A Study of Fruquintinib in Combination With Tislelizumab in Advanced Solid Tumors
- Conditions
- Triple Negative Breast CancerEndometrial CancerSolid Tumor, Unspecified, AdultColorectal Cancer
- Interventions
- Registration Number
- NCT04577963
- Lead Sponsor
- Hutchmed
- Brief Summary
This is an open-label, multi-center, non-randomized, Phase 1b/2 study to assess the safety and efficacy of fruquintinib in combination with tislelizumab in patients with locally advanced or metastatic solid tumors. This study will be conducted in 2 parts; a Safety Lead-in Phase (Part 1) and a Dose Expansion Phase (Part 2).
The Safety Lead-in Phase, open to any-comer solid tumors, will determine the RP2D. The RP2D will be administered to 3 cohorts of patients in the Dose Expansion Phase.
* Cohort A: Advanced or Metastatic Triple Negative Breast Cancer (TNBC) (IO-treated)
* Cohort B: Advanced or Metastatic Triple Negative Breast Cancer (TNBC) (IO-Naïve)
* Cohort C: Advanced or Metastatic Endometrial Cancer (EC) (IO-Naïve)
* Cohort D: Advanced or Metastatic Colorectal Cancer (mCRC) (IO-Naïve)
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 52
- Willing and able to provide informed consent signed by study patient or legally acceptable representative, as specified by health authorities and institutional guidelines;
- Age ≥18 years;
- Histologically or cytologically documented, advanced or metastatic Triple Negative Breast Cancer, histologically or cytologically documented, advanced or metastatic endometrial carcinoma, histologically or cytologically confirmed advanced or metastatic, unresectable adenocarcinoma of the colon or rectum.
- Tumor tissue (archival or fresh tumor tissues as formalin-fixed paraffin-embedded blocks or approximately 15 unstained slides) for central laboratory assessment.
- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1.
- At least 1 measurable lesion as defined by RECIST v1.1.
- Has at screening any central nervous system metastasis and/or leptomeningeal disease.
- Except for Cohort A, Prior therapy targeting CTLA-4, PD-1, PD-L1 or programmed cell death protein ligand-2 (PD-L2) or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways.
- Prior treatment with a VEGFR-TKI or anti-VEGFR antibody (eg, ramucirumab).
- Except for Cohort D, prior treatment with an anti-VEGFR antibody (eg, bevacizumab).
- Tumor tissue (archival or fresh tumor tissues as formalin-fixed paraffin-embedded blocks or approximately 15 unstained slides) for central laboratory assessment.
- Active autoimmune diseases or history of autoimmune diseases that may relapse, or history of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases including but not limited to pulmonary fibrosis, acute lung diseases, etc.
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 2 Fruquintinib Patients will be enrolled to one of the following expansion cohorts: * Cohort A: TNBC (immuno-oncology \[IO\]-treated in the metastatic setting) * Cohort B: TNBC (IO-Naïve in the metastatic setting) * Cohort C: EC * Cohort D: MSS CRC Part 1 Fruquintinib Approximately 6-12 patients with locally advanced or metastatic solid tumors will be enrolled to receive fruquintinib in combination with tislelizumab and assessed for DLTs during the 28-day DLT observation period Part 1 Tislelizumab Approximately 6-12 patients with locally advanced or metastatic solid tumors will be enrolled to receive fruquintinib in combination with tislelizumab and assessed for DLTs during the 28-day DLT observation period Part 2 Tislelizumab Patients will be enrolled to one of the following expansion cohorts: * Cohort A: TNBC (immuno-oncology \[IO\]-treated in the metastatic setting) * Cohort B: TNBC (IO-Naïve in the metastatic setting) * Cohort C: EC * Cohort D: MSS CRC
- Primary Outcome Measures
Name Time Method Part 1: Number of Patients With Dose-Limiting Toxicities (DLTs) From the first dose of study treatment (Day 1) up to Day 28 of Cycle 1 (cycle duration: 4 weeks) According to National Cancer Institute Common Terminology Criteria for Adverse Events(AEs) v5.0, DLT was defined as any 1 of following toxicities during DLT assessment window and considered by Investigator to be related to 1 or more study treatments:a)Hematologic: grade(G) 4 neutropenia lasting \>7 days, G ≥3 febrile neutropenia, G 3 thrombocytopenia with clinically significant bleeding, G 4 thrombocytopenia, G ≥4 anemia.b) Non-hematologic:all G ≥3 non-hematologic toxicities except:G 3 endocrinopathy controlled by hormonal replacement with no hospitalization and resolved to G ≤1 within 7 days, G 3 nausea/vomiting or diarrhea for \<72 hours with antiemetic and supportive care, G 3 fatigue for \<1 week, G ≥3 electrolyte abnormality lasting up to 72 hours and resolving with treatment, G 3 rash returning to baseline or G ≤1 within 7 days with treatment,G ≥3 amylase or lipase elevation without symptoms of pancreatitis,G 3 hypertension returning to baseline or G≤1 within 7 days with treatment.
