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

Phase 1

Completed

• Conditions: Hepatocellular Carcinoma (HCC); Solid Malignancies
• Interventions: Drug: FGF401; Biological: PDR001

• Registration Number: NCT02325739
• Lead Sponsor: Novartis Pharmaceuticals

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.

Study Timeline

• Study First Submitted: 2014-12-09
• Study First Submitted QC: 2014-12-24
• Study First Posted: 2014-12-25
• Study Start: 2014-12-29
• Primary Completion: 2019-05-30
• Study Completion: 2019-05-30
• Results First Submitted: 2020-05-29
• Results First Submitted QC: 2020-11-21
• Results First Posted: 2020-12-17
• Status Verified: 2024-09
• Last Update Submitted: 2024-09-30
• Last Update Posted: 2024-10-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 172

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase I: FGF401 80 mg + PDR001 300 mg	PDR001	Participants received FGF401 80 mg in combination with PDR001 300 mg while fasted
Phase I: FGF401 120 mg fed	FGF401	Participants received single agent FGF401 120 mg while fed
Phase I: FGF401 80 mg + PDR001 300 mg	FGF401	Participants received FGF401 80 mg in combination with PDR001 300 mg while fasted
Phase I: FGF401 50 mg fasted	FGF401	Participants received single agent FGF401 50 mg while fasted
Phase I: FGF401 80 mg fasted	FGF401	Participants received single agent FGF401 80 mg while fasted
Phase I: FGF401 120 mg fasted	FGF401	Participants received single agent FGF401 120 mg while fasted
Phase II: Group 2 - FGF401 120 mg QD	FGF401	Group 2 was comprised of HCC participants from non-Asian countries who took single agent FGF401 120 mg QD while fasted
Phase I: FGF401 120 mg + PDR001 300 mg	FGF401	Participants received FGF401 120 mg in combination with PDR001 300 mg while fasted
Phase I: FGF401 120 mg + PDR001 300 mg	PDR001	Participants received FGF401 120 mg in combination with PDR001 300 mg while fasted
Phase II: Group 1 - FGF401 120 mg QD	FGF401	Group 1 was comprised of HCC participants from Asian countries who received single agent FGF401 120 mg QD while fasted
Phase I: FGF401 150 mg fasted	FGF401	Participants received single agent FGF401 150 mg while fasted
Phase II: Group 3 - FGF401 120 mg QD	FGF401	Group 3 was comprised of participants with other solid malignancies regardless of geography who took single agent FGF401 120 mg QD while fasted
Phase I: FGF401 80 mg fed	FGF401	Participants received single agent FGF401 80 mg while fed

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR) Based on Local Assessment: Group 3 (Phase II Only)	approx. 4.5 years	ORR is defined as the percentage of patients with a best overall response of CR or PR (RECIST v1.1).; FGF401 single agent-Phase II part - Group 3 (non-HCC, other solid tumors).
Time to Progression (TTP): Group 1 & Group 2 (Phase II Only)	approx. 4.5 years	TTP is defined as the date of start treatment to the date of event defined as the first documented progression or death due to underlying cancer. Method used was Kaplan-Meier analysis.; Group 1: HCC subjects form Asian countries; Group 2: HCC subjects form non-Asian countries
Number of Participants With Dose-limiting Toxicity (DLT): Phase I Only	Cycle 1 (C1) (21 days) for FGF401 single agent, Cycle 1 and Cycle 2 (C2) (42 days) for FGF401 and PDR001 combination	A dose-limiting toxicity was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the evaluation period of DLTs and met any of the criteria listed. The estimation of the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of the treatment was based upon the estimation of the probability of DLT during the evaluation period for subjects in the dose determining set (DDS). A subject with multiple occurrences of a DLT under one treatment is counted only once in the AE category for that treatment. A subject with multiple DLTs within a primary system organ class is counted only once in the total row.

