Testing the Use of Neratinib or the Combination of Neratinib and Palbociclib Targeted Treatment for HER2+ Solid Tumors (A ComboMATCH Treatment Trial)

Malignant Solid Neoplasm Clinical Trial

Official title:

A Randomized Trial of Neratinib, A Pan-ERBB Inhibitor, Alone or in Combination With Palbociclib, a CDK4/6 Inhibitor, in Patients With HER2+ Gynecologic Cancers and Other Solid Tumors: A ComboMATCH Treatment Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06126276
• Other study ID #: NCI-2023-09270
• Secondary ID: NCI-2023-09270EA
• Status: Recruiting
• Phase: Phase 2
• Start date: May 7, 2024
• Est. completion date: April 30, 2025

Study information

• Verified date: May 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II ComboMATCH treatment trial compares the effect of neratinib to the combination of neratinib and palbociclib in treating patients with HER2 positive solid tumors. Neratinib and palbociclib are in a class of medications called kinase inhibitors. They work by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of tumor cells. Giving neratinib and palbociclib in combination may shrink or stabilize cancers that over-express a specific biomarker called HER2.

Description:

PRIMARY OBJECTIVE:

I. To investigate the efficacy of neratinib plus palbociclib (PD-0332991) compared to neratinib maleate (neratinib) alone in patients with HER2+ gynecologic cancers and HER2+ solid tumors by evaluating progression-free survival (PFS).

SECONDARY OBJECTIVES:

I. To investigate outcome in terms of objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

II. To investigate clinical benefit rate (ORR + stable disease at 16 weeks). III. To evaluate overall (OS) survival. IV. To evaluate the ORR of patients who crossed over from neratinib monotherapy to neratinib-palbociclib combination.

V. To investigate adverse events especially grade 3 and 4 toxicities by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.

VI. Collect tissue and provide it to the ComboMATCH Registration Protocol to assess concordance between the diagnostic tumor mutation profile generated by the Designated Laboratories, the pre-treatment biopsy mutation profile, and the pre-treatment circulating tumor-derived deoxyribonucleic acid (ctDNA) mutation profile from plasma, as described in ComboMATCH Registration Protocol.

EXPLORATORY TRANSLATIONAL OBJECTIVES:

I. To investigate the role of ctDNA-HER2 status at baseline and during follow up to assess if it predicts response to therapy and disease progression and if it does correlate with tumor tissue based HER2 status.

II. To investigate if activation of the pathways of interest (PI3K/mTOR and RB1, CCND1-CDK4/6 CDK and RAS/RAF/MAPK) in tumor tissue as well as blood/ctDNA correlate with response or resistance to therapy.

III. To correlate extent of HER2 amplification with response to treatment and with HER2 expression by immunohistochemistry or fluorescence in situ hybridization (FISH).

IV. To correlate the extent of HER2 amplification with HER2 expression by RNA and protein immunohistochemistry (IHC) analyses and FISH.

V. To correlate expression of Rb1, CCND1, CCNE1, CDK4/6 protein expression with response to treatment.

VI. Assess alteration in RB1-CDK pathway in neratinib resistant patients at time of progression on monotherapy compared to combination neratinib-palbociclib.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive neratinib maleate orally (PO) once daily (QD) on days 1-14 of cycle 0 in the absence of disease progression or unacceptable toxicity. Patients then receive neratinib maleate PO QD on days 1-28 of each subsequent cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience progression may crossover to Arm II. Patients undergo echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) during screening and on study, and computed tomography (CT) or magnetic resonance imaging (MRI) and collection of blood samples throughout the trial. Patients may also undergo tumor biopsy during screening and on study.

ARM II: Patients receive neratinib maleate PO QD on days 1-14 of cycle 0 in the absence of disease progression or unacceptable toxicity. Patients then receive neratinib maleate PO QD on days 1-28 and palbociclib PO QD on days 1-21 of each subsequent cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening and on study, and CT or MRI and collection of blood samples throughout the trial. Patients may also undergo tumor biopsy during screening and on study.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 70
• Est. completion date: April 30, 2025
• Est. primary completion date: April 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patient must have enrolled onto EAY191 and must have been given a treatment assignment to ComboMATCH to EAY191-N5 based on the presence of an actionable mutation as defined in EAY191

• Patients must have a HER2 amplified solid tumor except breast cancer. Patient's cancer must have HER2 amplification as defined with = 7 copies by next generation sequencing (NGS) testing

• Patients must have recurrent or persistent disease

• No known evidence of RB1 loss or deletion including copy number loss or deleterious mutation

• Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy or, if disease cannot be safely biopsied, have archival tissue available from within 12 months prior to the date of registration on the ComboMATCH Registration Trial (EAY191)

• Patients must have measurable disease based on RECIST 1.1. A second measurable lesion outside of the biopsiable lesion is required

• Patients with treated brain metastases are eligible if follow up brain imaging after central nervous system (CNS) directed therapy shows no evidence of progression for 3 months or more and patient is not on steroids and is asymptomatic

• No known leptomeningeal disease

• Patients may have received up to 5 prior lines of systemic therapy

• Prior therapy with trastuzumab or pertuzumab, either alone or in combination, is allowed

