A Study of Surufatinib in Combination With Gemcitabine in Pediatric, Adolescent, and Young Adult Patients With Recurrent or Refractory Solid Tumors

Phase 1

Completed

Conditions: Solid Tumor
Osteosarcoma
Ewing Sarcoma
Rhabdomyosarcoma
Non-rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
Lymphoma

Interventions: Drug: Surufatinib in combination with Gemcitabine

Registration Number: NCT05093322

Lead Sponsor: Hutchmed

Brief Summary: The purpose of this study is to evaluate the safety and tolerability of surufatinib, thereby identifying the Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of surufatinib administered in combination with gemcitabine in pediatric patients with recurrent or refractory solid tumors or lymphoma. The study will be conducted in 2 parts.

Detailed Description: The purpose of this study is to evaluate the safety and tolerability of surufatinib, thereby identifying the Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of surufatinib administered in combination with gemcitabine in pediatric patients with recurrent or refractory solid tumors or lymphoma. The study will be conducted in 2 parts:

Part 1 - evaluation of tolerability and safety of surufatinib administered in combination with gemcitabine, and confirmation of the recommended clinical dose of surufatinib in pediatric patients with recurrent or refractory solid tumors or lymphoma.

Part 2 - evaluation of anti-tumor activity and confirmation of tolerability of surufatinib administered in combination with gemcitabine in pediatric patients with recurrent or refractory osteosarcoma, Ewing sarcoma, RMS, and non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).

Part 1 will enroll 2 to 6 patients per dose level cohort (up to 4 cohorts) with recurrent or refractory solid tumors. During cycle 1, surufatinib will be administered, orally, once daily (QD), as a single agent for 14 days followed by surufatinib daily in combination with gemcitabine intravenously on days 15 and 22 (cycle 1 duration=35 days) and days 1 and 8 of all subsequent cycles (cycle duration=21 days). Assessment based on dose limiting toxicity (DLT) criteria will be performed in the first 35-day cycle (DLT Evaluation Period). This study will utilize a rolling 6 design for part 1, with 3 dose escalation levels and 1 de escalation level, if needed.

Part 2 of the study will use a Simon 2-stage design with a maximum of 18 patients per cohort (osteosarcoma, Ewing sarcoma, RMS, and non-rhabdomyosarcoma soft tissue sarcoma (NRSTS)).

Surufatinib will be administered orally at identified MTD/RP2D daily in combination with gemcitabine (1000 mg/m2 weekly × 2 doses) intravenously on days 1 and 8.

In both parts 1 and 2, patients can remain on treatment until completing cycle 17, or until progressive disease, unacceptable toxicity, or death; whichever comes first.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 13

Inclusion Criteria

Age: At time of study enrollment, patients must be

For US Sites:
1. Part 1 (including PK expansion cohort): ≥2 and <18 years of age;
2. Part 2: ≥2 and ≤18 years of age;
For EU/UK Sites:
1. Part 1 (including PK expansion cohort): from birth to <18 years of age;
2. Part 2: from birth to <18 years of age (except as noted below);
  - Note: Patients <2 years of age will only be enrolled in Europe, however, enrollment of patients <2 years of age will not begin until definitive juvenile animal toxicity data is available.
Diagnosis:
1. Part 1 - Patients with any recurrent or refractory solid tumors or lymphoma (not central nervous system [CNS]) that have a known or expected dysfunction of VEGFR 1, -2, and -3; FGFR-1, or CSF-1R pathways (based on literature) are eligible. Patients must have had histologic verification of malignancy at original diagnosis or relapse.
2. Part 2 - Recurrent or refractory osteosarcoma (US and EU), Ewing sarcoma (US and EU), RMS (US and EU), or NRSTS (EU only). Patients must have had histologic verification of malignancy at original diagnosis or relapse.
Disease status: Patients must have measureable or evaluable disease for part 1 dose escalation; for part 2, patients must have measurable disease by RECIST version 1.1.
Therapeutic options: Patient's current disease state must be one for which there is no known curative therapy.
Performance level: Karnofsky ≥50 for patients ≥16 and <18 years of age and Lansky ≥50 for patients <16 years of age, Eastern Cooperative Oncology Group (ECOG) ≤2 for patients ≥18 years of age.
Adequate organ and bone marrow function as defined in the current protocol.
Adequate cardiac function as indicated as defined in the current protocol.
Patients with known bone marrow metastatic disease will be eligible for the study provided they meet the blood counts in the inclusion criteria as defined in the current protocol.
Adequate BP control which is defined as a BP <95th percentile (≤ grade 1) for age, height, and sex.
Informed consent: Provision of signed and dated written informed consent (parent/legal guardian if patient <18 years of age) and assent (from patients aged >7 years) prior to any study-specific procedures, sampling, and analyses.
Patient must meet all defined Inclusion criteria as defined in the current protocol.

Exclusion Criteria

Patient must not meet any exclusion criteria as defined in the current protocol.
Pregnant, breast feeding or planning on becoming pregnant.
Patients is taking and prohibitive concomitant medications as outlined in the current protocol.
Patients have an uncontrolled infection.
Patients has had major surgery or significant traumatic injury within 28 days of the first dose.
Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy and without clinical imaging evidence of SD for 14 days or longer.
History of allergies to Surufatinib and/or Gemcitabine.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 2 - Dose expansion	Surufatinib in combination with Gemcitabine	Once the MTD/RP2D has been determined in the part 1 portion of the study, the part 2 disease specific cohorts for patients with refractory or recurrent osteosarcoma, Ewing Sarcoma, and RMS and NRSTS will open for enrollment.
Part 1- Dose escalation	Surufatinib in combination with Gemcitabine	Dose escalation study with sequential dose escalation of surufatinib in combination with gemcitabine. Patients with any recurrent or refractory solid tumors or lymphoma, who have a known or expected dysfunction of VEGFR-1, -2, and -3; FGFR-1; or CSF-1R pathways may be enrolled.

