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)
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
52
Oral VEGFR inhibitor
PD-1 inhibitor
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
St. 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
...and 6 more locations
Part 1: Number of Patients With Dose-Limiting Toxicities (DLTs)
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.
Time frame: From the first dose of study treatment (Day 1) up to Day 28 of Cycle 1 (cycle duration: 4 weeks)
Part 1: Recommended Phase 2 Dose (RP2D) of Fruquintinib in Combination With Tislelizumab
The RP2D of fruquintinib in combination with tislelizumab based on the safety and tolerability assessments in Part 1 patients.
Time frame: From the first dose of study treatment (Day 1) up to Day 28 of Cycle 1 (cycle duration: 4 weeks)
Part 2: Objective Response Rate (ORR)
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.
Time frame: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
Part 1: Objective Response Rate
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.
Time frame: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
Parts 1 and 2: Progression-free Survival (PFS)
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.
Time frame: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
Parts 1 and 2: Disease Control Rate (DCR)
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.
Time frame: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Parts 1 and 2: Clinical Benefit Rate (CBR)
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.
Time frame: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
Parts 1 and 2: Duration of Response (DoR)
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.
Time frame: Tumor assessments performed every 8 weeks (+/-1 week) until PD, up to a maximum of approximately 34 months
Parts 1 and 2: Overall Survival (OS)
The OS was defined as the time from start of study treatment until the date of death due to any cause.
Time frame: 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
Parts 1 and 2: Plasma Concentrations of Fruquintinib and Metabolite M11
Blood samples were collected at the specified timepoints to determine plasma concentrations of fruquintinib and metabolite M11.
Time frame: 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)
Parts 1 and 2: Serum Concentrations of Tislelizumab
Blood samples were collected at the specified timepoints to determine serum concentrations of tislelizumab.
Time frame: 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)
Parts 1 and 2: Number of Patients With Antidrug Antibodies (ADAs) to Tislelizumab
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.
Time frame: 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
Part 2: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Treatment Discontinuation
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.
Time frame: From the first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 21 months
Part 2: Change From Baseline in Programmed Death-Ligand 1 (PD-L1) Expression
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.
Time frame: Baseline (Day 1) up to end of treatment, up to approximately 20 months