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

NCT03065387 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 2016-0430NCI-2018-01218
• Study Type: interventional
• Target: 93
• Locations: 1 country
• Sites: 1

Brief 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.

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

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose (MTD) of neratinib when given in combination with everolimus, palbociclib, or trametinib

  Defined by dose-limiting toxicity (DLT). The MTD will be defined as the highest dose at which no more than 1 of 6 evaluable subjects has had a DLT.

  Up to 28 days

Secondary Outcomes (3)

• Incidence of adverse events of neratinib when given in combination with everolimus, palbociclib, or trametinib

  Up to 30 days post last dose

• Objective response

  Up to 5 years

• Determination of pharmacodynamics markers in tissue, blood, and plasma

  Up to completion of treatment

Study Arms (3)

Arm I (neratinib, everolimus)

EXPERIMENTAL

Participants receive neratinib PO daily and everolimus PO daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Everolimus; Drug: Neratinib

Arm II (neratinib, palbociclib)

EXPERIMENTAL

Participants receive Neratinib PO daily for 28 days and Palbociclib PO daily for 21 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Neratinib; Drug: Palbociclib

Arm III (neratinib, trametinib)

EXPERIMENTAL

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.

Drug: Neratinib; Drug: Trametinib

Interventions

Everolimus DRUG

Given PO

Also known as: 42-O-(2-Hydroxy)ethyl Rapamycin, Afinitor, Certican, RAD 001, RAD001, Votubia, Zortress

Arm I (neratinib, everolimus)

Neratinib DRUG

Given PO

Also known as: (2E)-N-(4-((3-chloro-4-((pyridin-2-yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide, HKI 272, HKI-272, PB 272, PB-272

Arm I (neratinib, everolimus); Arm II (neratinib, palbociclib); Arm III (neratinib, trametinib)

Palbociclib DRUG

Given PO

Also known as: 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-8h-pyrido(2,3-d)pyrimidin-7-one, Ibrance, PD 0332991, PD 332991, PD 991, PD-0332991

Arm II (neratinib, palbociclib)

Trametinib DRUG

Given PO

Also known as: GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist

Arm III (neratinib, trametinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects with advanced or metastatic solid tumors that are refractory to standard therapies known to provide clinical benefit. Subjects with hematologic malignancy including lymphoma/myeloma will not be enrolled on this study.
• Subjects must have one of the following:
• somatic mutations in human epidermal growth factor receptor (EGFR, HER2, HER3, and HER4)
• EGFR gene amplification (patients with 3+ results on immunohistochemistry testing for EGFR may be allowed to enroll if gene amplification results are unavailable)
• HER2 gene amplification (patients with 3+ results on immunohistochemistry testing for Her-2 may be allowed to enroll if gene amplification results are unavailable)
• Somatic mutation in KRAS (Patients will be enrolled only on neratinib and trametinib combination ARM).
• Subjects must have measurable disease by RECIST v1.1. (only for MTD Expansion Cohorts)
• Subjects must be ≥18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
• Abnormal organ function is permitted. However, subjects must have:
• absolute neutrophil count ≥ 1500/mL
• platelets ≥ 100,000/mL
• hemoglobin ≥ 9 g/dL
• creatinine ≤ 1.5 X upper limit of normal (ULN) or CrCl \>40 ml/min
• total bilirubin ≤ 1.5 X ULN

You may not qualify if:

• Subjects who are pregnant or breastfeeding;
• Known Hepatitis B, Hepatitis C or human immunodeficiency virus (HIV) infection.
• Inability or unwillingness to swallow pills.
• Active infection requiring intravenous (IV) antibiotics or other uncontrolled intercurrent illness requiring hospitalization.
• Clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. For example, subjects should have no more than 50% of the large intestine removed and no sign of malabsorption (e.g. gastrectomy, ileal bypass, chronic diarrhea, Crohn's disease, malabsorption, gastroparesis).
• Inability to comply with the study and follow-up procedures.
• History of cerebrovascular accident (CVA), myocardial infarction or unstable angina within the previous 6 months before starting therapy.
• Prolongation of QT/QTc interval (QTc interval \>450 ms for males or \>470 ms for females) using the Fredericia method of QTc analysis. For patients with bundle branch block (BBB), the Rautaharju method of QTc analysis (QTcR) will be used.
• Has active primary brain tumor, active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks with no neurological symptoms, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless or clinical stability.
• Uncontrolled concurrent disease or illness including but not limited to:
• symptomatic congestive heart failure (NYHA Class III or IV) per the NYHA Classification (see Appendix B), unstable angina pectoris, clinically significant cardiac arrhythmia
• unstable or untreated cardiac conditions or ejection fraction of \<50% as determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)
• diabetes mellitus (i.e. fasting blood glucose \>220 despite acceptable chronic diabetes therapy)
• psychiatric illness that would limit compliance with study requirements, as determined by the investigator
• Participating in any other clinical trials using an investigational product. Only for subjects enrolled in Arm 1 - Neratinib and Everolimus

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Piha-Paul SA, Tseng C, Tran HT, Gao M, Karp DD, Subbiah V, Tsimberidou AM, Kawedia JD, Fu S, Pant S, Yap TA, Morris VK, Kee BK, Blum Murphy M, Lim J, Meric-Bernstam F. A phase I trial of the pan-ERBB inhibitor neratinib combined with the MEK inhibitor trametinib in patients with advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation. Cancer Chemother Pharmacol. 2023 Aug;92(2):107-118. doi: 10.1007/s00280-023-04545-4. Epub 2023 Jun 14.

  PMID: 37314501 DERIVED

Related Links

• MD Anderson Cancer Center

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

Everolimus; neratinib; palbociclib; trametinib

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Study Officials

• Sarina A Piha-Paul

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 22, 2017
• First Posted: February 27, 2017
• Study Start: October 31, 2017
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 1, 2028
• Last Updated: January 12, 2026

Record last verified: 2026-01

Locations

US (1)