Surufatinib in Combination With Tislelizumab in Subjects With Advanced Solid Tumors

Phase 1

Terminated

Conditions: Neuroendocrine Tumors
Small Cell Lung Cancer
Metastatic Solid Tumor
Colorectal Cancer
Soft Tissue Sarcoma
Anaplastic Thyroid Cancer
Gastric Cancer

Interventions: Drug: Surufatinib and Tislelizumab _ Part 1
Drug: Surufatinib and Tislelizumab _ Part 2

Registration Number: NCT04579757

Lead Sponsor: Hutchmed

Brief Summary: This open-label, phase Ib/II study of surufatinib in combination with tislelizumab will evaluate the safety, tolerability, PK and efficacy in patients with advanced solid tumors. The study consists of 2 parts - dose finding (Part 1) and dose expansion (Part 2).

Detailed Description: This open-label, phase Ib/II study of surufatinib in combination with tislelizumab will evaluate the safety, tolerability, PK and efficacy in patients with advanced solid tumors. The study consists of 2 parts - dose finding (Part 1) and dose expansion (Part 2).

Part 1 will be conducted to determine the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose (MTD) of surufatinib in combination with tislelizumab in patients with advanced or metastatic solid tumors who have progressed on, or are intolerant to standard therapies.

Part 2 will be an open-label, multi-cohort design to evaluate the anti-tumor activity of surufatinib in combination with tislelizumab in patients with specific types of advanced or metastatic solid tumors. Patients will receive the RP2D determined in part 1 of this study.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 87

Inclusion Criteria

Willing and able to provide informed consent
≥18 years of age
Part 1-have evaluable lesions (according to Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1])
Part 2-have measurable lesions (according to RECIST v1.1)
Have a performance status of 0 or 1 on the ECOG scale
For female subjects of childbearing potential and male patients with partners of childbearing potential, agreement to use a highly effective form(s) of contraception

Dose Escalation:
Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type,.

Dose Expansion:
Histologically or cytologically documented, locally advanced or metastatic:

Cohort A: adenocarcinoma of the colon or rectum that is microsatellite stable. Subjects must have progressed on, or had intolerable toxicity to, at least 3 prior regimens of standard chemotherapy.

Cohort B: progressive, low or intermediate grade (grade 1 or grade 2) NETs of thoracic or GEP origins. Subjects must have radiological documentation of progression of disease in the last 6 months and must have progressed on at least one line of standard therapy for metastatic disease.

Cohort C: SCLC that has progressed on standard first line chemotherapy treatment.

Cohort D: adenocarcinoma of the stomach or gastroesophageal junction and have progressed on at least 2 prior lines of therapy. Tumor stain for PD-L1 by Combined Positive Score (CPS) ≥5%.

Cohort E: ASPS or UPS. Subjects must have radiological documentation of disease progression in the last 3 months and have progressed on at least one line of standard therapy or refused standard frontline cytotoxic chemotherapy.

Cohort F: Anaplastic thyroid cancer that is considered not curable by resection. Patients with a BRAFV600E mutation must have previously been treated with 1 line of systemic therapy with a BRAF-targeted therapy.

Exclusion Criteria

Adverse events (AEs) due to previous anti-tumor therapy has not recovered to Common Terminology Criteria for Adverse Event (CTCAE) ≤Grade 1;
Part 2 subjects with CRC , NETs and STS any previous treatment with anti-PD-1, anti PD-L1/L2 antibodies, anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) antibody, or any other antibody acting on T cell costimulatory or checkpoint pathway;
Previous treatment with surufatinib;
Uncontrollable hypertension;
History or presence of a serious hemorrhage (>30 ml within 3 months), hemoptysis (>5 ml blood within 4 weeks) or life threatening thromboembolic event within 6 months;
Clinically significant cardiovascular disease;
Any clinically significant active infection, including, but not limited to, known human immunodeficiency virus (HIV) infection;
Brain metastases and/or leptomeningeal disease and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of SD for 14 days or longer; subjects requiring steroids within 4 weeks prior to start of study treatment will be excluded;
Active autoimmune diseases or history of autoimmune diseases that may relapse with the following exceptions:
1. Controlled Type 1 diabetes
2. Hypothyroidism (provided it is managed with hormone-replacement therapy only)
3. Controlled celiac disease
4. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, or alopecia)
5. Any other disease that is not expected to recur in the absence of external triggering factors.
Arterial thrombosis or thromboembolic events (including stroke and/or transient ischemic attack) within 12 months prior to first dosing;
History of deep venous thrombosis within 6 months;
Female patients who are pregnant or breastfeeding;
Any condition by which investigators judge patients not suitable to participate in this study.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Surufatinib and tislelizumab (dose escalation_Part 1)	Surufatinib and Tislelizumab _ Part 1	In Part 1 (dose escalation), surufatinib and will be administered orally (PO) once daily (QD) and tislelizumab 200 mg intravenous (IV) infusion every 3 weeks (Q3W).
Surufatinib and tislelizumab (indication specific_Part 2)	Surufatinib and Tislelizumab _ Part 2	In Part 2, the indication-specific expansion portion of the study, patients will receive surufatinib at the Recommended Phase 2 Dose (RP2D) dose selected in Part 1 with 200 mg tislelizumab IV, Q3W

