Palbociclib With Cisplatin or Carboplatin in Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. Assess the safety and tolerability of palbociclib when administered along with cisplatin
or carboplatin.

II. Establish the recommended phase 2 dose (RP2D) of the tested combinations.

SECONDARY OBJECTIVES:

I. Characterize the pharmacokinetic (PK) profiles of cisplatin, carboplatin.

II. Obtain preliminary evidence of anti-tumor efficacy of the tested combination regimens.

III. Conduct PK/pharmacodynamics (PD) correlative analyses using palbociclib trough
concentration and cyclin-dependent kinase 4 (CDK4) inhibition read-outs in tumor and
surrogate samples collected on course 1 day 22 (C1D22).

IV. Assess potential association between tissue-based biomarkers and efficacy.

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

ARM A: Patients receive cisplatin intravenously (IV) over 30-60 minutes on day 1 and
palbociclib orally (PO) once daily (QD) on days 2-22. Treatment repeats every 28 days for up
to 6 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive carboplatin IV over 30-60 minutes on day 1 and palbociclib PO QD on
days 2-22. Treatment repeats every 28 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity.

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

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed solid organ malignancy

- Patients enrolled in the expansion cohort must have histologically or cytologically
confirmed squamous non-small cell lung cancer (NSCLC), breast or pancreaticobiliary
tract cancer

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

- 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) with
conventional techniques or as ≥ 10 mm (≥ 1 cm) with spiral computed tomography (CT)
scan, magnetic resonance imaging (MRI), or calipers by clinical exam

- Leukocytes ≥ 3,000/mL

- Absolute neutrophil count ≥ 1,500/mL

- Platelets ≥ 100,000/mL

- Hemoglobin ≥ 10 g/dL

- Total bilirubin ≤ 1.5 × institutional upper limit of normal (except for patients with
Gilbert disease)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 ×
institutional upper limit of normal (up to 5 X upper limit of normal [ULN] for
patients with liver metastasis)

- Creatinine within normal institutional limits OR creatinine clearance ≥ 60 mL/min/1.73
m² for patients with creatinine levels above institutional normal

- 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 for 6 months after completion of study drug administration

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

Exclusion Criteria:

- Patients who have had cytotoxic anticancer chemotherapy or immune checkpoint inhibitor
within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or palliative radiation
within 2 weeks (stereotactic radiation therapy [SRS] for brain metastasis within 48
hours) prior to entering the study or those who have not recovered from adverse events
due to agents administered more than 4 weeks earlier

- Patients receiving cytotoxic agent as immunomodulatory therapy for a non neoplastic
indication (e.g. methotrexate for rheumatoid arthritis) and who are unable to
discontinue such agents within 2 weeks prior to starting treatment

- Oral targeted therapy within five days or five half-lives, whichever is longer, prior
to initiating protocol therapy treatment

- Patients who are receiving any other investigational agents

- Use of strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors and inducers

- Patients with symptomatic uncontrolled brain metastases are excluded; (patients with
stable treated or asymptomatic untreated brain metastasis not requiring
glucocorticoids are allowed)

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to palbociclib, carboplatin or cisplatin

- Concurrent administration of strong inducers and inhibitors of CYP3A enzyme or CYP3A
substrates with narrow therapeutic window

- Uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection requiring intravenous antibiotics at the time of
treatment initiation

- Symptomatic congestive heart failure (requiring hospital stay within the last 6
months)

- Myocardial infarction within the last 6 months

- Unstable angina pectoris, cardiac arrhythmia

- Psychiatric illness

- Social situations or circumstances that would limit compliance with study requirements

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

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible