NCT03065387

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

Phase I Study of the Pan-ERBB Inhibitor Neratinib Given in Combination With Everolimus, Palbociclib, or Trametinib in Advanced Cancer Subjects With EGFR Mutation/Amplification, HER2 Mutation/Amplification, or HER3/4 Mutation or KRAS Mutation

• Status: Active Not Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 93 (actual)
• Sponsor: M.D. Anderson Cancer Center · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This phase I trial studies the side effects and best dose of neratinib in combination with everolimus, palbociclib, or trametinib in participants with solid tumors with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation, or KRAS mutation that do not respond to treatment (refractory) and have spread to other parts of the body (advanced or metastatic). Neratinib, palbociclib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as everolimus, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving neratinib with everolimus, palbociclib, or trametinib may work better than neratinib alone in treating participants with solid tumors.

Detailed 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 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.

Conditions

• Advanced Malignant Solid Neoplasm
• EGFR Gene Amplification
• EGFR Gene Mutation
• ERBB2 Gene Amplification
• ERBB2 Gene Mutation
• ERBB3 Gene Mutation
• ERBB4 Gene Mutation
• KRAS Gene Mutation
• Metastatic Malignant Solid Neoplasm
• Refractory Malignant Solid Neoplasm

Interventions

Type	Name	Description
DRUG	Everolimus	Given PO
DRUG	Neratinib	Given PO
DRUG	Palbociclib	Given PO
DRUG	Trametinib	Given PO

Timeline

• Start date: 2017-10-31
• Primary completion: 2028-10-01
• Completion: 2028-10-01
• First posted: 2017-02-27
• Last updated: 2026-01-12

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study