Hepatocellular Carcinoma (HCC) Clinical Trial
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
Verified date | November 2020 |
Source | Novartis |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 172 |
Est. completion date | May 30, 2019 |
Est. primary completion date | May 30, 2019 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | 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. |
Country | Name | City | State |
---|---|---|---|
China | Novartis Investigative Site | Shanghai | Shanghai |
France | Novartis Investigative Site | Lille Cedex | |
France | Novartis Investigative Site | Montpellier cedex 5 | |
France | Novartis Investigative Site | Pessac Cedex | |
France | Novartis Investigative Site | Rennes Cedex | Ille Et Vilaine |
France | Novartis Investigative Site | Toulouse Cedex 9 | |
Germany | Novartis Investigative Site | Essen | |
Germany | Novartis Investigative Site | Hannover | |
Germany | Novartis Investigative Site | Heidelberg | |
Germany | Novartis Investigative Site | Wuerzburg | |
Hong Kong | Novartis Investigative Site | Hong Kong | |
Italy | Novartis Investigative Site | Milano | MI |
Italy | Novartis Investigative Site | Modena | MO |
Japan | Novartis Investigative Site | Chuo ku | Tokyo |
Japan | Novartis Investigative Site | Osaka Sayama | Osaka |
Korea, Republic of | Novartis Investigative Site | Seoul | Korea |
Korea, Republic of | Novartis Investigative Site | Seoul | |
Korea, Republic of | Novartis Investigative Site | Seoul | |
Singapore | Novartis Investigative Site | Singapore | |
Spain | Novartis Investigative Site | Barcelona | Catalunya |
Spain | Novartis Investigative Site | Barcelona | Catalunya |
Spain | Novartis Investigative Site | Madrid | |
Taiwan | Novartis Investigative Site | Tainan | Taiwan ROC |
Taiwan | Novartis Investigative Site | Taipei | |
United States | Massachusetts General Hospital Oncology Dept | Boston | Massachusetts |
United States | University of Texas MD Anderson Cancer Center | Houston | Texas |
United States | University of California at Los Angeles Santa Monica Location | Los Angeles | California |
Lead Sponsor | Collaborator |
---|---|
Novartis Pharmaceuticals |
United States, China, France, Germany, Hong Kong, Italy, Japan, Korea, Republic of, Singapore, Spain, Taiwan,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | |
Primary | 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 | |
Primary | 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 | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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) | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) |
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