Secondary Outcome Measures

Name	Time	Method
Best Overall Response (BOR) by Investigator Assessment: Phase I and Phase II	approx. 4.5 years	BOR is the best response recorded from the start of the treatment until disease progression/recurrence. BOR is determined according to: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) and unknown.
Overall Response Rate (ORR) by Investigator Assessment Phase I and FGF401 Single Agent Phase II Groups 1 & 2	approx. 4.5 years	ORR is defined as the proportion of patients with a best overall response of CR or PR (RECIST v1.1).; Phase I part and FGF401 single agent Phase II Group 1 (HCC, Asians) and Group 2 (HCC, non-Asians)
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)	approx. 4.5 years	TTP is defined as the date of start treatment to the date of event defined as the first documented progression or death due to underlying cancer. Method used was Kaplan-Meier analysis.
AUCinf, AUClast & AUCtau of FGF401: Phase I	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)	AUCinf: The AUC from time zero to infinity (mass x time x volume-1); AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast) (mass x time x volume-1); AUCtau: The AUC calculated to the end of a dosing interval (tau) (amount x time x volume-1)
Progression-free Survival (PFS) - FGF401 Single Agent Phase II: Group 3	4.5 years	Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Group 3 - non-HCC, other solid tumors. Method used was Kaplan-Meier analysis.
Presence and/or Concentration of Anti-PDR001 Antibodies	Day 1 of Cycle 1 to 6, approx. 10 months after C1D1 and 150-day safety follow up (FU)	Serum PDR001 concentrations as well as immunogenicity analysis were performed for all subjects receiving PDR001. Treatment-induced ADA-positive percentage was based on percentage subjects ADA-negative at baseline. Treatment-boosted ADA-positive percentage was based on subjects ADA-positive at baseline.
Cmax of FGF401: Phase I	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)	Cmax is the maximum (peak) observed plasma drug concentration (mass x volume-1)
Cmax of FGF401 in Combination With PDR001: Phase I	C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h)	Cmax is the maximum (peak) observed plasma drug concentration (mass x volume-1)
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)	start of treatment to death, up to about 53 months	Overall survival (OS) is defined as the time from date of start of treatment to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last known date patient alive. Method used was Kaplan-Meier analysis.
Cmax of PDR001 in Combination With FGF401: Phase I	After the first dosing sample collection was at: C1D1 0hr , C1D1 1hr, C1D8 168hr, C1D15 336hr, C2D1 504hr; each cycle is 21 days	Cmax is the maximum (peak) observed plasma drug concentration (mass x volume-1)
T1/2 of PDR001: Phase I	After the first dosing sample collection was at: C1D1 0hr , C1D1 1hr, C1D8 168hr, C1D15 336hr, C2D1 504hr; each cycle is 21 days	Due to the sparse PK sampling designed from PDR001, the PDR001 concentration data was insufficient for accurate estimation of secondary PK parameters including T1/2.
AUCinf, AUClast & AUCtau of FGF401 in Combination With PDR001: Phase I	C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h)	AUCinf: The AUC from time zero to infinity (mass x time x volume-1); AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast) (mass x time x volume-1); AUCtau: The AUC calculated to the end of a dosing interval (tau) (amount x time x volume-1)
Disease Control Rate (DCR) by Local Investigator Assessment Phase I and FGF401 Single Agent Phase II Groups 1, 2 & 3	approx. 4.5 years	DCR is the percentage of participants with a best overall response of CR or PR or SD per local assessment according to RECIST v1.1. Phase I part and FGF401 single agent Phase II Group 1 (HCC, Asians) and Group 2 (HCC, non-Asians) and Group 3 (non-HCC, other solid tumors).
AUClast and AUCtau of PDR001 in Combination of FGF401: Phase I	After the first dosing sample collection was at: C1D1 0hr , C1D1 1hr, C1D8 168hr, C1D15 336hr, C2D1 504hr; each cycle is 21 days	AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast) (mass x time x volume-1); AUCtau (AUC0 504h): The AUC calculated to the end of a dosing interval (tau) (amount x time x volume-1)
T1/2 of FGF401: Phase I	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)	The elimination half-life associated with the terminal slope ( z) of a semi logarithmic concentration-time curve (time).

Trial Locations

Locations (4)

University of California LA Santa Monica Location; 🇺🇸 Los Angeles, California, United States

Uni Of TX MD Anderson Cancer Cntr; 🇺🇸 Houston, Texas, United States

Massachusetts General Hospital Oncology Dept; 🇺🇸 Boston, Massachusetts, United States

Novartis Investigative Site; 🇨🇳 Taipei, Taiwan