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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02325739
Recruitment Status : Completed
First Posted : December 25, 2014
Results First Posted : December 17, 2020
Last Update Posted : December 17, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( 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.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma (HCC) Solid Malignancies Drug: FGF401 Biological: PDR001 Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 172 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 29, 2014
Actual Primary Completion Date : May 30, 2019
Actual Study Completion Date : May 30, 2019

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.




Primary Outcome Measures :
  1. 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 ]
    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.

  2. Time to Progression (TTP): Group 1 & Group 2 (Phase II Only) [ Time Frame: 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


  3. Overall Response Rate (ORR) Based on Local Assessment: Group 3 (Phase II Only) [ Time Frame: 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).



Secondary Outcome Measures :
  1. Best Overall Response (BOR) by Investigator Assessment: Phase I and Phase II [ Time Frame: 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.

  2. Overall Response Rate (ORR) by Investigator Assessment Phase I and FGF401 Single Agent Phase II Groups 1 & 2 [ Time Frame: 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)


  3. 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 ]
    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).

  4. 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 ]
    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.

  5. 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 ]
    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.

  6. Progression-free Survival (PFS) - FGF401 Single Agent Phase II: Group 3 [ Time Frame: 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.

  7. 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) ]
    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.

  8. 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 ]
    Cmax is the maximum (peak) observed plasma drug concentration (mass x volume-1)

  9. 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 ]

    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)


  10. 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 ]
    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.

  11. 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) ]
    Cmax is the maximum (peak) observed plasma drug concentration (mass x volume-1)

  12. Cmax of FGF401 in Combination With PDR001: Phase I [ Time Frame: C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h) ]
    Cmax is the maximum (peak) observed plasma drug concentration (mass x volume-1)

  13. 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) ]

    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)


  14. AUCinf, AUClast & AUCtau of FGF401 in Combination With PDR001: Phase I [ Time Frame: 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)


  15. 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) ]
    The elimination half-life associated with the terminal slope ( z) of a semi logarithmic concentration-time curve (time).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02325739


Locations
Layout table for location information
United States, California
University of California at Los Angeles Santa Monica Location
Los Angeles, California, United States, 90095
United States, Massachusetts
Massachusetts General Hospital Oncology Dept
Boston, Massachusetts, United States, 02114
United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
China, Shanghai
Novartis Investigative Site
Shanghai, Shanghai, China, 200032
France
Novartis Investigative Site
Rennes Cedex, Ille Et Vilaine, France, 35062
Novartis Investigative Site
Lille Cedex, France, 59037
Novartis Investigative Site
Montpellier cedex 5, France, 34295
Novartis Investigative Site
Pessac Cedex, France, 33604
Novartis Investigative Site
Toulouse Cedex 9, France, 31059
Germany
Novartis Investigative Site
Essen, Germany, 45147
Novartis Investigative Site
Hannover, Germany, 30625
Novartis Investigative Site
Heidelberg, Germany, 69120
Novartis Investigative Site
Wuerzburg, Germany, 97080
Hong Kong
Novartis Investigative Site
Hong Kong, Hong Kong
Italy
Novartis Investigative Site
Milano, MI, Italy, 20132
Novartis Investigative Site
Modena, MO, Italy, 41124
Japan
Novartis Investigative Site
Osaka Sayama, Osaka, Japan, 589 8511
Novartis Investigative Site
Chuo ku, Tokyo, Japan, 104 0045
Korea, Republic of
Novartis Investigative Site
Seoul, Korea, Korea, Republic of, 05505
Novartis Investigative Site
Seoul, Korea, Republic of, 03080
Novartis Investigative Site
Seoul, Korea, Republic of, 06351
Singapore
Novartis Investigative Site
Singapore, Singapore, 169610
Spain
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08036
Novartis Investigative Site
Madrid, Spain, 28034
Taiwan
Novartis Investigative Site
Tainan, Taiwan ROC, Taiwan, 70403
Novartis Investigative Site
Taipei, Taiwan, 10002
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] September 27, 2018
Statistical Analysis Plan  [PDF] June 26, 2019

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02325739    
Other Study ID Numbers: CFGF401X2101
2014-002929-35 ( EudraCT Number )
First Posted: December 25, 2014    Key Record Dates
Results First Posted: December 17, 2020
Last Update Posted: December 17, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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

URL: https://www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
FGF401
PDR001
PD-1
FGFR4
FGF19
HCC
solid malignancies characterized by positive FGFR4 and KLB expression
Additional relevant MeSH terms:
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Carcinoma
Neoplasms
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases