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

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. 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.
2. 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.
3. 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.
4. Therapeutic options: Patient's current disease state must be one for which there is no known curative therapy.
5. 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.
6. Adequate organ and bone marrow function as defined in the current protocol.
7. Adequate cardiac function as indicated as defined in the current protocol.
8. 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.
9. Adequate BP control which is defined as a BP \<95th percentile (≤ grade 1) for age, height, and sex.
10. 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.
11. Patient must meet all defined Inclusion criteria as defined in the current protocol.

Exclusion Criteria:

1. Patient must not meet any exclusion criteria as defined in the current protocol.
2. Pregnant, breast feeding or planning on becoming pregnant.
3. Patients is taking and prohibitive concomitant medications as outlined in the current protocol.
4. Patients have an uncontrolled infection.
5. Patients has had major surgery or significant traumatic injury within 28 days of the first dose.
6. 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.
7. History of allergies to Surufatinib and/or Gemcitabine.