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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Malignant Female Reproductive System Neoplasm, Malignant Solid Neoplasm, Recurrent Malignant Female Reproductive System Neoplasm, Recurrent Malignant Solid Neoplasm

Intervention / Treatment
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* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Procedure: Echocardiography
* Procedure: Magnetic Resonance Imaging
* Procedure: Multigated Acquisition Scan
* Drug: Neratinib Maleate
* Drug: Palbociclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be enrolled on the ComboMATCH Master Registration Trial 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (neratinib maleate)<br>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 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 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. | Procedure: Biopsy<br>* Undergo tumor biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Neratinib Maleate<br>* Given PO<br>* Other names: Nerlynx;|
| Experimental: Arm II (neratinib maleate, palbociclib)<br>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. | Procedure: Biopsy<br>* Undergo tumor biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Neratinib Maleate<br>* Given PO<br>* Other names: Nerlynx;Drug: Palbociclib<br>* Given PO<br>* Other names: PD-0332991;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The impact of treatment on the hazard of death can be investigated with time dependent covariates. | Up to 2 years |