FGF401 in HCC and Solid Tumors Characterized by Positive FGFR4 and KLB Expression

A Phase I/II, Multicenter, Open-label Study of Oral FGF401 in Adult Patients With Hepatocellular Carcinoma or Solid Malignancies Characterized by Positive FGFR4 and KLB Expression

Estimate the maximum tolerated dose and/or recommended phase II dose and efficacy of FGF401 as single agent and in combination with PDR001 in patients with hepatocellular carcinoma and as single agent in patients with other solid malignancies based on RECIST 1.1.

The primary objectives of this study were in 2 parts: Phase l & Phase II.

The study included different periods starting by molecular pre-screening (applicable for all subjects enrolled under protocol versions 00 to 03, or applicable only for Phase I and Group 3 in Phase II of FGF401 single agent, for subjects enrolled under protocol version 04), Screening, Treatment, End of Treatment, Disease progression follow-up (if applicable), Safety follow-up and then ended by survival follow-up period

In the Phase I part, subjects with HCC or other advanced solid tumors characterized by positive FGFR4 and KLB expression were enrolled and treated with FGF401 as a single agent or in combination with PDR001. Subjects in this phase were dosed under fasted or fed conditions.

In the Phase 2 part, subjects with advanced HCC or other solid tumors bearing positive FGFR4 and KLB expression were enrolled into three groups (Group 1: HCC subjects from Asian countries; Group 2: HCC subjects from non-Asian countries; Group 3: Subjects with other solid malignancies regardless of geography) to assess the preliminary anti-tumor activity of FGF401 in Phase ll. This Phase II part investigated the anti-tumor activity of FGF401 single agent and in combination with PDR001.

Each group within the Phase II dose expansion part targeted a different number of subjects. Group 1 and Group 2 planned to enroll around 40 subjects each and Group 3 planned to enroll approximately 20 subjects. Subjects in this phase were dosed under fasted conditions.

Oral FGF401 was administered on a continuous once daily (QD) dosing regimen for both FGF401 single agent and in combination with PDR001 parts. Intravenous PDR001 was administered in a fixed dosing regimen of 300 mg iv every three weeks as per protocol until subject experienced unacceptable toxicity, progressive disease and/or treatment was discontinued at the discretion of the Investigator or withdrawal of consent.

Because the enrollment of new subjects in this study was halted for business reason on 03-Jul-2018 early enrollment termination was declared following the initial halt of enrollment once the global last subject last visit was achieved as per protocol, and consequently the phase II part of the FGF401+PDR001 combination did not start, none of the planned analyses related to the phase II part of the FGF401+PDR001 combination arm were performed.

Duration of treatment: Subjects could continue study treatment until they experienced any of the following: Disease progression (radiologically documented according to RECIST v1.1) as assessed by the Investigator, unacceptable toxicity, & treatment was discontinued at the discretion of the Investigator or the subject.

Subjects who permanently discontinued the study treatment for any reason other than disease progression or withdrawal of consent had to continue efficacy assessments as scheduled in the protocol until the time of disease progression.

Inclusion Criteria:

1. ECOG Performance Status ≤ 1
2. Presence of at least one measurable lesion according to RECIST v1.1. c-i) FGF401 single agent-Phase I and Phase II, Group 3: 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. c-ii) FGF401 single agent-Phase II, Groups 1 and 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 c-iii) FGF401 in combination with PDR001: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

Exclusion Criteria:

1. Previous treatment with a selective FGF19-FGFR4 targeted therapy and/or pan-FGFR inhibitor.

2. Symptomatic CNS metastases which are neurologically unstable or requiring increasing doses of steroids to control their CNS disease.

3. 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 ≥ 2 mg/dL AST and/or ALT > 3 x ULN Serum creatinine > 1.5 x ULN and/or creatinine clearance ≤ 45 mL/min
   • Coagulation: PT > 4 seconds more than ULN or INR > 1.7

4. Pregnant or nursing (lactating) women.

Other protocol-defined Inclusion/Exclusion criteria may apply.