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

Gastric Adenocarcinoma Clinical Trial

— FIDES-03  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04604132
• Other study ID #: DZB-CS-202
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: October 6, 2020
• Est. completion date: November 21, 2022

Study information

• Verified date: March 2024
• Source: Basilea Pharmaceutica
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 47
• Est. completion date: November 21, 2022
• Est. primary completion date: November 21, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Adenocarcinoma
• Gastric Adenocarcinoma

Intervention

Drug:
• Derazantinib
Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1 (Cohort 1.1).
• 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.
• 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.
• Derazantinib
Derazantinib was administered orally at a dose of 200 mg twice daily as monotherapy in the Substudy 1 (Cohort 1.3).
• Derazantinib
Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1 (Cohort 1.2).

Locations

Country	Name	City	State
Argentina	Hospital de Gastroenterologia Dr. Carlos Bonorino Udaondo	Ciudad Autonoma Buenos Aires
Argentina	Fundación Favaloro para la Docencia e Investigación Médica	Ciudad Autonoma de Buenos Aires
Australia	Monash Medical Centre Clayton	Clayton
Australia	Peter MacCallum Cancer Centre	Melbourne
Australia	The Alfred Hospital	Prahran
Belgium	UZA	Edegem
Belgium	UZ Leuven	Leuven
Belgium	AZ Delta	Menen
Brazil	Fundação Doutor Amaral Carvalho	Jaú
Brazil	Liga Norte-Rio-Grandense Contra o Câncer	Natal	Rio Grande Do Norte
Brazil	Instituto Nacional de Câncer José Alencar Gomes da Silva	Rio De Janeiro
Brazil	CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia	Santo André
Brazil	Fundação Faculdade Regional de Medicina de São José do Rio Preto	São José Do Rio Preto
Chile	CeCim Biocinetic	Santiago	Region Met
Chile	Centro de Estudios Clínicos SAGA	Santiago
Chile	Instituto Clinico Oncologico	Temuco
France	Institut Sainte Catherine	Avignon
France	CHU Besançon - Hôpital Jean Minjoz	Besancon
France	Centre Georges François Leclerc	Dijon
France	Hôpital Saint-Antoine	Paris
France	Hôpital Saint-Louis	Paris
France	Institut Gustave Roussy	Villejuif
Germany	Staedtisches Klinikum Dresden Standort Dresden-Friedrichstadt	Dresden
Germany	Universitaetsklinikum Carl Gustav Carus TU Dresden	Dresden	Sachsen
Germany	Krankenhaus Nordwest GmbH	Frankfurt
Germany	Medizinische Hochschule Hannover	Hannover	Niedersachsen
Germany	Uniklinik Mainz	Mainz
Germany	Universitaetsklinikum Ulm	Ulm	Baden Wuerttemberg
Italy	Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi	Bologna
Italy	Azienda Ospedaliero Universitaria Mater Domini	Catanzaro
Italy	Azienda Socio Sanitaria Territoriale Niguarda (Grande Ospedale Metropolitano Niguarda)	Milano
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano
Italy	IEO Istituto Europeo di Oncologia	Milano
Italy	IOV - Istituto Oncologico Veneto IRCCS	Padova
Italy	Istituto Clinico Humanitas	Rozzano
Italy	A.O.U. Senese Policlinico Santa Maria alle Scotte	Siena
Korea, Republic of	National Cancer Center	Goyang-si
Korea, Republic of	Chonnam National University Hwasun Hospital	Hwasun
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Korea, Republic of	Ajou University Hospital	Suwon
Poland	Centrum Terapii Wspolczesnej J.M. Jasnorzewska sp. komandytowo-akcyjna	Lódz
Poland	Examen sp. z o.o.	Skórzewo
Poland	Centrum Zdrowia MDM	Warszawa
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy	Warszawa
Russian Federation	SAIH "Republican Clinical Oncological Dispensary of the Ministry of Healthcare of Republic Tatarstan	Kazan
Russian Federation	"VitaMed" LLC	Moscow
Russian Federation	FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"	Moscow
Russian Federation	BHI of Omsk region "Clinical Oncology Dispensary"	Omsk
Russian Federation	FSBI "Clinical Research and Practical Center for specialized medical care (oncology)"	Pesochnyy
Russian Federation	FBI "Scientific Research Institute of Oncology n. a. N. N. Petrov"	Saint Petersburg
Russian Federation	Pavlov First Saint Petersburg State Medical University	Saint Petersburg
Russian Federation	Tomsk Research Instutite of Oncology	Tomsk
Russian Federation	SBIH Republican Clinical Oncological Dispensary of the MoH of Republic Bashkortostan	Ufa
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	ICO l'Hospitalet - Hospital Duran i Reynals	L'Hospitalet de Llobregat
Spain	Centro Integral Oncologico Clara Campal	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	MD Anderson Cancer Centre	Madrid
Spain	Clinica Universidad de Navarra	Pamplona
Turkey	Baskent University Adana Application and Research Center	Adana
Turkey	Ankara City Hospital	Ankara
Turkey	Dr. Abdurrahman Yurtaslan Oncology Teaching and Research Hospital	Ankara
Turkey	Hacettepe University Medical Faculty	Ankara
Turkey	Akdeniz University Medical Faculty	Antalya
Turkey	Istanbul Medeniyet Uni Goztepe Training&Res Hosp	Istanbul
Turkey	Istanbul University Cerrahpasa - Cerrahpasa Medical Faculty	Istanbul
Turkey	Kocaeli Universitesi Tip Fakultesi	Kocaeli
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	Ninewells Hospital	Dundee
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	University College London Hospitals	London
United Kingdom	The Christie	Manchester
United Kingdom	Royal Marsden Hospital- Sutton	Sutton
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	AdventHealth Cancer Institute	Orlando	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Basilea Pharmaceutica

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Chile,  France,  Germany,  Italy,  Korea, Republic of,  Poland,  Russian Federation,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	OS in Substudy 2	OS was measured from patient enrollment to time of death	From first dose and up to 15 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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