Clinical trial NCT03517956: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced or Metastatic Solid Tumor
Keywords: Phase I
Locally advanced or metastatic solid tumor
Urothelial cancer
FGFR inhibitor
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2018-05-08
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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).

Primary outcomes:
measure: Incidence of treatment-emergent adverse events (TEAEs)
timeFrame: Up to 32 months
measure: Incidence of drug-related TEAEs
timeFrame: Up to 32 months
measure: Incidence of treatment-emergent serious adverse events (TESAEs)
timeFrame: Up to 32 months
measure: Incidence of Dose-limiting toxicities (DLTs)
timeFrame: Approximately 10 months
measure: Objective response rate (ORR) at recommended dose
timeFrame: Up to 32 months
Secondary outcomes:
measure: Maximum plasma concentration of Copanlisib (Cmax)
timeFrame: 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
measure: Area under the plasma concentration versus time curve of Copanlisib (AUC (0-48))
timeFrame: 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
measure: Area under the plasma concentration versus time curve of Rogaratinib (AUC (0-8))
timeFrame: 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
measure: Maximum plasma concentration of Rogaratinib (Cmax)
timeFrame: 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
measure: Objective response rate (ORR)
timeFrame: Up to 32 months
measure: Disease control rate (DCR)
timeFrame: Up to 32 months
measure: Duration of response (DOR) for Partial Response and Complete Response
timeFrame: Up to 32 months
measure: Progression-free survival (PFS)
timeFrame: Up to 32 months
measure: Overall survival (OS)
timeFrame: Up to 32 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC Norris Hospital and Clinics
state: California
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute - Detroit
state: Michigan
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Tyler
country: United States
facility: Tyler Cancer Center
state: Texas
city: Bruxelles - Brussel
country: Belgium
facility: CU Saint-Luc/UZ St-Luc
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Liege
country: Belgium
facility: CHU de Liège
city: Frankfurt
country: Germany
facility: Krankenhaus Nordwest
state: Hessen
city: Köln
country: Germany
facility: Universitätsklinikum Köln
state: Nordrhein-Westfalen
city: Würzburg
country: Germany
facility: Klinikum der Universität Würzburg
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: National Cancer Center Singapore
city: Barcelona
country: Spain
facility: Ciutat Sanitària i Universitaria de la Vall d'Hebron
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
Study officials:
References: