Hepatocellular Carcinoma, Non-Small Cell Lung Cancer, Solid Tumors
Conditions
Keywords
FXB0871, TEV-56278, PD-1, IL-2, Dose Escalation, Dose Expansion
Brief summary
This is a phase 1a/1b, open-label, multicenter, dose-escalation and dose-expansion study evaluating the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of FXB0871 monotherapy in adults with selected locally advanced or metastatic solid tumors. In Part Ia, participants with selected solid tumors that have progressed after, are intolerant to, or are not suitable for standard therapy will receive FXB0871 in dose-escalation cohorts to determine the maximum tolerated dose and/or recommended phase 2 dose. In Part Ib, participants with PD-(L)1-resistant non-small cell lung cancer or hepatocellular carcinoma will receive FXB0871 in dose-expansion cohorts to further evaluate antitumor activity, safety, and dose optimization.
Detailed description
This first-in-human study consists of a dose-escalation part (Part Ia) and a dose-expansion part (Part Ib). In Part Ia, adults with selected locally advanced or metastatic solid tumors will receive FXB0871 monotherapy by intravenous infusion every 2 weeks in sequential pre-determinde dose cohorts using a Bayesian optimal interval design. The planned dosing schedule is every 2 weeks, with a dose-limiting toxicity observation period of the first 2 treatment cycles. Additional intermediate dose levels, cohort expansion, and schedule optimization to every 3 or 4 weeks may be allowed according to protocol-defined safety, PK/PD, and preliminary antitumor activity data. Part Ib will start after determination of the monotherapy recommended phase 2 dose (RP2D). Cohort A will enroll participants with PD-(L)1-resistant locally advanced or metastatic non-small cell lung cancer and randomize them 1:1 to receive FXB0871 at the RP2D or at a lower dose selected on the basis of Part Ia data. Cohort B will enroll participants with PD-(L)1-resistant locally advanced or metastatic hepatocellular carcinoma to receive FXB0871 at the RP2D. Participants may continue study treatment for up to 12 months or until unacceptable toxicity, disease progression, or another protocol-defined discontinuation criterion is met.
Interventions
BIOLOGICALIntervention1：FXB0871
FXB0871 is administered by intravenous infusion at pre-determined dose level in Part Ia every 2 weeks. Treatment may continue for up to 12 months or until unacceptable toxicity, disease progression, or another protocol-defined discontinuation criterion is met.
BIOLOGICALIntervention2：FXB0871
FXB0871 is administered by intravenous infusion at pre-determined dose level in Phase Ib every 2 weeks. Treatment may continue for up to 12 months or until unacceptable toxicity, disease progression, or another protocol-defined discontinuation criterion is met.
BIOLOGICALIntervention3：FXB0871
FXB0871 is administered by intravenous infusion at pre-determined dose level in Phase Ib every 2 weeks. Treatment may continue for up to 12 months or until unacceptable toxicity, disease progression, or another protocol-defined discontinuation criterion is met.
BIOLOGICALIntervention4：FXB0871
FXB0871 is administered by intravenous infusion at pre-determined dose level in Phase Ib every 2 weeks. Treatment may continue for up to 12 months or until unacceptable toxicity, disease progression, or another protocol-defined discontinuation criterion is met.
Sponsors
Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent. * Age ≥18 years. * Histologically confirmed selected locally advanced or metastatic solid tumor with progression on, intolerance to, or no suitable standard therapy. * ECOG performance status 0 or 1. * At least one measurable lesion per RECIST v1.1. * Pretreatment tumor tissue available (archival or fresh biopsy). * Life expectancy ≥12 weeks. * Oxygen saturation ≥92% on room air. * Left ventricular ejection fraction \>50%. * Adequate hematologic, coagulation, renal, hepatic, and cardiac function. * Women of childbearing potential and sexually active men must use highly effective contraception. * Tumor-specific eligibility applies, including prior anti-PD-(L)1 treatment failure for the selected cohorts. Key
Exclusion criteria
* Systemic anti-cancer therapy, major surgery, or radical radiotherapy within 4 weeks before first dose. * Prior treatment with IL-2, IL-15, or IL-7. * Active autoimmune disease requiring systemic treatment or immunodeficiency. * Systemic corticosteroids (≥10 mg/day prednisone equivalent) or other immunosuppressive therapy within 28 days before first dose, with limited protocol-defined exceptions. * Active or untreated central nervous system metastases, carcinomatous meningitis, or leptomeningeal disease. * Uncontrolled infection or clinically significant unresolved toxicities from prior therapy. * Clinically significant cardiovascular/cerebrovascular disease, uncontrolled effusions/ascites, uncontrolled hypertension, or QTcF \>470 ms. * Active hepatitis B/C, syphilis, or HIV infection. * Clinically significant interstitial lung disease or active noninfectious pneumonitis. * Pregnancy or breastfeeding. * Any other serious medical or psychiatric condition that, in the investigator's judgment, would make participation inappropriate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of dose-limiting toxicities (DLTs) in Phase Ia | First 2 cycles after first dose (each cycle = 14 days; approximately 28 days). | Percentage of participants with protocol-defined DLTs during the DLT observation period in the dose-escalation phase |
| Incidence and severity of adverse events (AEs), serious adverse events (SAEs), AEs leading to dose delay/interruption/reduction/treatment discontinuation in Phase Ia | From first dose through 90 days after last dose or initiation of new anti-tumor therapy, whichever occurs first | Safety assessed by the incidence of treatment-emergent adverse events, serious adverse events, AEs leading to dose delay/interruption/reduction/treatment discontinuation in Phase Ia. |
