Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Immunoglobulins

Spartalizumab

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Participants received single agent FGF401 50 mg while fasted

Participants received single agent FGF401 80 mg while fasted

Participants received single agent FGF401 80 mg while fed

Participants received single agent FGF401 120 mg while fasted

Participants received single agent FGF401 120 mg while fed

Participants received single agent FGF401 150 mg while fasted

Participants received FGF401 80 mg in combination with PDR001 300 mg while fasted

Participants received FGF401 120 mg in combination with PDR001 300 mg while fasted

Group 1 was comprised of HCC participants from Asian countries who received single agent FGF401 120 mg QD while fasted

Group 2 was comprised of HCC participants from non-Asian countries who took single agent FGF401 120 mg QD while fasted

Group 3 was comprised of participants with other solid malignancies regardless of geography who took single agent FGF401 120 mg QD while fasted

FGF401

PDR001 is a humanized anti-PD1 IgG4 antibody that blocks the binding of PD-L1 and PD-L2

PDR001

Novartis Pharmaceuticals

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.

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.

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

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

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.

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

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).

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.

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)

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).

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.

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.

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.

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 is the maximum (peak) observed plasma drug concentration (mass x volume-1)

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)

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: 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)

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

Adverse Event (AE): Any sign or symptom that occurs during the study treatment plus the 30 or 150 days post treatment depending on single dose or combination dose.

Phase I: 50 mg Fasted

Phase I: 80 mg Fasted

Phase I: 80 mg Fed

Phase I: 120 mg Fasted

Phase I: 120 mg Fed

Phase I: 150 mg Fasted

Group 1 was comprised of HCC participants from Asian contrives who took single agent FGF401 120 mg QD while fasted

Phase II: Group 1 - FGF401 120 mg QD

Phase II: Group 2 - FGF401 120 mg QD

Phase II: Group 3 - FGF401 120 mg QD

These were all the participants who received single dose of FGF401

All Patients of Single Agent FGF401

Phase I: FGF401 80 mg + PDR001 300 mg

Phase I: FGF401 120 mg + PDR001 300 mg

These were all the participants in the Phase I part who received combination dose of FGF401 and PDR001

All Patients of Combination Dose

Overall participants in the in Phase I \& Phase II of study

All Patients

PhaseII: Group 3 - FGF401 120 mg QD

Total

18 y - <65 y

65 y - <85 y

>=85 y

Age, Customized

Sex: Female, Male

Asian

Black

Caucasian

Not applicable

Other

Pacific Islander

Unknown

Race/Ethnicity, Customized

The full analysis set (FAS) comprised all subjects who received at least one dose of study medication. Subjects enrolled in the Phase I part were analyzed according to the treatment they had been assigned to. Subjects enrolled in the Phase II part were analyzed by group.

Study Director

Any Primary system organ class (SOC)

Invest.: Aspartate Aminotrans. increased

Invest.: Alanine aminotrans. increased

Invest.: Blood bilirubin increased

Dose Determining Set: All subjects from safety set (Phase I) who either met the minimum exposure criterion and had sufficient safety evaluations or had experienced a DLT during the DLT evaluation period.

Number of Participants With Dose-limiting Toxicity (DLT): Phase I Only

Full Analysis Set (FAS): Comprised all subjects who received at least one dose of study medication. Subjects enrolled in the Phase II part were analyzed by group.

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

FAS: The full analysis set (FAS) comprised all subjects who received at least one dose of study medication. Subjects enrolled in the Phase II part were analyzed by group.

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

Complete Response

Partial Response

Stable Disease

Progressive Disease

FAS: The full analysis set (FAS) comprised all subjects who received at least one dose of study medication. Subjects enrolled in the Phase I part were analyzed according to the treatment they had been assigned to. Subjects enrolled in the Phase II part were analyzed by group.

Best Overall Response (BOR) by Investigator Assessment: Phase I and Phase II

FAS: The FAS comprised all subjects who received at least one dose of study medication. Subjects enrolled in the Phase I part were analyzed according to the treatment they had been assigned to. Subjects enrolled in the Phase II part were analyzed by group.

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

Disease Control Rate (DCR) by Local Investigator Assessment Phase I and FGF401 Single Agent Phase II Groups 1, 2 & 3

The full analysis set (FAS) comprised all subjects who received at least one dose of study medication. Subjects enrolled in the Phase I part were analyzed according to the treatment they had been assigned to.

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)

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)

Progression-free Survival (PFS) - FGF401 Single Agent Phase II: Group 3

ADA-negative

ADA-positive (i.e. ADA incidence)

Treatment-induced ADA-positive

Treatment-boosted ADA-positive

FAS: The full analysis set (FAS) comprised all subjects who received at least one dose of study medication. Subjects enrolled in the Phase I part were analyzed according to the treatment they had been assigned to.

Presence and/or Concentration of Anti-PDR001 Antibodies

The PAS included all subjects who provided at least one evaluable drug concentration. For those requiring non-compartment analyses, the PAS included all subjects who provided an evaluable PK profile.

Cmax of PDR001 in Combination With FGF401: Phase I

AUClast

AUC0-504h

The PAS included all subjects who provided at least one evaluable drug concentration. For those requiring non-compartment analyses, the PAS included all subjects who provided an evaluable PK profile

AUClast and AUCtau of PDR001 in Combination of FGF401: Phase I

The PAS incl. all subjects who provided at least one evaluable drug concentration. For those requiring non-compartment analyses, PAS incl. all subjects who provided an evaluable PK profile. Due to the sparse PK sampling designed for PDR001, PDR001 concentration data was insufficient for accurate estimation of secondary PK parameters including T1/2.

T1/2 of PDR001: Phase I

Cycle 1 Day 1

Cycle 1 Day 8

Cycle 2 Day 1

Cmax of FGF401: Phase I

Cmax of FGF401 in Combination With PDR001: Phase I

AUCinf C1D1

AUClast C1D1

AUCtau C1D1

AUCinf C1D8

AUClast C1D8

AUCtau C1D8

AUCinf C2D1

AUClast C2D1

AUCtau C2D1

AUCinf, AUClast & AUCtau of FGF401: Phase I

AUCinf

AUCtau

AUCinf, AUClast & AUCtau of FGF401 in Combination With PDR001: Phase I

C1D1

C1D8

C2D1

T1/2 of FGF401: Phase I

Total deaths

Deaths on-treatment

Deaths post-treatment survival follow up

This includes on-treatment deaths collected from first patient first treatment up to 30 days after drug discontinuation for a maximum of approx. 135.3 weeks (treatment duration ranged from 0.1 to 135.3 weeks for FGF401 single agent and from 6.0 to 57.0 weeks for FGF401 plus PDR001 combination). Deaths post treatment survival follow up were collected after the on treatment period, up to approx. 4.5 years. Participants who had not died after study drug discontinuation were censored at the last date when the participant had some documented personal contact (visit or phone call) with the investigator.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
FGF401 in HCC and Solid Tumors Characterized by Positive FGFR4 and KLB Expression	NCT02325739	Hepatocellular ... Solid Malignanc...	FGF401 PDR001	18 Years -	Novartis
FGF401 in HCC and Solid Tumors Characterized by Positive FGFR4 and KLB Expression	NCT02325739	Hepatocellular ... Solid Malignanc...	FGF401 PDR001	18 Years -	Novartis

Spots Global Cancer Trial Database for solid malignancies characterized by positive fgfr4 and klb expression