Primary Outcome Measures

Name	Time	Method
Number of Patients With Clinically Significant Vital Signs Abnormalities	From the first dose of study drug (Day 1) up to 30 + 7 days after the last dose of study drug, approximately 19 weeks	Vital signs included systolic blood pressure (BP), diastolic BP, heart rate, height, weight, respiratory rate, and body temperature.
Number of Patients With Dose-Limiting Toxicities (DLT)	From the first dose of study drug (Day 1) up to Day 35 of Cycle 1	A DLT was defined as any of following events that were attributable to study treatment (at least possibly related). Adverse events (AE) were graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. * Any Grade 3 or greater nonhematological toxicity. * Grade 3 liver enzyme elevation. * Cases of Hy's law. * Any Grade 2 nonhematological toxicity that persisted for \>= 7 days. * Any Grade 4 hypertension. * Grade 3 corrected QT interval prolongation \> 500 millisecond. * Grade 4 thrombocytopenia for \> 7 days. * Grade 3 thrombocytopenia with clinically significant bleeding. * Grade 4 neutropenia that lasted for \> 7 days. * Myelosuppression that caused a delay of \> 7 days in the start of Cycle 2.
Number of Patients With Treatment Emergent Adverse Events (TEAEs) by Severity	From the first dose of study drug (Day 1) up to 30 + 7 days after the last dose of study drug, approximately 19 weeks	The AEs were graded using the NCI CTCAE version 5.0. The CTCAE displays Grades 1 through 5 where, Grade 1= mild, Grade 2= moderate, Grade 3= Severe, Grade 4= life-threatening consequences and Grade 5= death.
Number of Patients With Clinically Significant Physical Examination Abnormalities	From the first dose of study drug (Day 1) up to 30 + 7 days after the last dose of study drug, approximately 19 weeks	Physical examination included patient height, weight, and general condition, as well as an examination of the head, heart, chest (including the lungs), abdomen, extremities, skin, lymph nodes, nervous system, and additional areas/systems as clinically indicated.
Number of Patients With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities	From the first dose of study drug (Day 1) up to 30 + 7 days after the last dose of study drug, approximately 19 weeks	Standard 12-lead ECGs were performed after the patient rested for 5 to 10 minutes. The ECG parameters included heart rate, PR interval, RR interval, QT interval, QTcF, and QRS interval from the triplicate 12-lead ECG.
Number of Patients With Clinically Significant Laboratory Abnormalities	From the first dose of study drug (Day 1) up to 30 + 7 days after the last dose of study drug, approximately 19 weeks	Blood and urine samples were collected to determine the clinical chemistry, hematology, and urinalysis laboratory abnormalities.

Secondary Outcome Measures

Name	Time	Method
Disease Control Rate (DCR)	RECIST assessments performed at baseline (within 28 days before start of study treatment), Day 1 of Cycle 3 and until confirmed objective disease progression. Up to approximately 19 weeks.	The DCR was defined as the percentage of patients with a BOR of CR, PR, or stable disease as determined by the investigator using RECIST version 1.1. Stable disease 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.
Duration of Response (DoR)	RECIST assessments performed at baseline (within 28 days before start of study treatment), Day 1 of Cycle 3 and until confirmed objective disease progression. Up to approximately 19 weeks.	The DoR was defined as the time from the first occurrence of PR or CR whichever came first, until disease progression or death.
Objective Response Rate (ORR)	RECIST assessments performed at baseline (within 28 days before start of study treatment), Day 1 of Cycle 3 and until confirmed objective disease progression. Up to approximately 19 weeks.	The ORR was defined as the percentage of patients with a 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) version 1.1. The BOR was defined as the best response recorded from the start of study treatment until documented RECIST version 1.1 progression, death, or withdrawal of consent. The CR was defined as disappearance of all target lesions. 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 to Response (TTR)	RECIST assessments performed at baseline (within 28 days before start of study treatment), Day 1 of Cycle 3 and until confirmed objective disease progression. Up to approximately 19 weeks.	The TTR was defined as the time from the start of study treatment until the date of the first occurrence of PR or CR for responders only.
Progression-Free Survival (PFS)	RECIST assessments performed at baseline (within 28 days before start of study treatment), Day 1 of Cycle 3 and until confirmed objective disease progression. Up to approximately 19 weeks.	The 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 version 1.1 or death from any cause.
Number of Patients Who Performed Taste and Palatability Survey of Surufatinib	Days 1 and 8 of Cycle 1	The taste and palatability survey was assessed in patients who had taken surufatinib oral suspension. For pediatric patients, their parents completed the taste and palatability survey. Data for the evaluation of taste of surufatinib oral suspension was summarized on a scale of 1 (very bad) through 5 (very nice).

Trial Locations

Locations (11): Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
Childrens Hospital Orange County
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Orange, California, United States
Johns Hopkins University
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Baltimore, Maryland, United States
Riley Hospital for Children
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Indianapolis, Indiana, United States
Washington University School of Medicine
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Saint Louis, Missouri, United States
Cincinnati Children's Hospital Medical Center
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Cincinnati, Ohio, United States
UPMC Children's Hospital of Pittsburgh
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Pittsburgh, Pennsylvania, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Children's National Hospital
🇺🇸
Washington, District of Columbia, United States
The University of Texas Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
Seattle Children's Hospital
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Seattle, Washington, United States