Study of Seribantumab in Adult Patients With NRG1 Gene Fusion Positive Advanced Solid Tumors

Study Overview
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Brief Summary
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This study is an open-label, international, multi-center, Phase 2 study in adult patients with recurrent, locally-advanced or metastatic solid tumors, which harbor the NRG1 gene fusion.

Official Title
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CRESTONE: A Phase 2 Study of Seribantumab in Adult Patients With Neuregulin-1 (NRG1) Fusion Positive Locally Advanced or Metastatic Solid Tumors

Conditions
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Locally Advanced Solid Tumor, Metastatic Solid Tumor, Pancreatic Cancer, Lung Cancer, Head and Neck Cancer, Breast Cancer, Kidney Cancer, Colorectal Cancer, Bladder Cancer, Ovarian Cancer, Sarcoma, Gallbladder Cancer, Bile Duct Cancer, Esophageal Cancer, Uterine Cancer, Cholangiocarcinoma, Prostate Cancer

Intervention / Treatment
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* Drug: Seribantumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for participation in the study, patients must meet the following inclusion criteria: Locally-advanced or metastatic solid tumor with an NRG1 gene fusion identified through molecular assays, such as PCR, NGS (RNA or DNA) or FISH, by a CLIA-certified or similarly accredited laboratory Availability of fresh or archived FFPE tumor sample to be submitted to a central laboratory for confirmation of NRG1 gene fusion status Patients should have received a minimum of one prior standard therapy appropriate for their tumor type and stage of disease, progressed or been nonresponsive to these available therapies, with no further available curative therapy options ≥ 18 years of age ECOG performance status (PS) 0, 1 or 2 Patients must have at least one measurable extra-cranial lesion as defined by RECIST v1.1 Adequate hepatic function defined as: Serum AST and serum ALT < 2.5 × upper limit of normal (ULN), or AST and ALT < 5 × ULN if liver function abnormalities due to underlying malignancy Total bilirubin < 2.0 ULN. Subjects with a known history of Gilberts Disease and an isolated elevation of indirect bilirubin are eligible Adequate hematologic status, defined as: Absolute neutrophil count (ANC) ≥1.5 × 109/L not requiring growth factor support for at least 7 days prior to Screening, and Platelet count ≥100.0×109/L not requiring transfusion support for at least 7 days prior to Screening Able to provide informed consent or have a legal representative able and willing to do so Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following study completion; this may include barrier methods such as condom or diaphragm with spermicidal gel. Exclusion Criteria: Known, actionable oncogenic driver mutation other than NRG1 fusion where available standard therapy is indicated Life expectancy < 3 months Pregnant or lactating Prior treatment with ERBB3/HER3 directed therapy (Cohort 1 only) Prior treatment with pan-ERBB or any ERBB/HER2/HER3 directed therapy (Cohort 1 only) Symptomatic or untreated brain metastases (Note: Patients with asymptomatic brain metastases treated with radiation or surgery and without evidence of progression by imaging at screening are eligible to participate in the study. Patients requiring ongoing corticosteroids to treat brain metastases will not be eligible). Received other investigational agent or anticancer therapy within 28 days prior to planned start of seribantumab or 5 half-lives, whichever is shorter Prior to initiation of seribantumab treatment, patients must have recovered from clinically significant toxicities from prior anticancer or investigational therapy Any other active malignancy requiring systemic therapy Known hypersensitivity to any of the components of seribantumab or previous CTCAE grade 3 or higher hypersensitivity reactions to fully human monoclonal antibodies Clinically significant cardiac disease, including symptomatic congestive heart failure, unstable angina, acute myocardial infarction within 12 months of planned first dose, or unstable cardiac arrhythmia requiring therapy (including torsades de pointes) Active uncontrolled systemic bacterial, viral, or fungal infection Patients who are not appropriate candidates for participation in this clinical study for any other reason as deemed by the investigator

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>A minimum of 55 adult advanced solid tumor patients harboring NRG1 gene fusions, who have received prior standard treatment, excluding prior ERBB-directed therapy. Seribantumab 1-h IV infusion at various doses once weekly, every 2 weeks and every 3 weeks, during the induction, consolidation and maintenance dosing phases, respectively. | Drug: Seribantumab<br>* Anti-HER3 monoclonal antibody<br>|
| Experimental: Cohort 2<br>Up to 10 adult advanced solid tumor patients harboring NRG1 gene fusions, who have received prior standard treatment, including prior ERBB-directed therapy. Seribantumab 1-h IV infusion at various doses once weekly, every 2 weeks and every 3 weeks, during the induction, consolidation and maintenance dosing phases, respectively. | Drug: Seribantumab<br>* Anti-HER3 monoclonal antibody<br>|
| Experimental: Cohort 3<br>Up to 10 adult advanced solid tumor patients harboring NRG1 gene fusions lacking an EGF-like domain, who have received prior standard treatment, which may have included prior ERBB-directed therapy. Seribantumab 1-h IV infusion at various doses once weekly, every 2 weeks and every 3 weeks, during the induction, consolidation and maintenance dosing phases, respectively. | Drug: Seribantumab<br>* Anti-HER3 monoclonal antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | The primary objective of this study is to determine the overall objective response rate (ORR) by independent radiologic review to single agent seribantumab in patients with NRG1 gene fusion positive advanced cancer according to RECIST 1.1 | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NRG1, Neuregulin 1, Gene fusion