Clinical Trials /

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

NCT02325739

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: CFGF401X2101
  • SECONDARY ID: 2014-002929-35
  • NCT ID: NCT02325739

Conditions

  • Hepatocellular Carcinoma (HCC)
  • Solid Malignancies

Interventions

DrugSynonymsArms
FGF401Phase I: FGF401 120 mg + PDR001 300 mg
PDR001Phase I: FGF401 120 mg + PDR001 300 mg

Purpose

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.
    

Trial Arms

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

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants With Dose-limiting Toxicity (DLT): Phase I Only
Time Frame:Cycle 1 (C1) (21 days) for FGF401 single agent, Cycle 1 and Cycle 2 (C2) (42 days) for FGF401 and PDR001 combination
Safety Issue:
Description: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

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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • FGF401
  • PDR001
  • PD-1
  • FGFR4
  • FGF19
  • HCC
  • solid malignancies characterized by positive FGFR4 and KLB expression

Last Updated

December 17, 2020