Primary Outcome Measures

Name	Time	Method
Dose Escalation Phase: Number of Patients With Dose-Limiting Toxicities (DLTs)	From the first dose of study drug (Day 1) up to Day 21 of Cycle 1 (cycle duration: 3 weeks)	According to National Cancer Institute Common Terminology Criteria for Adverse Events(AEs) version (v)5.0,DLT was defined as any of the following AEs during DLT observation period: Nonhematologic toxicities:grade 3 or higher nonhematologic toxicity, except for grade 3 fatigue lasting \<7 days, grade 3 rash returning to baseline or ≤grade 1 within 7 days with treatment, grade 3 hypertension downgraded to ≤grade 1 within 7 days with therapy, grade 3 endocrinopathy controlled by hormonal replacement with no hospitalization and resolving to ≤grade 1 within 7 days, grade 3 or higher amylase or lipase elevation without symptoms of pancreatitis, grade 3 nausea/vomiting or diarrhea for \<72 hours with care, grade 3 or higher electrolyte abnormality lasting up to 72 hours and resolving with treatment. Hematologic toxicities: grade 3 or higher febrile neutropenia, grade 4 neutropenia and grade 4 thrombocytopenia lasting \>7 days, grade 3 thrombocytopenia with severe bleeding, and grade 4 anemia.
Dose Escalation Phase: 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 9 months	An AE was any untoward medical occurrence in a clinical study patient temporally associated with the use of a study treatment in humans, 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 a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as 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.
Dose Expansion Phase: Objective Response Rate (ORR)	Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 37 months	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 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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. 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). 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
Dose Escalation Phase: Objective Response Rate	Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months	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. 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. 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. 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.
Dose Escalation and Dose Expansion Phases: Progression-free Survival (PFS)	Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 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. 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 one or more new lesions was also considered progression.
Dose Escalation and Dose Expansion Phases: Disease Control Rate (DCR)	Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months	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. 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. 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. 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. 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.
Dose Escalation and Dose Expansion Phases: Number of Patients With Antidrug Antibodies (ADA) to Tislelizumab	From the first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 9 months for dose escalation phase and approximately 33 months for dose expansion phase	Blood samples were collected at the specified timepoints to detect ADAs to tislelizumab. Treatment-boosted ADA was defined as ADA positive at baseline that was boosted to a 4-fold or higher-level following treatment administration. Treatment-induced ADA was defined as ADA negative at baseline and ADA positive post-baseline.
Dose Expansion Phase (Cohorts A and F): Overall Survival (OS)	From the first dose of study treatment (Day 1) up to date of death due to any cause, up to approximately 42 months	OS was defined as the time from the start of study treatment until the date of death due to any cause.
Dose Expansion Phase: Number of Patients With Treatment-Emergent Adverse Events, Treatment-Emergent Serious Adverse Events 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 33 months	An AE was any untoward medical occurrence in a clinical study patient temporally associated with the use of a study treatment in humans, 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 a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as 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.
Dose Escalation and Dose Expansion Phases: Clinical Benefit Rate (CBR)	Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months	CBR was defined as the percentage of patients with a BOR of CR, PR, or durable SD as determined by the investigator using RECIST v1.1. Durable SD was SD for at least 6 months. 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. 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. 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. 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.
Dose Escalation and Dose Expansion Phases: Duration of Response (DoR)	Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months	DoR was defined as the time from the first occurrence of PR or CR by RECIST v1.1, until PD or death, whichever came first. 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. 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.
Dose Escalation and Dose Expansion Phases: Time to Response (TTR)	Tumor assessments performed every 6 weeks (+/-1 week) for the first 24 weeks and every 9 weeks (+/-1 week) thereafter, up to a maximum of approximately 42 months	TTR was defined as the time from start of study treatment until the date of first documented objective response, either CR or PR (whichever status was recorded first), according to RECIST v1.1. 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. 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.
Dose Escalation and Dose Expansion Phases: Plasma Concentration of Surufatinib	Pre-dose on Day 1 of Cycles 1, 2, 5, 9, 17 and on Days 8 and 15 of Cycle 1; 2 to 4 hours post-dose on Days 1 and 15 of Cycle 1 (cycle duration: 3 weeks)	Blood samples were collected at the specified timepoints to determine plasma concentration of surufatinib.
Dose Escalation and Dose Expansion Phases: Serum Concentration of Tislelizumab	Preinfusion on Day 1 of Cycles 1, 2, 5, 9, 17; end of infusion on Day 1 of Cycles 1 and 5; on Days 8 and 15 of Cycle 1 (cycle duration: 3 weeks)	Blood samples were collected at the specified timepoints to determine serum concentration of tislelizumab.

Trial Locations

Locations (17): Arizona Oncology Associated, PC-HOPE
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Tucson, Arizona, United States
City of Hope
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Duarte, California, United States
Johns Hopkins University - Sibley Memorial Hospital
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Washington, District of Columbia, United States
Emory University - Winship Cancer Institute
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Atlanta, Georgia, United States
Holden Comprehensive Cancer Center, University of Iowa
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Iowa City, Iowa, United States
University Hospitals Cleveland Medical Center
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Cleveland, Ohio, United States
Memorial Sloan Kettering Cancer Center
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New York, New York, United States
University of Pennsylvania, Perelman Center for Advanced Medicine
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Philadelphia, Pennsylvania, United States
Prisma Health - Upstate (ITOR)
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Greenville, South Carolina, United States
Mary Crowley Cancer Research
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Dallas, Texas, United States
Texas Oncology - Baylor Charles A. Sammons Cancer Center
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Dallas, Texas, United States
Texas Oncology, P.A.
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Tyler, Texas, United States
Virginia Cancer Specialists, PC
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Fairfax, Virginia, United States
Sarah Cannon
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Nashville, Tennessee, United States
Vanderbilt University Medical Center
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Nashville, Tennessee, United States
The University of Texas MD Anderson Cancer Center
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Houston, Texas, United States
Rocky Mountain Cancer Centers Midtown
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Denver, Colorado, United States