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

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

The purpose of this study was to evaluate the efficacy of derazantinib monotherapy or derazantinib in combination with paclitaxel and ramucirumab in patients with gastric adenocarcinoma (GAC) i.e. with human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the stomach or gastro-esophageal junction harboring fibroblast growth factor receptor 2 (FGFR2) genetic aberrations (GA).

Study Overview

• Status: Terminated
• Conditions: Gastric Adenocarcinoma
• Intervention / Treatment: Drug: Derazantinib; Drug: Derazantinib; Drug: Derazantinib; Drug: Derazantinib-paclitaxel-ramucirumab combination; Drug: Derazantinib-paclitaxel-ramucirumab combination

Detailed Description

The study comprised two 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.

In Substudy 1, GAC patients with specified FGFR GAs, after either first- or second-line treatment, and no approved treatment alternative were treated with derazantinib 300 mg once daily or 200 mg twice daily, with the aim of evaluating the safety, tolerability, and efficacy of derazantinib monotherapy in this patient population.

In Substudy 2, GAC patients with specified FGFR GAs after standard first-line treatment, were treated with a derazantinib-paclitaxel-ramucirumab combination with the aim of evaluating the safety, tolerability, and efficacy of the combination therapy and determining the recommended phase 2 dose (RP2D).

The study originally planned to include three substudies but was prematurely terminated for administrative reasons before the third substudy (including combination therapy with derazantinib plus atezolizumab) was initiated.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Argentina
  • Ciudad Autonoma Buenos Aires, Argentina, B1264AAA
    • Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo
  • Ciudad Autonoma de Buenos Aires, Argentina, C1093AAS
    • Fundación favaloro para la Docencia e Investigación Médica
• Australia
  • Clayton, Australia, 3168
    • Monash Medical Centre Clayton
  • Melbourne, Australia, 3000
    • Peter MacCallum Cancer Centre
  • Prahran, Australia, 3181
    • The Alfred Hospital
• Belgium
  • Edegem, Belgium, 2650
    • UZA
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Menen, Belgium, 8930
    • AZ Delta
• Brazil
  • Jaú, Brazil, 17210-120
    • Fundação Doutor Amaral Carvalho
  • Rio De Janeiro, Brazil, 20230-230
    • Instituto Nacional de Cancer Jose Alencar Gomes da Silva
  • Santo André, Brazil, 09060-870
    • CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia
  • São José Do Rio Preto, Brazil, 15090-000
    • Fundação Faculdade Regional de Medicina de São José do Rio Preto
  • Rio Grande Do Norte
    • Natal, Rio Grande Do Norte, Brazil, 59075-740
      • Liga Norte-Rio-Grandense Contra O Câncer
• Chile
  • Santiago, Chile, 7500000
    • Centro de estudios clinicos SAGA
  • Temuco, Chile, 4810469
    • Instituto Clinico Oncologico
  • Region Met
    • Santiago, Region Met, Chile, 8331143
      • CeCim Biocinetic
• France
  • Avignon, France, 84918
    • Institut Sainte Catherine
  • Besancon, France, 25030
    • CHU Besancon - Hôpital Jean Minjoz
  • Dijon, France, 21079
    • Centre Georges François Leclerc
  • Paris, France, 75475
    • Hopital Saint-Louis
  • Paris, France, 75571
    • Hôpital Saint-Antoine
  • Villejuif, France, 94805
    • Institut Gustave Roussy
• Germany
  • Dresden, Germany, 01067
    • Staedtisches Klinikum Dresden Standort Dresden-Friedrichstadt
  • Frankfurt, Germany, 60488
    • Krankenhaus Nordwest GmbH
  • Mainz, Germany, 55131
    • Uniklinik Mainz
  • Baden Wuerttemberg
    • Ulm, Baden Wuerttemberg, Germany, 89081
      • Universitaetsklinikum Ulm
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hannover
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Universitaetsklinikum Carl Gustav Carus TU Dresden
• Italy
  • Bologna, Italy, 40138
    • Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi
  • Catanzaro, Italy, 88100
    • Azienda Ospedaliero Universitaria Mater Domini
  • Milano, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori
  • Milano, Italy, 20162
    • Azienda Socio Sanitaria Territoriale Niguarda (Grande Ospedale Metropolitano Niguarda)
  • Milano, Italy, 20141
    • IEO Istituto Europeo di Oncologia
  • Padova, Italy, 35128
    • Iov - Istituto Oncologico Veneto Irccs
  • Rozzano, Italy, 20089
    • Istituto Clinico Humanitas
  • Siena, Italy, 53100
