Neratinib and Everolimus, Palbociclib, or Trametinib in Treating Participants With Refractory and Advanced or Metastatic Solid Tumors With EGFR Mutation/Amplification, HER2 Mutation/Amplification, or HER3/4 Mutation or KRAS Mutation

Summary

Participation Requirements

Description

PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of neratinib when combined with one of the following agents: Ia. Arm 1: Everolimus (mTOR inhibitor) Ib. Arm 2: Palbociclib (CDK 4/6 inhibitor) Ic. Arm 3: Trametinib (MEK inhibitor). II. To determine the maximum tolerated dose (MTD) and d...

PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of neratinib when combined with one of the following agents: Ia. Arm 1: Everolimus (mTOR inhibitor) Ib. Arm 2: Palbociclib (CDK 4/6 inhibitor) Ic. Arm 3: Trametinib (MEK inhibitor). II. To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of neratinib combination therapy. SECONDARY OBJECTIVES: I. To determine preliminary anti-tumor efficacy of neratinib combination therapy. II. To determine pharmacodynamic markers in tissue, blood and plasma that may predict outcome. III. To explore the potential of drug-drug interactions by evaluating the pharmacokinetic profile of each agent when administered in these combinations: neratinib+everolimus, neratinib+palbocclib, and neratinib+trametinib and blood-based biomarkers. EXPLORATORY OBJECTIVES: I. To determine baseline molecular markers (deoxyribonucleic acid [DNA], ribonucleic acid [RNA] and protein) that may predict clinical benefit. II. To determine concordance of human epidermal growth factor receptor mutation (EGFR, HER2, HER3, and HER4) or EGFR, HER2 amplification in archival tissue and pre-treatment biopsies. Impact of these correlatives on response will be explored. III. To determine concordance of human epidermal growth factor receptor mutation (EGFR, HER2, HER3, and HER4) or EGFR, HER2 amplification in tumor and cell-free DNA (cfDNA). Impact of these correlatives on response will be explored. IV. To utilize cfDNA from plasma specimens collected during the course of treatment to explore mechanisms of primary and acquired resistance to neratinib combination therapy. OUTLINE: This is a dose-escalation study. Participants are assigned to 1 of 3 arms. ARM I: Participants receive neratinib orally (PO) daily and everolimus PO daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM II: Participants receive neratinib PO daily and palbociclib PO daily for 3 weeks followed by 1 week off. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM III: Participants receive neratinib PO daily and trametinib PO daily as directed. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up at 30 days.

Tracking Information