Part 1: Recommended Phase 2 Dose (RP2D) of Fruquintinib in Combination With Tislelizumab From the first dose of study treatment (Day 1) up to Day 28 of Cycle 1 (cycle duration: 4 weeks) The RP2D of fruquintinib in combination with tislelizumab based on the safety and tolerability assessments in Part 1 patients.
Part 2: Objective Response Rate (ORR) Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months The ORR was defined as the percentage of patients with a confirmed best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator using RECIST v1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 millimeters (mm). The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
- Secondary Outcome Measures
Name Time Method Parts 1 and 2: Progression-free Survival (PFS) Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months PFS was defined as the time from the start of study treatment until the first radiographic documentation of objective progression as assessed by the investigator using RECIST v1.1, or death from any cause. The PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum also demonstrated an absolute increase of at least 5 mm. The appearance of 1 or more new lesions was also considered progression.
Parts 1 and 2: Disease Control Rate (DCR) Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months The DCR was defined as the percentage of patients with a BOR of CR, PR, or stable disease (SD) lasting for at least 7 weeks as determined by the investigator using RECIST v1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum on study.
Parts 1 and 2: Clinical Benefit Rate (CBR) Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months The CBR was defined as the percentage of patients with a BOR of CR, PR, or durable SD (i.e., lasting for at least 6 months) as determined by the investigator using RECIST v1.1. Durable SD was SD for at least 6 months. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum on study.
Part 1: Objective Response Rate Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months The ORR was defined as the percentage of patients with a confirmed BOR of CR or PR as determined by the investigator using RECIST v1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST v1.1 progression or the start date of new anticancer therapy, whichever came first. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Parts 1 and 2: Duration of Response (DoR) Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months The DoR was defined as the time from the first occurrence of PR or CR by RECIST v1.1, whichever came first until PD or death. The CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum also demonstrated an absolute increase of at least 5 mm. The appearance of 1 or more new lesions was also considered progression.
Parts 1 and 2: Overall Survival (OS) From the first dose of study treatment (Day 1) up to date of death due to any cause, up to a maximum of approximately 34 months The OS was defined as the time from start of study treatment until the date of death due to any cause.
Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11 Pre-dose on Days 1, 8, 15, 21 of Cycle 1 and on Day 1 of Cycles 2, 4, 7, 13; 2 to 4 hours post-dose on Days 1 and 21 of Cycle 1 (cycle duration: 4 weeks) Blood samples were collected at the specified timepoints to determine plasma concentrations of fruquintinib and metabolite M11.
Parts 1 and 2: Serum Concentrations of Tislelizumab Pre-infusion on Day 1 of Cycles 1, 2, 4, 7, 13; at end of infusion on Day 1 of Cycles 1 and 4; on Days 8, 15, and 21 of Cycle 1 (cycle duration: 4 weeks) Blood samples were collected at the specified timepoints to determine serum concentrations of tislelizumab.
Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab From the first dose of study treatment (Day 1) up to end of treatment, up to approximately 17 months for Part 1 and 20 months for Part 2 Blood samples were collected at the specified timepoints to detect ADAs to tislelizumab. Treatment-induced ADA was defined as ADA negative at baseline and ADA positive post-baseline. Treatment-boosted ADA was defined as ADA positive at baseline that was boosted to a 4-fold or higher-level following treatment administration.
Part 2: Change From Baseline in Programmed Death-Ligand 1 (PD-L1) Expression Baseline (Day 1) up to end of treatment, up to approximately 20 months Expression of PD-L1 biomarker was planned to be assessed in tumor tissues of the patients. Baseline was defined as the last non-missing assessment prior to the first administration of any study treatment (whichever occurred first), including scheduled and unscheduled visits, unless otherwise specified.
Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation From the first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 21 months An AE was any untoward medical occurrence in a clinical study patient temporally associated with the use of a study treatment, whether or not considered related to the treatment. An AE was considered "serious" if, in the view of either the investigator or sponsor, it resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, was a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, was an abnormal pregnancy outcome in a child born to a female patient/female partner of a male patient exposed to study treatment or was an important medical event. TEAEs were AEs that started or worsened in severity on or after the first dose of study treatment and up to 30 days after the date of last study treatment administration.
Trial Locations
- Locations (16)
Mayo Clinic Arizona
🇺🇸Phoenix, Arizona, United States
Highlands Oncology
🇺🇸Springdale, Arkansas, United States
Beverly Hills Cancer Center
🇺🇸Beverly Hills, California, United States
University of Colorado
🇺🇸Aurora, Colorado, United States
Florida Cancer Specialists - FCS South
🇺🇸Port Charlotte, Florida, United States
Florida Cancer Center North
🇺🇸Saint Petersburg, Florida, United States
Florida Cancer Specialists Panhandle
🇺🇸Tallahassee, Florida, United States
Florida Cancer Specialists - East (FCS East)
🇺🇸West Palm Beach, Florida, United States
HOC AON Baton Rouge / Sarah Cannon
🇺🇸Baton Rouge, Louisiana, United States
Messino Cancer Center
🇺🇸Asheville, North Carolina, United States
Scroll for more (6 remaining)Mayo Clinic Arizona🇺🇸Phoenix, Arizona, United States