    • A.O.U. Senese Policlinico Santa Maria alle Scotte
• Korea, Republic of
  • Goyang-si, Korea, Republic of, 10408
    • National Cancer Center
  • Hwasun, Korea, Republic of, 58128
    • Chonnam National University Hwasun Hospital
  • Seongnam, Korea, Republic of, 13620
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 06591
    • The Catholic University of Korea, Seoul St. Mary's Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Suwon, Korea, Republic of, 16499
    • Ajou University Hospital
• Poland
  • Skórzewo, Poland, 60-185
    • Examen sp. z o.o.
  • Warszawa, Poland, 02-781
    • Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy
  • Warszawa, Poland, 01-401
    • Centrum Zdrowia MDM
  • Łódź, Poland, 90-242
    • Centrum Terapii Wspolczesnej J.M. Jasnorzewska Sp. Komandytowo-Akcyjna
• Russian Federation
  • Kazan, Russian Federation, 420029
    • SAIH "Republican Clinical Oncological Dispensary of the Ministry of Healthcare of Republic Tatarstan
  • Moscow, Russian Federation, 115478
    • FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"
  • Moscow, Russian Federation, 121309
    • "VitaMed" LLC
  • Omsk, Russian Federation, 644013
    • BHI of Omsk region "Clinical Oncology Dispensary"
  • Pesochnyy, Russian Federation, 197758
    • FSBI "Clinical Research and Practical Center for specialized medical care (oncology)"
  • Saint Petersburg, Russian Federation, 197022
    • Pavlov First Saint Petersburg State Medical University
  • Saint Petersburg, Russian Federation, 197758
    • FBI "Scientific Research Institute of Oncology n. a. N. N. Petrov"
  • Tomsk, Russian Federation, 634045
    • Tomsk Research Instutite of Oncology
  • Ufa, Russian Federation, 450054
    • SBIH Republican Clinical Oncological Dispensary of the MoH of Republic Bashkortostan
• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Barcelona, Spain, 08036
    • Hospital Clínic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • L'Hospitalet de Llobregat, Spain, 08908
    • ICO l'Hospitalet - Hospital Duran i Reynals
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain, 28050
    • Centro Integral Oncologico Clara Campal
  • Madrid, Spain, 28033
    • Md Anderson Cancer Centre
  • Pamplona, Spain, 31008
    • Clinica Universidad de Navarra
• Turkey
  • Adana, Turkey, 01220
    • Baskent University Adana Application and Research Center
  • Ankara, Turkey, 06100
    • Hacettepe University Medical Faculty
  • Ankara, Turkey, 06800
    • Ankara City Hospital
  • Ankara, Turkey, 06105
    • Dr. Abdurrahman Yurtaslan Oncology Teaching and Research Hospital
  • Antalya, Turkey, 07058
    • Akdeniz University Medical Faculty
  • Istanbul, Turkey, 34854
    • Istanbul Medeniyet Uni Goztepe Training&Res Hosp
  • Istanbul, Turkey, 34098
    • Istanbul University Cerrahpasa - Cerrahpasa Medical Faculty
  • Kocaeli, Turkey, 41380
    • Kocaeli Universitesi Tip Fakultesi
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital
  • Dundee, United Kingdom, DD1 9SY
    • Ninewells Hospital
  • Glasgow, United Kingdom, G12 OYN
    • Beatson West of Scotland Cancer Centre
  • London, United Kingdom, W1T7HA
    • University College London Hospitals
  • Manchester, United Kingdom, M20 4BX
    • The Christie
  • Sutton, United Kingdom, SM2 5PT
    • Royal Marsden Hospital- Sutton
• United States
  • Florida
    • Orlando, Florida, United States, 32806
      • AdventHealth Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Main inclusion criteria

Patients meeting all of the inclusion criteria at screening were eligible for enrollment in the study, including:

1. Histologically-confirmed adenocarcinoma of the gastro-esophageal junction or stomach.
2. Negative HER2 status obtained from the most recent available tissue sample.

3. Inoperable recurrent, locally advanced adenocarcinoma or progressing stage IV adenocarcinoma of the gastro-esophageal junction or stomach, and prior anti-tumor treatment as specified for each Substudy. Patients were required to be staged as inoperable at the time of screening in order to avoid interference of any potentially planned surgery with RECIST requirements during the study:

   Substudy 1: Patients with radiographically documented disease progression after either standard first- or second-line treatment, and no approved and/or tolerable treatment alternative.

   Substudy 2: Patients with radiographically documented disease progression after standard first-line treatment, and per Investigator assessment considered suitable to tolerate the treatment regimen.

