Derazantinib Alone or in Combination With Paclitaxel, Ramucirumab or Atezolizumab in Gastric Adenocarcinoma (FIDES-03)

• ClinicalTrials.gov Identifier: NCT04604132
• Recruitment Status: Terminated
• First Posted: October 27, 2020
• Last Update Posted: February 16, 2023
• Sponsor: Basilea Pharmaceutica
• Information provided by (Responsible Party): Basilea Pharmaceutica

Tracking Information

• First Submitted Date: October 21, 2020
• First Posted Date: October 27, 2020
• Last Update Posted Date: February 16, 2023
• Actual Study Start Date: October 6, 2020
• Actual Primary Completion Date: December 29, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 13, 2021)

• Objective response rate (ORR) per RECIST 1.1 in Substudy 1 (in two subgroups Cohort 1.1 and 1.2) and Substudy 3) [ Time Frame: Approximately 30 months ]
  ORR will be measured by the proportion of patients with confirmed complete response (CR) or partial response (PR) by blinded independent central review (BICR).
• 4-month progression-free survival rate (PFS4, in a subgroup (Cohort 1.3) within Substudy 1) [ Time Frame: Approximately 18 months ]
  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
• Recommended phase 2 dose (RP2D) of derazantinib-paclitaxel-ramucirumab in combination (Substudy 2) [ Time Frame: Approximately 18 months ]
  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.

Original Primary Outcome Measures (submitted: October 21, 2020)

• Overall response rate (ORR) per RECIST 1.1 (Substudies 1 and 3) [ Time Frame: Approximately 30 months ]
  ORR of will be measured by the proportion of patients with confirmed complete response (CR) or partial response (PR) by blinded independent central review (BICR).
• Recommended phase 2 dose (RP2D) of derazantinib-paclitaxel-ramucirumab in combination (Substudy 2) [ Time Frame: Approximately 8 months ]
  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.

Current Secondary Outcome Measures (submitted: December 13, 2021)

• ORR per RECIST 1.1 in subgroup Cohort 1.3 within Substudy 1and in Substudy 3 [ Time Frame: Approximately 24 months ]
  ORR will be measured by the proportion of patients with confirmed complete response (CR) or partial response (PR) by blinded independent central review (BICR).
• Disease Control Rate (DCR) [ Time Frame: Approximately 24 months ]
  Measured by the proportion of patients with confirmed CR, PR or stable disease (SD) by BICR
• Duration of Response (DOR) [ Time Frame: Approximately 24 months ]
  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)
• Progression-free Survival (PFS) [ Time Frame: Approximately 24 months ]
  PFS will be measured from patient enrollment to progressive disease (PD) date by BICR
• Overall Survival (OS) [ Time Frame: Approximately 24 months ]
  OS will be measured from patient enrollment to time of death
• Pharmacokinetic (PK) profile: Peak Plasma Concentration (Cmax) of derazantinib 200 mg twice daily monotherapy [ Time Frame: Approximately 24 months ]
  Derazantinib plasma concentrations including Cmax will be assessed by measurements in plasma samples
• Pharmacokinetic (PK) profile: Area under the plasma concentration versus time curve (AUC) of derazantinib 200 mg twice daily monotherapy [ Time Frame: Approximately 24 months ]
  AUC will be assessed by measurements of derazantinib in plasma samples
• Pharmacokinetic (PK) profile: The time to reach Cmax (Tmax) of derazantinib 200 mg twice daily monotherapy [ Time Frame: Approximately 24 months ]
  Tmax will be assessed by measurements of derazantinib in plasma samples

Original Secondary Outcome Measures (submitted: October 21, 2020)

• Progression-free Survival (PFS) [ Time Frame: Approximately 2 years ]
  PFS will be measured from patient enrollment to progressive disease (PD) date by BICR
• Disease Control Rate (DCR) [ Time Frame: Approximately 2 years ]
  Measured by the proportion of patients with confirmed CR, PR or stable disease (SD) by BICR
• Duration of Response (DOR) [ Time Frame: Approximately 2 years ]
  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)
• Overall Survival (OS) [ Time Frame: Approximately 2 years ]
  OS will be measured from patient enrollment to time of death

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Derazantinib Alone or in Combination With Paclitaxel, Ramucirumab or Atezolizumab in Gastric Adenocarcinoma
• Official Title: 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
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Gastric Adenocarcinoma

Intervention

• Drug: Derazantinib
  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.
• Drug: Derazantinib-paclitaxel-ramucirumab

  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.

• Drug: Derazantinib-atezolizumab

  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.

• Drug: Paclitaxel-ramucirumab

  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.

Study Arms

• Experimental: Derazantinib
  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.
  Intervention: Drug: Derazantinib
• Experimental: Derazantinib-paclitaxel-ramucirumab
  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.
  Intervention: Drug: Derazantinib-paclitaxel-ramucirumab
• Experimental: Derazantinib-atezolizumab
  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.
  Intervention: Drug: Derazantinib-atezolizumab
• Active Comparator: Standard of care
  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.
  Intervention: Drug: Paclitaxel-ramucirumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 8, 2022): 47
• Original Estimated Enrollment (submitted: October 21, 2020): 254
• Actual Study Completion Date: December 29, 2022
• Actual Primary Completion Date: December 29, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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:

  1. One chemotherapy or biological (e.g., antibody) cycle interval
  2. Five half-lives of any small molecule investigational or licensed medicinal product
  3. Two weeks, for any investigational medicinal product with an unknown half-life
  4. Four weeks of curative radiotherapy
  5. 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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Chile, France, Germany, Italy, Korea, Republic of, Poland, Russian Federation, Spain, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04604132
• Other Study ID Numbers: DZB-CS-202
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Basilea Pharmaceutica
• Original Responsible Party: Same as current
• Current Study Sponsor: Basilea Pharmaceutica
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Manuel Häckl, MD; Basilea Pharmaceutica International Ltd

• PRS Account: Basilea Pharmaceutica
• Verification Date: February 2023