Derazantinib Alone or in Combination With Paclitaxel, Ramucirumab or Atezolizumab in Gastric Adenocarcinoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of derazantinib monotherapy or derazantinib in combination with paclitaxel, ramucirumab, or atezolizumab in patients with HER2-negative adenocarcinoma of the stomach or gastro-esophageal junction harboring FGFR2 genetic aberrations (GA).

Detailed Description
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The study comprises three open-label substudies in patients with HER2-negative adenocarcinoma of the stomach or gastro-esophageal junction harboring FGFR2 gene translocations, FGFR2 gene amplifications, or FGFR1-3 mutations. Patients will be treated with single-agent derazantinib or derazantinib in combination with paclitaxel, ramucirumab, or atezolizumab. The study enrolls patients with either metastatic or recurrent locally advanced HER2-negative adenocarcinoma of the stomach or gastro-esophageal junction inoperable at the time of screening, and radiologically confirmed disease progression after one or at least one standard treatment regimen.

Official Title
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A Phase 1b/2 Study of Derazantinib as Monotherapy and Combination Therapy With Paclitaxel, Ramucirumab or Atezolizumab in Patients With HER2-negative Gastric Adenocarcinoma Expressing FGFR2 Genetic Aberrations

Conditions
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Gastric Adenocarcinoma

Intervention / Treatment
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* Drug: Derazantinib
* Drug: Derazantinib-paclitaxel-ramucirumab
* Drug: Derazantinib-atezolizumab
* Drug: Paclitaxel-ramucirumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically-confirmed adenocarcinoma of the gastro-esophageal junction or stomach Male or female aged ≥ 18 years Negative HER2 status obtained from the most recent available tissue sample Inoperable recurrent, locally advanced adenocarcinoma or progressing stage IV adenocarcinoma of the gastro-esophageal junction or stomach, and disease progression after either standard first- or second-line treatment (Substudy 1), or after standard first-line treatment (Substudies 2 and 3) Positive test for eligible FGFR aberrations (FGFR2 fusions / rearrangements / amplifications; FGFR1, FGFR2, or FGFR3 mutations / short variants) Measurable disease as defined by the Investigator using RECIST 1.1 criteria ECOG PS of 0 or 1 Men and women of childbearing potential must agree to avoid impregnating a partner or becoming pregnant, respectively, during the study, and for at least 150 days after the last dose of either investigational drug Key Exclusion Criteria: Prior anticancer or investigational drug treatment within an interval shorter than the following, as applicable: One chemotherapy or biological (e.g., antibody) cycle interval Five half-lives of any small molecule investigational or licensed medicinal product Two weeks, for any investigational medicinal product with an unknown half-life Four weeks of curative radiotherapy Seven days of palliative radiotherapy Prior treatment with FGFR Inhibitors (all substudies), and prior treatment with taxanes within 6 months prior to randomization and/or anti-VEGF(R) therapeutic antibody or pathway-targeting agents (Substudies 2 and 3), and prior treatment with anti-programmed cell death receptor-1 (PD-1) or anti-programmed death ligand-1 (PD-L1) therapeutic antibody or pathway-targeting agents (Substudy 3) Concurrent evidence of clinically significant corneal or retinal disorder History of clinically significant cardiac disorders and/or a QT interval corrected by Fridericia's formula (QTcF) > 450 ms for males or > 460 ms for females Known CNS metastases Concurrent uncontrolled or active infection with human immunodeficiency virus (HIV; known HIV 1/2 antibodies positive); active or chronic hepatitis B without current antiviral therapy and an HBV DNA ≥ 100 IU/mL virus (HBV); active hepatitis C virus (HCV) co-infection; active tuberculosis (for Substudies 2 and 3) Child-Pugh B or C liver cirrhosis, or a history of hepatic encephalopathy, hepatorenal syndrome, or clinically-meaningful ascites related to cirrhosis (for Substudies 2 and 3) Administration of a live, attenuated vaccine within 30 days prior to randomization (for Substudy 3) Treatment with systemic corticosteroids (except for steroidal replacement therapy) or other systemic immunosuppressive medications within 2 weeks prior to first dose of study drug or anticipated requirement for systemic immunosuppressive medications during the study (for Substudy 3)