4. Eligible FGFRfus/amp/mt positive test result. For Substudy 1 Cohort 1.1, FGFR2fus/amp; for Cohort 1.2, FGFR1-3mt; for Cohort 1.3, FGFRfus/amp/mt. For Substudy 2, FGFRfus/amp/mt.
5. Measurable disease as defined by the Investigator using RECIST 1.1 criteria
6. Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1
7. Adequate organ functions as indicated by Screening visit laboratory values.

Main exclusion criteria

Patients meeting any of the following exclusion criteria at screening were not eligible to be enrolled in the study:

• Receipt of prior cancer treatment within specific interval periods.
• For patients enrolled in Substudy 1, prior treatment with FGFR inhibitors.

• For patients enrolled in Substudy 2, prior treatment with:

  • Taxanes within 6 months prior to randomization
  • FGFR inhibitors or pathway-targeting agents
  • Anti-VEGF(R) therapeutic antibody or pathway-targeting agents
• Concurrent evidence of clinically significant corneal or retinal disorder likely to increase the risk of eye toxicity, including but not limited to bullous/band keratopathy, keratoconjunctivitis (unless keratoconjunctivitis sicca), corneal abrasion (unless related to trauma), inflammation/ulceration, confirmed by ophthalmological examination.
• History of clinically significant cardiac disorders, including myocardial infarction, or New York Heart Association Class II to IV congestive heart failure, within 6 months of the first dose of study drug, and/or any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months of the first dose of study drug, and/or concurrent and clinically significant abnormalities on ECG at Screening, including QTcF > 450 ms for males or > 460 ms for females (mean values from triplicate ECGs).
• Any unresolved (at the time of Screening) clinically significant CTCAE Grade ≥ 2 toxicity (except for alopecia, Grade ≤ 2 platinum-therapy related neuropathy, or Grade ≤ 2 anemia from previous anti-tumor treatment and/or from medical/surgical procedures/interventions).
• Known central nervous system metastases.
• Severe bacterial, fungal, viral and/or parasitic infections on therapeutic oral or IV medication at the time of first dose of study drug administration.
• Significant gastrointestinal disorders that could interfere with the absorption, metabolism, or excretion of derazantinib.
• History of additional malignancy that was progressing or required active treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Substudy 1: Cohort 1.1 Derazantinib 300 mg once daily; Patients with FGFR2 fusions or amplifications were treated with 300 mg Derazantinib monotherapy once daily	Drug: Derazantinib; Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1 (Cohort 1.1).; Drug: Derazantinib; Derazantinib was administered orally at a dose of 200 mg twice daily as monotherapy in the Substudy 1 (Cohort 1.3).; Drug: Derazantinib; Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1 (Cohort 1.2).
Experimental: Substudy 1: Cohort 1.2 Derazantinib 300 mg once daily; Patients with FGFR1-3 mutations were treated with 300 mg Derazantinib monotherapy once daily	Drug: Derazantinib; Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1 (Cohort 1.1).; Drug: Derazantinib; Derazantinib was administered orally at a dose of 200 mg twice daily as monotherapy in the Substudy 1 (Cohort 1.3).; Drug: Derazantinib; Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1 (Cohort 1.2).
Experimental: Substudy 1: Cohort 1.3 Derazantinib 200 mg twice daily; Patients with FGFR fusions, amplifications or mutations were treated with 200 mg Derazantinib monotherapy twice daily	Drug: Derazantinib; Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1 (Cohort 1.1).; Drug: Derazantinib; Derazantinib was administered orally at a dose of 200 mg twice daily as monotherapy in the Substudy 1 (Cohort 1.3).; Drug: Derazantinib; Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1 (Cohort 1.2).
Experimental: Substudy 2: Derazantinib 200 mg once daily +Paclitaxel+ Ramucirumab; Patients with FGFR fusions, amplifications or mutations were treated with 200 mg Derazantinib once daily in combination with Paclitaxel and Ramucirumab	Drug: Derazantinib-paclitaxel-ramucirumab combination; Derazantinib was administered orally at a dose of 200 mg once daily in combination with paclitaxel and ramucirumab. Paclitaxel was 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 was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel.; Drug: Derazantinib-paclitaxel-ramucirumab combination; Derazantinib was administered orally at a dose of 300 mg once daily in combination with paclitaxel and ramucirumab. Paclitaxel was 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 was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel.
