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.

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma (HCC); Solid Malignancies
• Intervention / Treatment: Drug: FGF401; Biological: PDR001

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 Type: Interventional
• Enrollment (Actual): 172
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Novartis Investigative Site
• France
  • Lille, France, 59037
    • Novartis Investigative Site
  • Montpellier, France, 34295
    • Novartis Investigative Site
  • Pessac Cedex, France, 33604
    • Novartis Investigative Site
  • Toulouse, France, 31059
    • Novartis Investigative Site
  • Ille Et Vilaine
    • Rennes, Ille Et Vilaine, France, 35062
      • Novartis Investigative Site
• Germany
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Wuerzburg, Germany, 97080
    • Novartis Investigative Site
• Hong Kong
  • Hong Kong, Hong Kong
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41124
      • Novartis Investigative Site
• Japan
  • Osaka
    • Osaka Sayama, Osaka, Japan, 589 8511
      • Novartis Investigative Site
  • Tokyo
    • Chuo ku, Tokyo, Japan, 104 0045
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06351
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 05505
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
• Taiwan
  • Tainan, Taiwan, 70403
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California LA Santa Monica Location
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Oncology Dept
  • Texas
    • Houston, Texas, United States, 77030
      • Uni Of TX MD Anderson Cancer Cntr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I: FGF401 50 mg fasted; Participants received single agent FGF401 50 mg while fasted	Drug: FGF401; FGF401 is a FGFR4 inhibitor.
Experimental: Phase I: FGF401 80 mg fasted; Participants received single agent FGF401 80 mg while fasted	Drug: FGF401; FGF401 is a FGFR4 inhibitor.
Experimental: Phase I: FGF401 80 mg fed; Participants received single agent FGF401 80 mg while fed	Drug: FGF401; FGF401 is a FGFR4 inhibitor.
Experimental: Phase I: FGF401 120 mg fasted; Participants received single agent FGF401 120 mg while fasted	Drug: FGF401; FGF401 is a FGFR4 inhibitor.
Experimental: Phase I: FGF401 120 mg fed; Participants received single agent FGF401 120 mg while fed	Drug: FGF401; FGF401 is a FGFR4 inhibitor.
Experimental: Phase I: FGF401 150 mg fasted; Participants received single agent FGF401 150 mg while fasted	Drug: FGF401; FGF401 is a FGFR4 inhibitor.
Experimental: Phase I: FGF401 80 mg + PDR001 300 mg; Participants received FGF401 80 mg in combination with PDR001 300 mg while fasted	Drug: FGF401; FGF401 is a FGFR4 inhibitor.; Biological: PDR001; PDR001 is a humanized anti-PD1 IgG4 antibody that blocks the binding of PD-L1 and PD-L2
Experimental: Phase I: FGF401 120 mg + PDR001 300 mg; Participants received FGF401 120 mg in combination with PDR001 300 mg while fasted	Drug: FGF401; FGF401 is a FGFR4 inhibitor.; Biological: PDR001; PDR001 is a humanized anti-PD1 IgG4 antibody that blocks the binding of PD-L1 and PD-L2
Experimental: Phase II: Group 1 - FGF401 120 mg QD; Group 1 was comprised of HCC participants from Asian countries who received single agent FGF401 120 mg QD while fasted	Drug: FGF401; FGF401 is a FGFR4 inhibitor.
Experimental: Phase II: Group 2 - FGF401 120 mg QD; Group 2 was comprised of HCC participants from non-Asian countries who took single agent FGF401 120 mg QD while fasted	Drug: FGF401; FGF401 is a FGFR4 inhibitor.
Experimental: Phase II: Group 3 - FGF401 120 mg QD; Group 3 was comprised of participants with other solid malignancies regardless of geography who took single agent FGF401 120 mg QD while fasted	Drug: FGF401; FGF401 is a FGFR4 inhibitor.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-limiting Toxicity (DLT): Phase I Only	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.	Cycle 1 (C1) (21 days) for FGF401 single agent, Cycle 1 and Cycle 2 (C2) (42 days) for FGF401 and PDR001 combination
Time to Progression (TTP): Group 1 & Group 2 (Phase II Only)	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	approx. 4.5 years
Overall Response Rate (ORR) Based on Local Assessment: Group 3 (Phase II Only)	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).	approx. 4.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Response (BOR) by Investigator Assessment: Phase I and Phase II	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.	approx. 4.5 years
Overall Response Rate (ORR) by Investigator Assessment Phase I and FGF401 Single Agent Phase II Groups 1 & 2	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)	approx. 4.5 years
Disease Control Rate (DCR) by Local Investigator Assessment Phase I and FGF401 Single Agent Phase II Groups 1, 2 & 3	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).	approx. 4.5 years
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)	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.	approx. 4.5 years
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)	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.	start of treatment to death, up to about 53 months
Progression-free Survival (PFS) - FGF401 Single Agent Phase II: Group 3	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.	4.5 years
Presence and/or Concentration of Anti-PDR001 Antibodies	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.	Day 1 of Cycle 1 to 6, approx. 10 months after C1D1 and 150-day safety follow up (FU)
Cmax of PDR001 in Combination With FGF401: Phase I	Cmax is the maximum (peak) observed plasma drug concentration (mass x volume-1)	After the first dosing sample collection was at: C1D1 0hr , C1D1 1hr, C1D8 168hr, C1D15 336hr, C2D1 504hr; each cycle is 21 days
AUClast and AUCtau of PDR001 in Combination of FGF401: Phase I	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)	After the first dosing sample collection was at: C1D1 0hr , C1D1 1hr, C1D8 168hr, C1D15 336hr, C2D1 504hr; each cycle is 21 days
T1/2 of PDR001: Phase I	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.	After the first dosing sample collection was at: C1D1 0hr , C1D1 1hr, C1D8 168hr, C1D15 336hr, C2D1 504hr; each cycle is 21 days
Cmax of FGF401: Phase I	Cmax is the maximum (peak) observed plasma drug concentration (mass x volume-1)	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 of FGF401 in Combination With PDR001: Phase I	Cmax is the maximum (peak) observed plasma drug concentration (mass x volume-1)	C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h)
AUCinf, AUClast & AUCtau of FGF401: Phase I	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)	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, AUClast & AUCtau of FGF401 in Combination With PDR001: Phase I	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)	C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h)
T1/2 of FGF401: Phase I	The elimination half-life associated with the terminal slope ( z) of a semi logarithmic concentration-time curve (time).	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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 29, 2014
• Primary Completion (Actual): May 30, 2019
• Study Completion (Actual): May 30, 2019

Study Registration Dates

• First Submitted: December 9, 2014
• First Submitted That Met QC Criteria: December 24, 2014
• First Posted (Estimated): December 25, 2014

Study Record Updates

• Last Update Posted (Actual): October 21, 2024
• Last Update Submitted That Met QC Criteria: September 30, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: HCC; PD-1; PDR001; FGF401; FGFR4; FGF19; solid malignancies characterized by positive FGFR4 and KLB expression
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Spartalizumab
• Other Study ID Numbers: CFGF401X2101; 2014-002929-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No