Phase 1 Study of the Combination of Rogaratinib With Copanlisib in Patients With Fibroblast Growth Factor Receptor (FGFR)-Positive, Locally Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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The primary objective of this study is to determine the safety, tolerability, maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) and efficacy of rogaratinib in combination with copanlisib in patients with locally advanced or metastatic solid tumors that are mRNA-positive for at least one FGFR1-4 subtype. The secondary objectives of this study are to characterize the pharmacokinetics (PK) of rogaratinib and copanlisib alone and in combination, and to assess the anti-tumor efficacy of rogaratinib in combination with copanlisib for locally advanced or metastatic solid tumors that are mRNA-positive for at least one FGFR1-4 subtype.

Official Title
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A Multicenter Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of the Combination of Rogaratinib and Copanlisib in Patients With FGFR-positive, Locally Advanced or Metastatic Solid Tumors

Conditions
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Advanced or Metastatic Solid Tumor

Intervention / Treatment
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* Drug: Rogaratinib (BAY1163877)
* Drug: Copanlisib (BAY80-6946)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: High FGFR mRNA expression levels (RNAscope score of ≥3; measurement is part of this protocol) in archival or fresh tumor biopsy specimen. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. At least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in contrast enhanced (unless contraindicated) CT or MRI. Adequate bone marrow, liver and renal function. Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m*2 according to the Modification of Diet in Renal Disease (MDRD) formula. Left ventricular ejection fraction (LVEF) equal to or above the lower limit of normal (LLN) at the institution. Life expectancy of at least 3 months. For the dose escalation part: Patients with histologically confirmed, locally advanced or metastatic solid tumors who are not candidates for or refuse standard therapy or whose disease progressed and for which standard anti-cancer treatment is no longer effective, excluding primary brain or spinal tumors. Patients who have been advised with all standard treatment options and still refuse them must be documented and can be allowed to enter the trial. For the dose expansion part: Patients with histologically confirmed, locally advanced or metastatic urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra who are not candidates for or refuse standard therapy or whose disease progressed and for which standard anticancer treatment is no longer effective. Patients who have been advised with all standard treatment options and still refuse them must be documented and can be allowed to enter the trial. Exclusion Criteria: Previous or concurrent cancer that is distinct from tumor for which the patient is enrolled in the study, except curatively treated cervical carcinoma in situ treated basal-cell carcinoma localized prostate cancer treated with curative intent and known absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL undergoing active surveillance and treatment-naïve) any cancer curatively treated > 3 years before planned start of study treatment. Ongoing or previous anti-cancer treatment within 4 weeks of study treatment start (or 6 weeks for mitomycin C, nitrosoureas and monoclonal antibodies); with exceptions. Prior toxicity to anti-FGFR-directed or anti-PI3K-directed therapies leading to treatment discontinuation (previous exposure is allowed in other circumstances). If prior toxicity to anti-FGFR-directed or anti-PI3K-directed therapies leading to treatment discontinuation is different from the known safety profile of rogaratinib or copanlisib, enrollment is allowed. Symptomatic brain or meningeal metastatic tumors unless the patient is >6 months from definitive therapy, has no evidence of tumor growth on an imaging study and is clinically stable with respect to the tumor at the start of study treatment. Also the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies). History or current condition of an uncontrolled cardiovascular disease including congestive heart failure NYHA > Class 2, unstable angina (symptoms of angina at rest) or new-onset angina (within last 3 months) or myocardial infarction within past 6 months and cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted). Active hepatitis B (HBV) or C (HCV) infection. Active clinically serious infections (≥ CTCAE v4.03 Grade 2).

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with FGFR1-4 - positive solid tumors<br>Dose escalation: The starting dose of the combination will be escalated in a stepwise fashion, escalating one drug at a time. Dose expansion (urothelial cancer): Patients in the dose expansion will be treated with the combination identified in the dose escalation part of the study. | Drug: Rogaratinib (BAY1163877)<br>* Dose escalation: Starting dose is rogaratinib 400 mg twice daily (b.i.d.) in continuous 28-day cycles from Cycle 1 Day 3 onwards. Dose expansion: With dose identified in dose escalation part.<br>Drug: Copanlisib (BAY80-6946)<br>* Dose escalation: Starting dose is 45 mg on Days 1, 8 and 15 of each 28-day cycle. Dose expansion: With dose identified in dose escalation part.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs) |  | Up to 32 months | 
| Incidence of drug-related TEAEs |  | Up to 32 months | 
| Incidence of treatment-emergent serious adverse events (TESAEs) |  | Up to 32 months | 
| Incidence of Dose-limiting toxicities (DLTs) |  | Approximately 10 months | 
| Objective response rate (ORR) at recommended dose | ORR in patients receiving the recommended dose of the rogaratinib-copanlisib-combination during the dose expansion part | Up to 32 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration of Copanlisib (Cmax) |  | 0 (pre-dose), 0.5, 1 (end of infusion), 2, 4, 8, 24, 48 hours after drug administration (Days 1, 2, 3) and 0, 0.5, 1, 2, 4, 8, 24, 48 hours after drug administration (Days 15, 16, 17) in dose escalation | 
| Area under the plasma concentration versus time curve of Copanlisib (AUC (0-48)) |  | 0 (pre-dose), 0.5, 1 (end of infusion), 2, 4, 8, 24, 48 hours after drug administration (Days 1, 2, 3) and 0, 0.5, 1, 2, 4, 8, 24, 48 hours after drug administration (Days 15, 16, 17) in dose escalation | 
| Area under the plasma concentration versus time curve of Rogaratinib (AUC (0-8)) |  | 0 (pre-dose), 0.5, 1, 2, 4, 6, 8 hours after drug (Day 14) and 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 24, 48 hours after drug (Days 15 to 17) in dose escalation; 0 (pre-dose) and 1 hour after drug on Day 1 of dose expansion | 
| Maximum plasma concentration of Rogaratinib (Cmax) |  | 0 (pre-dose), 0.5, 1, 2, 4, 6, 8 hours after drug (Day 14) and 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 24, 48 hours after drug (Days 15 to 17) in dose escalation; 0 (pre-dose) and 1 hour after drug on Day 1 of dose expansion | 
| Objective response rate (ORR) |  | Up to 32 months | 
| Disease control rate (DCR) |  | Up to 32 months | 
| Duration of response (DOR) for Partial Response and Complete Response |  | Up to 32 months | 
| Progression-free survival (PFS) |  | Up to 32 months | 
| Overall survival (OS) |  | Up to 32 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, Locally advanced or metastatic solid tumor, Urothelial cancer, FGFR inhibitor