Experimental: Substudy 2: Derazantinib 300 mg once daily+Paclitaxel+ Ramucirumab; Patients with FGFR fusions, amplifications or mutations were treated with 300 mg Derazantinib once daily combination with Paclitaxel and Ramucirumab	Drug: Derazantinib-paclitaxel-ramucirumab combination; Derazantinib was administered orally at a dose of 200 mg once daily in combination with paclitaxel and ramucirumab. Paclitaxel was 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 was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel.; Drug: Derazantinib-paclitaxel-ramucirumab combination; Derazantinib was administered orally at a dose of 300 mg once daily in combination with paclitaxel and ramucirumab. Paclitaxel was 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 was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) in Substudy 1 (in Cohorts 1.1 and 1.2)	ORR was defined by the percentage of patients with confirmed complete response (CR, which means disappearance of all target lesions) or partial response (PR, which means >=30% decrease in the sum of the longest diameter of target lesions) by blinded independent central review (BICR) using the internationally recognized criteria for the radiological assessment in tumor response of solid tumors (RECIST 1.1). Overall Response (OR) = CR + PR. The patients in Cohort 1.1 had FGFR2 fusions or amplification gastric adenocarcinoma (GAC) and FGFR1-3 mutations GAC in Cohort 1.2.	From first dose and up to 18 months
Progression-free Survival at 4 Months (PFS4) in Substudy 1 in Cohort 1.3	PFS4 was defined by the percentage of patients alive and free of disease progression (defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions) by BICR per RECIST. 1.1. Patients in this Cohort had FGFR fusions, amplifications or mutations GAC	From first dose and up to 4 months
Recommended Phase 2 Dose (RP2D) in Substudy 2 (Derazantinib-paclitaxel-ramucirumab in Combination)	RP2D was 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 derazantinib-paclitaxel-ramucirumab combination in patients with FGFR fusions, amplifications or mutations GAC.	From first dose and up to 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR in Substudy 1 in Cohort 1.3	ORR was defined by the percentage of patients with CR or PR by BICR according to RECIST Version 1.1.	From first dose and up to 9 months
Disease Control Rate (DCR) in Substudy 1: Cohort 1.1, 1.2 and 1.3 and Combined Cohorts	Defined as the percentage of patients with confirmed CR, PR or stable disease (SD) by BICR per RECIST version 1.1.	From first dose and up to 18 months
PFS in Substudy 1 in Cohort 1.3	PFS was calculated from patient enrollment to progressive disease (PD) date by BICR per RECIST version 1.1	From first dose and up to 9 months
Overall Survival (OS) in Substudy 1 in Cohort 1.3	OS was measured from patient enrollment to time of death.	From first dose and up to 9 months
OS in Substudy 2	OS was measured from patient enrollment to time of death	From first dose and up to 15 months
ORR in Substudy 2	ORR was defined by the percentage of patients with CR or PR by BICR per RECIST version 1.1.	From first dose and up to 15 months
DCR in Substudy 2	Defined as the percentage of patients with confirmed CR, PR or SD by BICR per RECIST version 1.1.	From first dose and up to 15 months
DOR in Substudy 2 (Separate and Combined Cohorts)	DOR was calculated from the first date of documented tumor response to disease progression by BICR per RECIST version 1.1 (or death if no documentation of PD is obtained).	From first dose and up to 15 months
PFS in Substudy 2	PFS was calculated from patient enrollment to progressive disease (PD) date by BICR per RECIST version 1.1.	From first dose and up to 15 months
Number of Patients With at Least Grade 3 Treatment-emergent Adverse Events (TEAEs)	Number of patients experiencing TEAE of Grade 3 and above according to Common Terminology Criteria for Adverse Events (CTCAE). CTCAE are a set of criteria for the standardized classification of TEAEs of drugs used in cancer therapy. It uses a range of grades from 1 to 5 describing increasing levels of severity of the TEAEs.	TEAEs defined as AEs which were assessed per patient from the patient's first dose and until 90 days after the last dose, which corresponded up to 19 months

Collaborators and Investigators

• Sponsor: Basilea Pharmaceutica
• Investigators: Study Director: Manuel Häckl, MD, Basilea Pharmaceutica International Ltd, Allschwil

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2020
• Primary Completion (Actual): November 21, 2022
• Study Completion (Actual): November 21, 2022

Study Registration Dates

• First Submitted: October 21, 2020
• First Submitted That Met QC Criteria: October 21, 2020
• First Posted (Actual): October 27, 2020

Study Record Updates

• Last Update Posted (Actual): April 4, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: paclitaxel; gastric cancer; solid tumor; targeted therapy; atezolizumab; ramucirumab; Cyramza; Tecentriq; adenocarcinoma of the stomach or gastro-esophageal junction; FGFR genetic aberration; derazantinib; gastro-esophageal adenocarcinoma; fibroblast growth factor receptor
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Paclitaxel; Albumin-Bound Paclitaxel; Antibodies, Monoclonal; Ramucirumab
• Other Study ID Numbers: DZB-CS-202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No