Derazantinib and Atezolizumab in Patients With Urothelial Cancer

Study Overview
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Brief Summary
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The purpose of this study was to evaluate efficacy of derazantinib monotherapy or derazantinib-atezolizumab in combination in patients with advanced urothelial cancer harboring fibroblast growth factor receptor (FGFR) genetic aberrations (GA) of various clinical stages of disease progression and prior treatments.

Detailed Description
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The study comprised five open-label substudies (1-5) in patients with advanced urothelial cancer harboring FGFR GA (with the exception of substudy 2 which did not require a FGFR GA) who were treated by derazantinib monotherapy or derazantinib in combination with atezolizumab. The study enrolled patients with cisplatin-ineligible status, or patients whose disease progressed after either first-line treatment or prior treatment with FGFR inhibitors.

Official Title
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An Open-label Multi-cohort Phase 1b/2 Study of Derazantinib and Atezolizumab in Patients With Urothelial Cancer Expressing Activating Molecular FGFR Aberrations

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Drug: Derazantinib 300 mg once daily monotherapy
* Drug: Derazantinib 200 mg once daily + atezolizumab 1200 mg
* Drug: Derazantinib 300 mg once daily+ atezolizumab 1200 mg
* Drug: Derazantinib 200 mg twice daily + atezolizumab 1200 mg
* Drug: Derazantinib 300 mg once daily monotherapy (QD)
* Drug: Derazantinib 300 mg once daily + atezolizumab 1200 mg
* Drug: Derazantinib 200 mg twice daily monotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed transitional cell carcinoma of the urothelium of the upper or lower urinary tract Recurrent or progressing stage IV disease, or surgically unresectable, recurrent or progressing disease Documented central FGFR genetic aberration (FGFR1, FGFR2, or FGFR3 mutations / short variants and rearrangements / fusions) (Note; Substudy 2 started with patients requiring an FGFR GA, but this requirement was removed from the protocol later on) Measurable disease, as defined by the Investigator using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2 Adequate organ functions as indicated by Screening visit local laboratory values Exclusion Criteria: Receipt of prior cancer treatment within specific interval periods Concurrent evidence of any clinically significant corneal or retinal disorder History of clinically significant cardiac disorders Known CNS metastases Concurrent uncontrolled or active infection with human immunodeficiency virus Active hepatitis B or chronic hepatitis B without current antiviral therapy Active hepatitis C Active tuberculosis Severe bacterial, fungal, viral and/or parasitic infections on therapeutic oral or IV medication at the time of first dose of study drug administration

