E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
FGFR-positive locally advanced or metastatic urothelial carcinoma |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064467 |
E.1.2 | Term | Urothelial carcinoma |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Part A: • To determine the safety and tolerability of rogaratinib in combination with atezolizumab in patients with FGFR-positive locally advanced or metastatic urothelial carcinoma • To determine the recommended Phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab in this patient population.
|
|
E.2.2 | Secondary objectives of the trial |
Part A: • To assess the efficacy of the combination of rogaratinib and atezolizumab in this patient population. • To characterize the pharmacokinetics (PK) of rogaratinib in combination with atezolizumab in this patient population
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part A: •Male/female patients ≥18 years of age (at least age of legal maturity) •Urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra, meeting all of the following criteria: oHistologically confirmed. oPatients with mixed histology required to have dominant transitional cell pattern oLocally advanced (T4, any N; or any T, N2-3) or metastatic disease (any T, any N +M1) Note:Locally advanced bladder cancer must be unresectable i.e. invading the pelvic or abdominal wall (stage T4b) or presenting with bulky nodal disease (N2-3) •High FGFR1 or 3 mRNA expression levels (RNAscope score of 3+ or 4+;measurement is part of this protocol) in archival or fresh tumor biopsy specimen •Measurable disease according to RECIST v1.1 •ECOG PS 0 or 1 •Adequate hematological and end organ function •Recovery to NCI CTCAE v.4.03 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure-related toxicity (patients with persistent alopecia, anemia [hemoglobin ≥ 9g/dl], any grade peripheral neuropathy, impaired renal function (GFR>30ml/min/1.73m2), hearing loss and/or hypothyroidism that is adequately controlled by hormone replacement can be included •No prior systemic treatment for locally advanced or metastatic urothelial carcinoma. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval >12 months between the last treatment administration+the date of recurrence is required in order to be considered treatment-naïve in the metastatic setting. Prior local intra-vesical chemotherapy/local immunotherapy allowed if completed at least 4 weeks before first study drug admin. Regionally available standard of care options must be considered for all patients •Ineligibility for cisplatin-based chemotherapy •Negative serum pregnancy test in women of childbearing potential (performed within 7 days before the first treatment). Negative results must be available before the first study drug administration •WOCBP+fertile men must agree to use adequate contraception when sexually active from signing of ICF for study treatment eligibility until at least 5 months after last study atezolizumab administration or until at least one week after the last rogaratinib intake, whichever is later. Investigator or designated associate is requested to advise patient how to achieve highly effective birth control. Highly effective (failure rate of less than 1% per year) contraception methods include: •Combined (estrogen+progesterone containing: oral, intravaginal, transdermal) +progesterone-only (oral, injectable, implantable) hormonal contraception associated with inhibition of ovulation •IUD/IUS •Bilateral tubal occlusion/vasectomized partner •Sexual abstinence oPeriodic abstinence+withdrawal are not acceptable methods of contraception. Male patients with female partner of childbearing potential must use condom+ensure that an additional form of contraception is also used during treatment and until 5 months after last atezolizumab administration or until at least one week after the last rogaratinib intake, whichever is later. Part B: •Male/female patients ≥18 years of age (at least age of legal maturity) •Urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra, meeting all of the following criteria: oHistologically confirmed oPatients with mixed histology are required to have a dominant transitional cell pattern. oLocally advanced (T4, any N; or any T, N2-3) or metastatic disease (any T, any N, +M1) Note:Locally advanced bladder cancer must be unresectable i.e. invading the pelvic or abdominal wall (stage T4b) or presenting with bulky nodal disease (N2-3) •High FGFR1 or 3 mRNA expression levels (RNAscope score of 3+ or 4+; measurement is part of this protocol) in archival or fresh tumor biopsy specimen •Measurable disease according to RECIST v1.1 •ECOG PS 0 or 1 •Adequate haematological and end organ function •Recovery to NCI CTCAE v.4.03 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug / procedurerelatedtoxicity (patients with persistent alopecia, anemia [hemoglobin ≥ 9 g/dl for Cohort B1, +/ or hypothyroidism can be included) •No prior systemic treatment for locally advanced or metastatic urothelial carcinoma. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval >12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment-naïve in the metastatic setting. Prior local intra-vesical chemotherapy or local immunotherapy is allowed if completed at least 4 weeks before randomization •Ineligibility for cisplatin-based chemotherapy •Pregnancy serum test+contraception part identical with Part A |
|
E.4 | Principal exclusion criteria |