• One prior line of anti-HER2 therapy is allowed except tyrosine kinase inhibitors (TKI) such as neratinib or tucatinib or antibody drug conjugates (ADC) such as DS8201a or T-DM1

• No prior therapy with CDK4/6 inhibition

• No cancer directed therapy within 3 weeks prior to registration. For oral therapy, the washout can be reduced to greater than or equal to 5 half lives of the drug

• Age = 18

• Eastern Cooperative Oncology Group (ECOG) Performance Status of = 2

• Not pregnant and not nursing

• Absolute neutrophil count (ANC) = 1,500 cells/mm^3

• Platelets = 100,000 cells/mm^3

• Hemoglobin = 9 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin (Hgb) = 9 g/dl is acceptable)

• Creatinine clearance (CrCL) of = 30 mL/min by the Cockcroft-Gault formula

• Total bilirubin level = 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level = 3 x institutional ULN may be enrolled)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3 x institutional upper limit of normal (ULN)

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better

• No active infection requiring parenteral antibiotics

• No current evidence of intra-abdominal abscess, abdominal/pelvic fistula (not diverted), gastrointestinal perforation, gastrointestinal (GI) obstruction, and/or need for drainage nasogastric or gastrostomy tube

• No current evidence of malabsorption or chronic diarrhea or any other significant gastro-intestinal disease (e.g gastrectomy, ileal bypass, Crohn's disease, gastroparesis), associated with moderate to severe diarrhea (grade 2 or more) or inability to tolerate oral therapy

• No lung disease causing dyspnea at rest

• No interstitial lung disease with ongoing signs and symptoms at the time of registration

• No history of allergic reaction to the study agents, compound of similar chemical or biologic composition of the study agents or any of their excipients

Related Conditions & MeSH terms

• Genital Neoplasms, Female
• Malignant Female Reproductive System Neoplasm
• Malignant Solid Neoplasm
• Neoplasms
• Recurrence
• Recurrent Malignant Female Reproductive System Neoplasm
• Recurrent Malignant Solid Neoplasm

Intervention

Procedure:
• Biopsy
Undergo tumor biopsy
• Biospecimen Collection
Undergo collection of blood samples
• Computed Tomography
Undergo CT scan
• Echocardiography
Undergo ECHO
• Magnetic Resonance Imaging
Undergo MRI
• Multigated Acquisition Scan
Undergo MUGA

Drug:
• Neratinib Maleate
Given PO
• Palbociclib
Given PO

Locations

Country	Name	City	State
United States	UPMC Altoona	Altoona	Pennsylvania
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Mission Cancer and Blood - Ankeny	Ankeny	Iowa
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	Duluth Clinic Ashland	Ashland	Wisconsin
United States	National Institutes of Health Clinical Center	Bethesda	Maryland
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Bozeman Health Deaconess Hospital	Bozeman	Montana
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Miami Valley Hospital South	Centerville	Ohio
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	UPMC Western Maryland	Cumberland	Maryland
United States	Dayton Physician LLC - Englewood	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Premier Blood and Cancer Center	Dayton	Ohio
United States	Beaumont Hospital - Dearborn	Dearborn	Michigan
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Essentia Health - Deer River Clinic	Deer River	Minnesota
United States	Mission Cancer and Blood - Des Moines	Des Moines	Iowa
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Crossroads Cancer Center	Effingham	Illinois
United States	UPMC Hillman Cancer Center Erie	Erie	Pennsylvania
United States	Beaumont Hospital - Farmington Hills	Farmington Hills	Michigan
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Miami Valley Cancer Care and Infusion	Greenville	Ohio
United States	Essentia Health Hibbing Clinic	Hibbing	Minnesota
United States	M D Anderson Cancer Center	Houston	Texas
United States	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina
United States	Kettering Medical Center	Kettering	Ohio
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion	Mechanicsburg	Pennsylvania
United States	Community Medical Center	Missoula	Montana
United States	UPMC Hillman Cancer Center - Monroeville	Monroeville	Pennsylvania
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Saint Alphonsus Cancer Care Center-Ontario	Ontario	Oregon
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Kootenai Clinic Cancer Services - Sandpoint	Sandpoint	Idaho
United States	Essentia Health Sandstone	Sandstone	Minnesota
United States	Saint Vincent Hospital Cancer Center at Sheboygan	Sheboygan	Wisconsin
United States	Memorial Medical Center	Springfield	Illinois
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Saint Vincent Hospital Cancer Center at Sturgeon Bay	Sturgeon Bay	Wisconsin
United States	Upper Valley Medical Center	Troy	Ohio
United States	William Beaumont Hospital - Troy	Troy	Michigan
United States	Essentia Health Virginia Clinic	Virginia	Minnesota
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression free survival	The stratified log-rank statistic will be used to draw inferences about the relative activity of the two regimens. Characterized by medians and Kaplan-Meier (KM) curves.	From study entry to time of progression or death, whichever occurs first, or date of last contact if neither progression nor death has occurred, assessed up to 2 years
Secondary	Overall survival	The impact of treatment on the hazard of death can be investigated with time dependent covariates.	Up to 2 years