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Substudy 1: Derazantinib 300 mg once daily<br>Patients with urothelial cancer were treated with derazantinib 300 mg once daily | Drug: Derazantinib 300 mg once daily monotherapy<br>* Derazantinib was administered orally at a dose of 300 mg once daily<br>|
| Experimental: Substudy 2 (Dose-Level 1): Derazantinib 200 mg once daily + atezolizumab 1200 mg<br>Patients with any solid tumors were treated with derazantinib 200 mg once daily in combination with atezolizumab 1200 mg given every 3 weeks as intravenous (IV) infusion | Drug: Derazantinib 200 mg once daily + atezolizumab 1200 mg<br>* Derazantinib was administered orally at a dose of 200 mg once daily in combination with atezolizumab 1200 mg every 3 weeks<br>|
| Experimental: Substudy 2 (Dose-Level 2): Derazantinib 300 mg once daily + atezolizumab 1200 mg<br>Patients with any solid tumors were treated with derazantinib 300 mg once daily in combination with atezolizumab 1200 mg given every 3 weeks as IV infusion | Drug: Derazantinib 300 mg once daily+ atezolizumab 1200 mg<br>* Derazantinib was administered orally at a dose of 300 mg once daily in combination with atezolizumab 1200 mg every 3 weeks<br>|
| Experimental: Substudy 3: Derazantinib 200 mg twice daily + atezolizumab 1200 mg<br>Patients with urothelial cancer were treated with derazantinib 200 mg twice daily in combination with atezolizumab 1200 mg given every 3 weeks as IV infusion | Drug: Derazantinib 200 mg twice daily + atezolizumab 1200 mg<br>* Derazantinib was administered orally at a dose of 200 mg twice daily in combination with atezolizumab 1200 mg every 3 weeks<br>|
| Experimental: Substudy 4 (Cohort 4a):Derazantinib 300 mg once daily<br>Patients with FGFR inhibitor resistant urothelial cancer were treated with derazantinib 300 mg once daily | Drug: Derazantinib 300 mg once daily monotherapy (QD)<br>* Derazantinib was administered orally at a dose of 300 mg once daily<br>|
| Experimental: Substudy 4 (Cohort 4b):Derazantinib 300 mg once daily + atezolizumab 1200 mg<br>Patients with urothelial cancer were treated with derazantinib 300 mg once daily in combination with atezolizumab 1200 mg given every 3 weeks as IV infusion | Drug: Derazantinib 300 mg once daily + atezolizumab 1200 mg<br>* Derazantinib was administered orally at a dose of 300 mg once daily in combination with atezolizumab 1200 mg every 3 weeks<br>|
| Experimental: Substudy 5: Derazantinib 200 mg twice daily<br>Patients with urothelial cancer were treated with derazantinib 200 mg twice daily | Drug: Derazantinib 200 mg twice daily monotherapy<br>* Derazantinib was administered orally at a dose of 200 mg twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Based on RECIST 1.1 (Substudies 1,3,4 and 5) | ORR was defined as the proportion of patients who achieved a confirmed clinical response (CR) or partial response (PR) by blinded investigator central review (BICR) using the internationally recognized criteria for the radiological assessment in tumor response of solid tumors (RECIST) Version 1.1 | From first dose up to 2 years | 
| Recommended Phase 2 Dose (RP2D) of Derazantinib-atezolizumab in Combination Based on DLT Criteria, Safety and Efficacy Data (Substudy 2) | The RP2D was determined by a joint decision taken by the Independent Data Monitoring Committee (IDMC), Investigators, and the Sponsor in reviewing the aggregate of DLT and AE data, and considering efficacy data | From first dose up to 2 years | 
| Number of Patients With Dose-limiting Toxicities (DLTs) in Substudy 2 | In Substudy 2, the primary endpoint was the number of patients with DLTs. A DLT was defined as a clinically-significant adverse event (AE) or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications. Any DLT had to be a toxicity considered at least possibly related to derazantinib or the combination of derazantinib and atezolizumab | From first dose up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) Per RECIST 1.1 in All Substudies | DCR was defined as the proportion of patients who achieved a confirmed clinical response (CR), partial response (PR) or stable disease (SD) by BICR using the internationally recognized criteria in accordance with RECIST Version 1.1 | From first dose up to 2 years | 
| Duration of Response (DOR) Per RECIST 1.1 | DOR was calculated from the first date of documented tumor response (confirmed CR or PR) to the date of disease progression as assessed by BICR or death per RECIST 1.1 | From first dose up to 2 years | 
| ORR Based on RECIST 1.1 (Substudy 2) | ORR was defined as the proportion of patients who achieved a confirmed clinical response (CR) or partial response (PR) by blinded investigator central review (BICR) using the internationally recognized criteria for the radiological assessment in tumor response of solid tumors (RECIST) Version 1.1 | From first dose up to 2 years | 
| Progression-free Survival (PFS) by RECIST in All Substudies | PFS was calculated as the time from cohort assignment until disease progression as assessed by BICR, or death from any cause, whichever came first | From first dose up to 2 years | 
| Overall Survival (OS) in All Substudies | OS was calculated from the date of cohort assignment until death from any cause | From first dose up to 2 years | 
| Number of Patients With at Least Grade 3 Adverse Events (AEs) | Common Terminology Criteria for Adverse Events (CTCAE) displayed by increasing severity grades 3 to 5 (CTCAE grade 3/4/5 ) | From first dose and until 90 days following the last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic urothelial cancer, bladder cancer, Fibroblast Growth Factor Receptor, FGFR genetic aberration, targeted therapy, derazantinib, checkpoint inhibitor, immune checkpoint blockade, atezolizumab, Tecentriq, solid tumor