Part A: • Inability to swallow oral medications • Any malabsorption condition • Current diagnosis of retinal disorders including retinal detachment, retinal pigment epithelial detachment (RPED), central serous retinopathy or retinal vein occlusion • Previous or concurrent cancer except o cervical carcinoma in situ o treated basal-cell carcinoma or squamous cell skin cancer o localized prostate cancer treated with curative intent and 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) o any other cancer curatively treated > 3 years before the first study drug administration • Investigational drug treatment outside of this study during or within 4 weeks before the first study drug administration • Ongoing or previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors including rogaratinib or FGFR-specific antibodies) • Previous assignment to treatment during this study • Severe (CTCAE v.4.03 Grade 3) infections within 4 weeks before the first study drug administration, including but not limited to hospitalization for complication of infection, bacteremia, or severe pneumonia • History of autoimmune disease except: a) autoimmune-related hypothyroidism clinically stable on thyroid replacement hormone; b) controlled Type-I diabetes mellitus on a stable dose of insulin regimen • History or current condition of uncontrolled cardiovascular disease • Systolic/diastolic blood pressure ≤ 100/60 mmHg and heart rate ≥ 100/min • Renal failure requiring peritoneal dialysis or hemodialysis • Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia) • Concomitant therapies that are known to increase serum calcium or phosphate levels and that cannot be discontinued or switched to a different medication before start of study treatment • Evidence or history of bleeding diathesis or coagulopathy • Any hemorrhage / bleeding event CTCAE v.4.03 ≥ Grade 3 within 4 weeks before the first study drug administration
Part B: • Inability to swallow oral medications • Any malabsorption condition • Current diagnosis of retinal disorders including retinal detachment, retinal pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion • Previous or concurrent cancer except o cervical carcinoma in situ o treated basal-cell carcinoma or squamous cell skin cancer o localized prostate cancer treated with curative intent and 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 o any other cancer curatively treated > 3 years before randomization • Ongoing or previous anti-cancer treatment within 4 weeks before randomization • Ongoing or previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors including rogaratinib or FGFR-specific antibodies) • Previous assignment to treatment during this study • Severe (CTCAE v.4.03 Grade 3) infections within 4 weeks before randomization, including but not limited to hospitalization for complication of infection, bacteremia, or severe pneumonia • History of autoimmune disease except: a) autoimmune-related hypothyroidism clinically stable on thyroid replacement hormone; b) controlled Type-I diabetes mellitus on a stable dose of insulin regimen • History or current condition of uncontrolled cardiovascular disease • Systolic/diastolic blood pressure ≤ 100/60 mmHg and heart rate ≥ 100/min • Renal failure requiring peritoneal dialysis or hemodialysis • Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia) • Concomitant therapies that are known to increase serum calcium or phosphate levels and that cannot be discontinued or switched to a different medication before randomization • Evidence or history of bleeding diathesis or coagulopathy • Any hemorrhage / bleeding event CTCAE v.4.03 ≥ Grade 3 within 4 weeks before randomization. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Part A: • The incidence of DLTs used to determine the MTD and/or RP2D • The incidence of treatment-emergent adverse events (TEAEs) • The incidence of treatment-emergent drug-related TEAEs • The incidence of treatment-emergent serious adverse events
Part B: • Treatment efficacy as assessed by progression-free survival, as assessed by RECIST 1.1
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: • Safety - throughout the study • MTD – up to 21 days
Part B: • RECIST - every 9 weeks |
|
E.5.2 | Secondary end point(s) |
Part A: • Treatment efficacy as assessed by Objective response rate (ORR), as assessed by RECIST 1.1 • Cmax of rogaratinib • AUC(0-8) of rogaratinib
Part B: • The incidence of treatment-emergent adverse events (TEAEs) • The incidence of treatment-emergent drug-related TEAEs • The incidence of treatment-emergent serious adverse events • Change in vital signs, physical finding and clinical laboratory results • Treatment efficacy as assessed by Disease control rate (DCR), as assessed by RECIST 1.1 • Treatment efficacy as assessed by Duration of response (DOR), as assessed by RECIST 1.1 • Treatment efficacy as assessed by Objective response rate (ORR), as assessed by RECIST 1.1 • Treatment efficacy as assessed by Overall survival (OS), as assessed by RECIST 1.1 • Rogaratinib and Atezolizumab pharmacokinetic concentration data |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A: • RECIST - every 9 weeks • PK – up to C5D1
Part B: • Safety - throughout the study • PK – up to C5D1 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
|
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Part A open design; Part B double blind design |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Japan |
Korea, Republic of |
United States |
Austria |
France |
Spain |
Germany |
Italy |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |