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

Study Overview
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Brief Summary
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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
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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-RMS. 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-RMS). 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.

Official Title
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An Open-Label, Multicenter Phase 1/2 Study of Surufatinib in Combination With Gemcitabine in Pediatric, Adolescent, and Young Adult Patients With Recurrent or Refractory Solid Tumors

Conditions
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Solid Tumor, Lymphoma, Osteosarcoma, Ewing Sarcoma, Rhabdomyosarcoma, Non-rhabdomyosarcoma Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Surufatinib in combination with Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: At time of study enrollment, patients must be Part 1 (including PK expansion cohort): ≥2 and ≤21 years of age; Part 2: ≥2 and ≤21 years of age; Patients with osteosarcoma can enroll up to <30 years old. Diagnosis: 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. 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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 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 NRSTS.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1- Dose escalation<br>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. | Drug: Surufatinib in combination with Gemcitabine<br>* Surufatinib in combination with Gemcitabine<br>* Other names: HMPL-012, sulfatinib in combination with Gemcitabine;|
| Experimental: Part 2 - Dose expansion<br>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 non- RMS will open for enrollment. | Drug: Surufatinib in combination with Gemcitabine<br>* Surufatinib in combination with Gemcitabine<br>* Other names: HMPL-012, sulfatinib in combination with Gemcitabine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of patients with Dose-Limiting Toxicity (DLT) at each dose level studied. | To determine maximum tolerated dose of surufatinib in combination with gemcitabine | up to 90 days | 
| Part 1: Number of patients with treatment-emergent adverse events as assessed by CTCAE v5.0 | To determine the safety and tolerability of surufatinib in combinations with gemcitabine | up to 4 years | 
| Part 2: To study the rate of patients who have achieved Complete Response (CR) or Partial Response (PR) in pediatric patients with Ewing sarcoma, Rhabdomyosarcoma (RMS), or Non-RMS (NRSTS) treated with the combination of surufatinib and gemcitabine. | The rate of patients who have achieved CR or PR will be reported. | up to 4 years | 
| Part 2: To study the Time to Response (TTR) of the combination of surufatinib and gemcitabine in pediatric patients with Ewing sarcoma, RMS, or NRSTS. | The time to CR or PR will be reported. | up to 4 years | 
| Part 2: To study the duration of response (DoR) of the combination of surufatinib and gemcitabine in pediatric patients with Ewing sarcoma, RMS, or NRSTS. | The duration of CR or PR will be reported. | up to 4 years | 
| Part 2: To study the progression-free survival (PFS) of the combination of surufatinib and gemcitabine in pediatric patients with Ewing sarcoma, RMS, or NRSTS. | The time from enrollment in the clinical trial to disease progression or death will be reported. | up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate number of patients with treatment-emergent adverse events as assessed | To evaluate the safety in the pediatric patient population when treated with the combination of surufatinib and gemcitabine | up to 4 years |