0C-14-2: An Open-Label, Phase 2 Study of Neratinib in Patients with Solid Tumors with Somatic Human Epidermal Growth Factor Receptor (Egfr, Her2, Her3) Mutations or EGFR Gene Amplification
DescriptionThis is an open-label, non-randomized, multicenter, multinational, Phase 2 study exploring the efficacy and safety of neratinib as monotherapy or in combination with other therapies in patients with ERBB mutation-positive or EGFR gene amplified solid tumors. Neratinib (PB-272) is a small molecule that inhibits EGFR, HER2, and HER4. Aberrant expression of EGFR, HER2, and HER3 are linked to development of many epithelial cancers including colorectal, gastric, breast and head and neck cancers. Preclinical data suggest that neratinib will have antitumor activity in EGFR- and/or HER2-expressing carcinoma cell lines. The study will include the following cohorts of patients with tumors harboring somatic ERBB (EGFR, ERBB2, ERBB3) mutations or EGFR gene amplification. 1. Bladder/Urinary Tract ERBB2 Mutant - Neratinib 240mg daily + Paclitaxel 80mg/m^2 IV on Days 1, 8, and 15 of every 4 week cycle 2. Biliary Tract ERBB2 mutant HR Negative- Neratinib 240mg daily 3.Breast a. ERBB2 mutant HR Negative - Neratinib 240mg daily b. ERBB2 mutant HR Positive - Neratinib 240mg daily + Fulvestrant 500mg on Days 1, 15 of the first month, then Day 1 of every 4 week cycle 4. Endometrial ERBB2 mutant - Neratinib 240mg daily 5. Gastroesophageal ERBB2 mutant - Neratinib 240mg daily 6. Ovarian ERBB2 mutant - Neratinib 240mg daily 7. Solid tumors (NOS) ERBB2 Mutant - Neratinib 240 mg daily *Cohorts given combination therapy are "Combination Therapy" and all cohorts given Neratinib alone are labeled "Monotherapy." The following cohorts have closed to accrual: 1. EGFR mutation and/or EGFR amplification Primary brain tumors Cohort: Primary brain tumors (glioblastoma multiforme [GBM] Grade III, glioma, gliosarcoma) Closed to Accrual The trial will consist of a screening period, a treatment period, safety follow-up and end of treatment (EOT) assessments, follow-up for disease progression every 8 weeks, and a survival follow-up period. Treatment will consist of neratinib by mouth with food once daily in the morning administered on a continuous basis or combination therapy as listed above. The primary endpoint of this study for all cohorts is to determine the objective response rate at 8 weeks (ORR8) following treatment with neratinib. The secondary objectives of this study are: To determine the confirmed objective response rate (ORR) according to RECIST v1.1 or other defined response criteria with neratinib monotherapy and combination therapy. To determine the clinical benefit rate (CBR) of neratinib monotherapy and combination therapy. To determine PFS. To determine change in tumor growth rate for patients with primary brain tumors. To determine the duration of response (DOR) of neratinib monotherapy and combination therapy, defined as the time from which measurement criteria are met for overall response of CR and PR until the first date of documented disease progression. To determine overall survival (OS). To determine the role of dual modality PET/CT scans in measuring metabolic response to neratinib monotherapy and combination therapy. To assess the safety profile and tolerability of neratinib monotherapy and combination therapy. To assess Patient Reported Outcomes using the EuroQol EQ-5D-5L instrument. A Simon 2-stage optimal design will be used to determine whether neratinib has sufficient activity to warrant further development in the following cohorts: colorectal, endometrial, gastroesophageal, ovarian, and listed breast cancers. At the end of the trial, a 2-sided 80% confidence interval for Objective Response Rate will be determined for each cohort separately using the method of Koyama and Chen (2008). Patient-related outcomes (EQ-5D-5L instrument) will be summarized and plotted over time. Changes from baseline will be provided with both point estimates and confidence intervals. All analyses are descriptive and no formal testing is planned.
PhasePhase 2 - takes the treatment one step further, assessing the activity of a particular therapy in a disease, often building upon leads from the Phase I trial. While patients are generally required to be previously untreated, participation in a Phase II trial doesn't usually preclude the patient from getting the standard treatment after they've received the investigational agent. At best they are allowed to get a new drug they wouldn't be able to get otherwise that may turn out to be better for their disease.
Inclusion and Exclusion Criteria
- Histologically confirmed cancers for which no curative therapy exists.
- Documented HER2 mutation.
- Prior treatment with any pan-HER TKI (eg, lapatinib, afatinib, dacomitinib, neratinib).
- Patients who are receiving any other anticancer agents.
- Symptomatic or unstable brain metastases.
- Women who are pregnant or breast-feeding. Note: There are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria.
- UCLA, Los Angeles, California, 90095
- MD Anderson Cancer Center, Houston, Texas, 77030
- Washington University, St. Louis, Missouri, 63110
- Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, 37232
- Oncologia Medica-Istituti Ospitalieri di Cremona, Cremona, 90095