Advanced or Metastatic Solid Tumor
Conditions
Keywords
Phase I, Locally advanced or metastatic solid tumor, Urothelial cancer, FGFR inhibitor
Brief summary
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.
Interventions
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.
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.
Sponsors
Bayer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to 32 months | ORR in patients receiving the recommended dose of the rogaratinib-copanlisib-combination during the dose expansion part |
Secondary
| Measure | Time frame |
|---|---|
| Disease control rate (DCR) | Up to 32 months |
| Duration of response (DOR) for Partial Response and Complete Response | Up to 32 months |
| 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 |
| Overall survival (OS) | Up to 32 months |
| Progression-free survival (PFS) | Up to 32 months |
| 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 |
Countries
Belgium, Germany, Singapore, South Korea, Spain, United States
Outcome results
None listed