| Objective response rate (ORR) in Phase Ib | From first dose until disease progression, start of new anti-tumor therapy, withdrawal, death, or end of study (assessed every 8±1 weeks; approximately up to 24 months). | ORR defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) per RECIST v1.1 in Phase Ib. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR) in Phase Ia | From first dose until disease progression, start of new anti-tumor therapy, withdrawal, death, or end of study, whichever occurs first (tumor assessments every 8 ± 1 weeks; approximately up to 24 months). | Objective response rate (ORR), defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR), as assessed per RECIST v1.1 in Phase Ia. |
| Disease control rate (DCR) in Phase Ia | From first dose until disease progression, start of new anti-tumor therapy, withdrawal, death, or end of study, whichever occurs first (tumor assessments every 8 ± 1 weeks; approximately up to 24 months). | Disease control rate (DCR), defined as the proportion of participants with a best overall response of CR, PR, or stable disease (SD), as assessed per RECIST v1.1 in Phase Ia. |
| Duration of response (DOR) in Phase Ia | From first documented CR or PR until first documented disease progression or death from any cause, whichever occurs first (approximately up to 24 months). | Duration of response (DOR), defined for participants with confirmed CR or PR as the time from first documented response to first documented disease progression or death from any cause, whichever occurs first, as assessed per RECIST v1.1 in Phase Ia. |
| Progression-free survival (PFS) in Phase Ia | From first dose until first documented disease progression or death from any cause, whichever occurs first (approximately up to 24 months). | Progression-free survival (PFS), defined as the time from first dose to first documented disease progression or death from any cause, whichever occurs first, as assessed per RECIST v1.1 in Phase Ia. |
| Peak serum concentration (Cmax) | Predose up to Day 8 | Maximum observed concentration |
| Time to maximum observed concentration (Tmax) | Predose up to Day 8 | Time to maximum observed drug concentration |
| Area under the serum concentration-time curve (AUC0-last) | Predose up to Day 8 | Area under the serum concentration-time curve from time 0 to last measurable drug concentration |
| Area under the serum concentration-time curve (AUC0-∞) | Predose up to Day 8 | Area under the concentration-time curve from time zero (pre-dose) extrapolation to infinite time |
| Area under the serum concentration-time curve (AUCtau) | Predose up to Day 8 | Area under the concentration-time curve over the dosing interval |
| Trough concentration (Ctrough) | up to Day 8 | Observed concentration at the end of a dosing interval, immediately before next administration |
| Clearance (CL) | Predose up to Day 8 | Systemic (total body) clearance following iv administration |
| Volume of distribution (Vz) | Predose up to Day 8 | Volume of distribution following iv administration |
| Half-life (t1/2) | Predose up to Day 8 | Terminal phase half-life |
| Average concentration (Cavg) | Predose up to Day 8 | Average concentration over a dosing interval |
| Accumulation ratio (Rac) | Predose up to Day 8 | Accumulation ratio |
| Incidence and severity of AEs/SAEs and AEs leading to dose modification or discontinuation in Phase Ib | From first dose through 90 days after last dose or initiation of new anti-tumor therapy, whichever occurs first. | Safety and tolerability in the dose-expansion phase. |
| ORR by modified RECIST (mRECIST) in the HCC cohort of Phase Ib | From first dose until disease progression, start of new anti-tumor therapy, withdrawal, death, or end of study (assessed every 8±1 weeks; approximately up to 24 months). | ORR in participants with hepatocellular carcinoma assessed by mRECIST. |
| Disease control rate (DCR) in Phase Ib | From first dose until disease progression, start of new anti-tumor therapy, withdrawal, death, or end of study, whichever occurs first (tumor assessments every 8 ± 1 weeks; approximately up to 24 months). | Disease control rate (DCR), defined as the proportion of participants with a best overall response of CR, PR, or SD, as assessed per RECIST v1.1 in Phase Ib. |
| Time to response (TTR) in Phase Ib | From first dose to first documented CR or PR (tumor assessments every 8 ± 1 weeks; approximately up to 24 months). | Time to response (TTR), defined as the time from first dose to the first documented CR or PR, as assessed per RECIST v1.1 in Phase Ib. |
| Duration of response (DOR) in Phase Ib | From first documented CR or PR until first documented disease progression or death from any cause, whichever occurs first (approximately up to 24 months). | Duration of response (DOR), defined for participants with confirmed CR or PR as the time from first documented response to first documented disease progression or death from any cause, whichever occurs first, as assessed per RECIST v1.1 in Phase Ib. |
| Title:Progression-free survival (PFS) in Phase Ib | From first dose until first documented disease progression or death from any cause, whichever occurs first (approximately up to 24 months). | Progression-free survival (PFS), defined as the time from first dose to first documented disease progression or death from any cause, whichever occurs first, as assessed per RECIST v1.1 in Phase Ib. |
| Overall survival (OS) in Phase Ib | From first dose until death from any cause (approximately up to 24 months). | Overall survival measured from first dose to death from any cause. |
Countries
China
Contacts
CONTACTCaicun Zhou
CONTACTFei Zhou
Outcome results
None listed