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Derazantinib<br>In Substudies 1 and 3.1, patients with HER2-negative adenocarcinoma of the stomach or gastro-esophageal junction harboring FGFR genetic aberrations will receive derazantinib. | Drug: Derazantinib<br>* Derazantinib will be administered orally at a dose of 300 mg once a day and at a dose of 200 mg twice daily as monotherapy in the Substudy 1.<br>|
| Experimental: Derazantinib-paclitaxel-ramucirumab<br>In Substudies 2 and 3.2, patients with HER2-negative adenocarcinoma of the stomach or gastro-esophageal junction harboring FGFR genetic aberrations will receive derazantinib-paclitaxel-ramucirumab in combination. | Drug: Derazantinib-paclitaxel-ramucirumab<br>* Derazantinib will be administered at the RP2D for derazantinib-paclitaxel-ramucirumab determined in Substudy 2 in combination with paclitaxel and ramucirumab. Paclitaxel will be administered intravenously at the RP2D for derazantinib-paclitaxel-ramucirumab determined in Substudy 2 on days 1, 8, and 15 of a 28-day cycle in combination with derazantinib and ramucirumab. Ramucirumab will be administered intravenously at the RP2D for derazantinib-paclitaxel-ramucirumab determined in Substudy 2 every 2 weeks in combination with derazantinib and paclitaxel.<br>|
| Experimental: Derazantinib-atezolizumab<br>In Substudy 3.3, patients with HER2-negative adenocarcinoma of the stomach or gastro-esophageal junction harboring FGFR genetic aberrations will receive derazantinib-atezolizumab in combination. | Drug: Derazantinib-atezolizumab<br>* Derazantinib will be administered orally at a dose of 300 mg once a day in combination with atezolizumab. Atezolizumab will be administered intravenously at a dose of 1200 mg every 3 weeks in combination with derazantinib.<br>|
| Active Comparator: Standard of care<br>In Substudy 3.4, patients with HER2-negative adenocarcinoma of the stomach or gastro-esophageal junction harboring FGFR genetic aberrations will receive the Standard of Care drugs paclitaxel-ramucirumab in combination. | Drug: Paclitaxel-ramucirumab<br>* Paclitaxel will be administered intravenously at a dose of 80 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with ramucirumab. Ramucirumab will be administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) per RECIST 1.1 in Substudy 1 (in two subgroups Cohort 1.1 and 1.2) and Substudy 3) | ORR will be measured by the proportion of patients with confirmed complete response (CR) or partial response (PR) by blinded independent central review (BICR). | Approximately 30 months | 
| 4-month progression-free survival rate (PFS4, in a subgroup (Cohort 1.3) within Substudy 1) | PFS4 will be measured by the proportion of patients alive and free of disease progression by blinded independent central review (BICR) per RECIST. 1.1 | Approximately 18 months | 
| Recommended phase 2 dose (RP2D) of derazantinib-paclitaxel-ramucirumab in combination (Substudy 2) | RP2D will be determined from safety and tolerability according to the aggregate of dose-limiting toxicity criteria and adverse event (AE) data, and considering further pharmacokinetic and efficacy data of the combination. | Approximately 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR per RECIST 1.1 in subgroup Cohort 1.3 within Substudy 1and in Substudy 3 | ORR will be measured by the proportion of patients with confirmed complete response (CR) or partial response (PR) by blinded independent central review (BICR). | Approximately 24 months | 
| Disease Control Rate (DCR) | Measured by the proportion of patients with confirmed CR, PR or stable disease (SD) by BICR | Approximately 24 months | 
| Duration of Response (DOR) | DOR will be calculated from the first date of documented tumor response to disease progression by BICR (or death if no documentation of PD is obtained) | Approximately 24 months | 
| Progression-free Survival (PFS) | PFS will be measured from patient enrollment to progressive disease (PD) date by BICR | Approximately 24 months | 
| Overall Survival (OS) | OS will be measured from patient enrollment to time of death | Approximately 24 months | 
| Pharmacokinetic (PK) profile: Peak Plasma Concentration (Cmax) of derazantinib 200 mg twice daily monotherapy | Derazantinib plasma concentrations including Cmax will be assessed by measurements in plasma samples | Approximately 24 months | 
| Pharmacokinetic (PK) profile: Area under the plasma concentration versus time curve (AUC) of derazantinib 200 mg twice daily monotherapy | AUC will be assessed by measurements of derazantinib in plasma samples | Approximately 24 months | 
| Pharmacokinetic (PK) profile: The time to reach Cmax (Tmax) of derazantinib 200 mg twice daily monotherapy | Tmax will be assessed by measurements of derazantinib in plasma samples | Approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gastric cancer, gastro-esophageal adenocarcinoma, adenocarcinoma of the stomach or gastro-esophageal junction, fibroblast growth factor receptor, FGFR genetic aberration, targeted therapy, derazantinib, atezolizumab, Tecentriq, paclitaxel, ramucirumab, Cyramza, solid tumor