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

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.