E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hepatocellular carcinoma or other solid tumors characterized by positive FGFR4 and KLB expression |
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E.1.1.1 | Medical condition in easily understood language |
Hepatocellular carcinoma (liver cancer) or other types of cancer. |
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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 | 10065252 |
E.1.2 | Term | Solid tumor |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073071 |
E.1.2 | Term | Hepatocellular carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
1. Phase I part: to estimate the MTD and/or RP2D of FGF401 single agent and in combination with PDR001
2. Phase II part: to investigate the anti-tumor activity of FGF401 single agent and in combination with PDR001 |
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E.2.2 | Secondary objectives of the trial |
1. To characterize the safety and tolerability of FGF401 single agent and in combination with PDR001
2. To further investigate the anti-tumor activity of FGF401 single agent and in combination with PDR001
3. To characterize the PK properties of FGF401 single agent and in combination with PDR001
4. To evaluate food effect on FGF401 exposure and safety profile. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients (male or female) ≥ 18 years of age
2. ECOG Performance Status ≤ 1
3. Presence of at least one measurable lesion according to RECIST v1.1.
4. FGF401 single agent-Phase II, Group 3: Patients with confirmed positive expression of FGFR4 and KLB at pre-screening.
5. For HCC patients: the diagnosis must be made based on AASLD Guidelines with confirmed stage C advanced HCC (BCLC staging classification). Current cirrhotic status of Child-Pugh class A (5-6 points), with no encephalopathy and/or ascites.
6. FGF401 single agent Phase I: Patients with HCC or advanced solid tumors, who have progressed despite standard therapy or are intolerant of standard therapy, or for whom no standard therapy exists.
7. FGF401 single agent Phase 2: HCC patients previously treated with sorafenib for advanced HCC with documented disease progression during or after discontinuation of sorafenib treatment, or intolerance to sorafenib treatment.
8. FGF401 in combination with PDR001-PhaseI and Phase II: Advanced HCC patients who have received up to 2 previous lines of systemic
treatment and one treatment must have included sorafenib with documented disease progression during or after discontinuation of sorafenib treatment, or intolerance to sorafenib treatment.
9. FGF401 in combination with PDR001-Phase II-Stage 2: Documented FGF19 expression level and/or FGF19 pathway activation
Other protocol-defined inclusion criteria may apply. |
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E.4 | Principal exclusion criteria |
1. Previous treatment with a FGF19-FGFR4 targeting therapy.
2. For HCC patients in FGF401 single agent Phase II part: any previous systemic anti-cancer therapies other than sorafenib or any anti-cancer
therapy (including locoregional therapy) after disease progression during or after sorafenib treatment.
3. Ongoing active diarrhea requiring medications (e.g. BAS, loperamide)
4. Irritable bowel syndrome with signs/symptoms and requires medications
5. Symptomatic CNS metastases which are neurologically unstable or requiring increasing doses of steroids to control their CNS disease.
6. Patient having out of range laboratory values defined as:
• Hematology
Hemoglobin ≤ 9 g/dL (SI Units: 90 g/L)
Platelet count < 75000/mm3
Absolute neutrophil count (ANC) < 1500/mm3
• Chemistry
Total bilirubin > 1.5 x ULN
AST and/or ALT > 3 x ULN
Serum creatinine > 1.5 x ULN and/or creatinine clearance < 40 mL/min
• Coagulation: PT > 4 seconds more than the ULN or INR > 1.7
7. Unable to stop any prohibited medications, including CYP1A2, CYP2C9 and CYP3A4/5 substrates with a narrow therapeutic index and known BSEP efflux transporter inhibitors.
8. Additional exclusion criteria for FGF401 and PDR001 combination:
- Impaired cardiac function
- History of liver or other organ transplantation
- Patients who discontinued prior anti-PD-1/PD-L1 therapy due to an anti PD-1/PD-L1-related toxicity
Other protocol-defined exclusion criteria may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Incidence rate and characteristics of DLT during the first cycle of dosing for FGF401 single agent and during the first two cycles of dosing for FGF401 in combination with PDR001
2.FGF401 single agent: Group 1 and Group 2: Time to progression (TTP); Group 3: Overall response rate (ORR), based on local assessment per RECIST v1.1 FGF401 in combination with PDR001: ORR based on local assessment per RECIST v1.1. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs and ECGs Tolerability: Dose interruptions and reductions
2. Phase I part
BOR, ORR, DCR, TTP and OS, based on local assessment per RECIST v1.1 for FGF401 single agent or RECISTv1.1. and irRC for the FGF401 and PDR001 combination
Phase II part- FGF401 single agent
• Group 1 and Group 2: BOR, ORR, OS and DCR, based on local assessment per RECIST v1.1
• Group 3: BOR, DCR, OS and PFS, based on local assessment per RECIST v1.1
Phase II part- FGF401 and PDR001 combination TTP, PFS, OS, BOR, DOR and DCR, based on local assessment per RECIST v1.1. and irRC
3. Plasma concentration of FGF401,PDR001 and PK parameters including but not limited to Cmax, Cmin, AUCinf, AUClast, AUCtau and T1/2
4. Plasma concentration of FGF401 and PK parameters when dosing under fed condition Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs and ECGs when dosing under fed condition |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Continuously throughout the study until 30 days after safety follow up
2. Baseline and every 6 weeks
3. During phase I: Cycle 1 Day 1, 2, 8, 9 and 15; Cycle 2 Day 1 and 2; Cycle 3 and Cycle 4 Day 1
During Phase II: Cycle 1 Day 1, 2, 8 and 15; Cycle 2 Day 1 and 2; Cycle 3 to Cycle 6 Day 1 |
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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 | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
China |
France |
Germany |
Hong Kong |
Italy |
Japan |
Korea, Republic of |
Singapore |
Spain |
Taiwan |
United States |
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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
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The study will end when the treatment period, safety follow-up, disease progression follow-up and survival follow-up have been completed for
all patients or when the study is terminated early. Completion of the survival follow-up period will occur once a minimum of 80% of patients in the phase II part of both FGF401 single agent and FGF401 in combination with PDR001 have died, lost to follow-up, or followed for survival for min 18 months after receiving the study treatment,whichever is sooner. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 21 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 21 |