Clinical trial NCT02325739: FGF401 in HCC and Solid Tumors Characterized by Positive FGFR4 and KLB Expression
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hepatocellular Carcinoma (HCC)
Solid Malignancies
Keywords: FGF401
PDR001
PD-1
FGFR4
FGF19
HCC
solid malignancies characterized by positive FGFR4 and KLB expression
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-12-25
Enrollment: 172
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Dose-limiting Toxicity (DLT): Phase I Only
timeFrame: Cycle 1 (C1) (21 days) for FGF401 single agent, Cycle 1 and Cycle 2 (C2) (42 days) for FGF401 and PDR001 combination
measure: Time to Progression (TTP): Group 1 & Group 2 (Phase II Only)
timeFrame: approx. 4.5 years
measure: Overall Response Rate (ORR) Based on Local Assessment: Group 3 (Phase II Only)
timeFrame: approx. 4.5 years
Secondary outcomes:
measure: Best Overall Response (BOR) by Investigator Assessment: Phase I and Phase II
timeFrame: approx. 4.5 years
measure: Overall Response Rate (ORR) by Investigator Assessment Phase I and FGF401 Single Agent Phase II Groups 1 & 2
timeFrame: approx. 4.5 years
measure: Disease Control Rate (DCR) by Local Investigator Assessment Phase I and FGF401 Single Agent Phase II Groups 1, 2 & 3
timeFrame: approx. 4.5 years
measure: Time to Progression (TTP) in Participants Dosed With Single Agent FGF401 120 mg (Fasted & Fed) & With Combination FGF401 120 mg + PDR001 300 mg Q3W (Phase I)
timeFrame: approx. 4.5 years
measure: Overall Survival (OS) in Participants Dosed With Single Agent FGF401 120 mg (Fasted & Fed) and in Participants Dosed With Combination FGF401 120 mg and PDR001 300 mg Q3W (Phase I & II)
timeFrame: start of treatment to death, up to about 53 months
measure: Progression-free Survival (PFS) - FGF401 Single Agent Phase II: Group 3
timeFrame: 4.5 years
measure: Presence and/or Concentration of Anti-PDR001 Antibodies
timeFrame: Day 1 of Cycle 1 to 6, approx. 10 months after C1D1 and 150-day safety follow up (FU)
measure: Cmax of PDR001 in Combination With FGF401: Phase I
timeFrame: After the first dosing sample collection was at: C1D1 0hr , C1D1 1hr, C1D8 168hr, C1D15 336hr, C2D1 504hr; each cycle is 21 days
measure: AUClast and AUCtau of PDR001 in Combination of FGF401: Phase I
timeFrame: After the first dosing sample collection was at: C1D1 0hr , C1D1 1hr, C1D8 168hr, C1D15 336hr, C2D1 504hr; each cycle is 21 days
measure: T1/2 of PDR001: Phase I
timeFrame: After the first dosing sample collection was at: C1D1 0hr , C1D1 1hr, C1D8 168hr, C1D15 336hr, C2D1 504hr; each cycle is 21 days
measure: Cmax of FGF401: Phase I
timeFrame: C1D1 (0 hour (h), 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h), C1D8 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h), and C2D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h)
measure: Cmax of FGF401 in Combination With PDR001: Phase I
timeFrame: C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h)
measure: AUCinf, AUClast & AUCtau of FGF401: Phase I
timeFrame: C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h), C1D8 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h), and C2D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h)
measure: AUCinf, AUClast & AUCtau of FGF401 in Combination With PDR001: Phase I
timeFrame: C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h)
measure: T1/2 of FGF401: Phase I
timeFrame: C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h), C1D8 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h), and C2D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California LA Santa Monica Location
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital Oncology Dept
state: Massachusetts
city: Houston
country: United States
facility: Uni Of TX MD Anderson Cancer Cntr
state: Texas
city: Shanghai
country: China
facility: Novartis Investigative Site
state: Shanghai
city: Rennes
country: France
facility: Novartis Investigative Site
state: Ille Et Vilaine
city: Lille
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Pessac Cedex
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Osaka Sayama
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Chan SL, Schuler M, Kang YK, Yen CJ, Edeline J, Choo SP, Lin CC, Okusaka T, Weiss KH, Macarulla T, Cattan S, Blanc JF, Lee KH, Maur M, Pant S, Kudo M, Assenat E, Zhu AX, Yau T, Lim HY, Bruix J, Geier A, Guillen-Ponce C, Fasolo A, Finn RS, Fan J, Vogel A, Qin S, Riester M, Katsanou V, Chaudhari M, Kakizume T, Gu Y, Porta DG, Myers A, Delord JP. A first-in-human phase 1/2 study of FGF401 and combination of FGF401 with spartalizumab in patients with hepatocellular carcinoma or biomarker-selected solid tumors. J Exp Clin Cancer Res. 2022 Jun 2;41(1):189. doi: 10.1186/s13046-022-02383-5.
citation: Castanon Alvarez E, Giallombardo M, Gil-Bazo I, Papadimitriou K, Pauwels P, Peeters M, Rolfo C. Looking into the "Garden of the Hesperides": new drugs for hepatocellular carcinoma. Minerva Chir. 2015 Apr;70(2):119-29. Epub 2015 Jan 23.