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