin and non-steroidal
anti-inflammatory drug [NSAIDS] or other medicines with similar effects)