Cabozantinib and Pamiparib for the Treatment of Advanced of Refractory Solid Tumors

Description

PRIMARY OBJECTIVES:

I. To define the maximum tolerated dose (MTD) or maximum administered dose (MAD) and dose-limiting toxic effects (DLTs) of cabozantinib and pamiparib.

II. To define the safety profiles of cabozantinib and pamiparib.

SECONDARY OBJECTIVES:

I. To perform plasma pharmacokinetic analyses of cabozantinib and pamiparib interaction.

II. To evaluate patient reported outcomes (PRO). III. To evaluate pre-identified mutations in circulating free deoxyribonucleic acid (DNA) (cfDNA) by next generation sequencing (NGS).

IV. To estimate complete responses (CRs), partial responses (PRs), stable disease >= 6 months (SD >= 6months), progression free survival (PFS) and overall survival (OS).

V. To relate changes in phosphorylated AKT (pAKT), phosphorylated ERK2 (pERK2), phosphorylated c-MET (pc-MET), phosphorylated PARP1 (PARP1-pY907), phosphorylated histone H2A variant H2AX (gamma-H2AX) and RAD51 in tumor specimens with antitumor efficacy.

VI. To relate cancer-associated mutations at baseline with antitumor efficacy. VII. To explore potential biomarkers of acquired resistance by comparing molecular signatures at baseline with those at time of relapse in patients in whom SD >= 6 months/CR/PR or a mixed response are documented, by next-generation deep sequencing or more sophisticated techniques.

OUTLINE: This is a dose-escalation study.

Patients receive cabozantinib orally (PO) once daily (QD) and pamiparib PO twice daily (BID). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 6 months.