Derazantinib/atezolizumab in urothelial cancer
Research type
Research Study
Full title
An open-label multi-cohort Phase 1/2 study of derazantinib and atezolizumab in patients with urothelial cancer expressing activating molecular FGFR aberrations (FIDES-02)
IRAS ID
270299
Contact name
Thomas Powles
Contact email
Sponsor organisation
Basilea Pharmaceutica International Ltd.
Eudract number
2019-000359-15
Clinicaltrials.gov Identifier
Duration of Study in the UK
2 years, 5 months, 21 days
Research summary
Summary of Research
The study will take place in approximately 85 study sites in around 15 countries in Europe, USA, Canada, and Asia Pacific, with about 303 participants (in 4 substudies).
Genes contain the codes to make specific proteins in the body, and sometimes these change (Genetic Aberrations – GA). Participants in this study will have tumours containing Fibroblast Growth Factor Receptor (FGFR) GAs, resulting in a potentially faulty FGFR protein being made, which can cause a variety of diseases. There are different types of FGFRs, for example FGFR1, FGFR2, and FGFR3.
The purpose of the study is to evaluate effectiveness and safety of derazantinib taken orally alone or in combination with intravenously (IV) administered atezolizumab as a possible treatment for patients whose tumours contain FGFR with GAs.
Derazantinib blocks the FGFR protein from being activated and may be useful in treatment of cancers with FGFR GAs like bladder cancer or urinary passage cancer (collectively also called urothelial cancer).
Atezolizumab is used to treat patients with advanced urothelial cancer and other tumour types such as breast cancer and lung cancer. It will be used in combination with oral derazantinib in this study.
The study is divided into 4 substudies: In Substudies 1, 3 and 4, participants with urothelial cancers that cannot be surgically removed, or urothelial cancer which has spread to new areas of the body, and known FGFR GAs in FGFR1, FGFR2, FGFR3 will be enrolled. There is a translational clinical study (TCS) group which will investigate specific molecules which may predict how patients will respond to treatment. Substudy 2 enrols participants with any advanced solid tumours and any FGFR GA.
Each substudy will consist of screening (around 15 days), treatment period (21 days per cycle until cancer progression), end of treatment visit, and follow-up period (on-site visits at 28 days and 90 days after last dose, and thereafter in person/ telephone contact at least every 3 months).
Summary of Results
This study was a multiple cohort, multi-center Phase 1b/2 study. The efficacy of derazantinib or derazantinib-atezolizumab in combination was evaluated in cohorts addressing various clinical stages of disease progression and prior treatments.
This study comprises five open-label sub-studies.
The study was conducted at 57 sites in 15 countries: 7 in United States and Canada, 40 in Europe (Austria, Belgium, Czech Republic, France, Germany, Hungary, Italy, Poland, Spain, Switzerland, and United Kingdom), 10 in Asia Pacific (Australia and South Korea).
The study planned to enrol up to 272 evaluable patients in total across all five sub-studies.
A total of 321 patients underwent molecular screening, 131 underwent clinical screening, and 95 were assigned study treatment.
STUDY PERIOD
First patient, first visit: 02 August 2019 Last patient, last visit: 04 October 2022 BACKGROUND AND RATIONALE FOR THE STUDY Urothelial cancer (UC) is the most common cancer of the urinary system worldwide, with UC of the bladder being the predominant histologic type and location. Although less common, UC may also originate in the renal pelvis, ureter or urethra.
Current choices for standard treatment of patients with locally-advanced or metastatic and recurrent or progressing UC (hereafter identified by the acronym mUC) are cisplatin-based chemotherapy, immune-checkpoint blockade, and combinations thereof. Specifically identified subgroups of mUC patients represent the indications investigated in this study.
DURATION OF TREATMENT
In this study, a treatment cycle was 21 days in both monotherapy and combination cohorts (groups).
The cycle duration of derazantinib was adapted from 4 weeks to 3 weeks continuous oral administration and matched the cycle duration of the registered atezolizumab dosage of every 3 weeks (Q3W).
All patients were treated until disease progression, patient withdrawal, patient lost to follow up, unacceptable toxicity, until the Investigator decided to remove the patient from treatment, or until the cohort, substudy, or the study was terminated by the Sponsor, whichever occurred first.SUMMARY OF RESULTS AND CONCLUSIONS
Derazantinib monotherapy and derazantinib in combination with atezolizumab were evaluated in terms of safety and efficacy in five substudies. Substudies 1, 3, 4, and 5 enrolled patients with UC, with GAs in FGFR genes, at various clinical stages of PD and prior treatments. Substudy 2 enrolled patients with any advanced solid tumours.
A total of 321 patients underwent molecular screening, 131 underwent clinical screening, and 95 were assigned study treatment. All patients assigned treatment were dispensed study drug and received at least one dose of derazantinib with or without atezolizumab.
Mean treatment duration for derazantinib and atezolizumab overall was 14.3 and 11.9 weeks, respectively. Compliance for derazantinib and atezolizumab treatment was high in the majority of patients.
All patients in all substudies discontinued derazantinib, in most cases due to developing progressive disease (PD), discontinued due to AEs, withdrew consent, or due to death. All patients who received atezolizumab (Substudies 2, 3 and 4) discontinued it, predominantly due to PD.
Conclusions
Overall, derazantinib monotherapy in cohorts 1, 4a, and 5, did not show efficacy comparable to contemporary treatment in ORR (overall response rate) for the primary analysis or for secondary analyses (DCR, DOR, PFS and OS), although a small proportion of patients showed response to derazantinib treatment. In Substudy 5, the interim analysis met the criteria for futility and the cohort was stopped.
Results from the substudies combining derazantinib with atezolizumab were not suggestive of a clinically relevant synergistic effect.
Overall, derazantinib did not demonstrate sufficient efficacy in terms of the observed ORR and PFS to warrant further development as monotherapy or in combination with atezolizumab in the treatment of this tumour type, especially when compared to results already reported from recent similar studies conducted in UC.
Derazantinib monotherapy, or in combination with atezolizumab, showed an acceptable safety profile in this study. Overall, the system organ class most commonly affected by AEs (adverse events) including TRAEs (adverse events related to treatment)was gastrointestinal disorders. While most patients experienced TRAEs and AESIs, the rate of FGFR inhibitor-related AEs such as hand-foot syndrome, stomatitis, nail toxicity and retinal side effects were low. TEAEs classified as DLTs were rare, occurring in only two patients. Deaths in this study were predominantly due to progressive disease.
Overall, a small proportion of patients permanently discontinued study drug due to AEs (e.g. five patients in Substudy 1 and 2 patients in Substudy 5). Few patients treated with derazantinib (or in combination with atezolizumab) had unexpected or notable changes from baseline in vital signs or laboratory values.REC name
London - Central Research Ethics Committee
REC reference
19/LO/1720
Date of REC Opinion
16 Dec 2019
REC opinion
Further Information Favourable Opinion