The goal of this study is to build on the experience of the SAINT trial by evaluating the safety and efficacy of the addition of pazopanib to their published chemotherapy regimen.

Primary Objectives:

• To determine the maximum tolerated dose (MTD)/ recommended phase 2 dose (RP2D) of Pazopanib in combination with Trabectedin, Ipilimumab and Nivolumab.
• To determine the safety and tolerance of Pazopanib when given in conjunction with Trabectedin, Ipilimumab and Nivolumab in pediatric and young adult patients with Recurrent STS.

Secondary Objective:

• To observe and record disease response (anti-tumor activity). Although the clinical benefit of the combination (Pazopanib when given in conjunction with Trabectedin, Ipilimumab and Nivolumab) has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief. Outcomes for disease response include Best OverallResponse (BOR), Duration of Response (DOR), and Progression-Free Survival (PFS) will be analyzed.

Inclusion Criteria:

All Recurrent STS are eligible for enrollment. All laboratory studies will need to be complete within 7 days prior to initiating protocol therapy. All imaging studies will need to be done within 28 days prior to starting treatment.

1. Age: Patients must be > 1 year of age and . 30 years of age at time of initiation of protocol therapy.

2. Diagnosis: Patients have a histologically or radiographically confirmed relapsed or refractory STS.

3. Disease Status: Patients must have evaluable disease.

   a. Patients may have CNS metastases at study entry, if they are previously treated or stable (defined by not requiring initiation or the need for increased steroids for 7 days).

4. Performance Level: Karnofsky . 50% for patients > 16 years old, and Lansky . 50 for patients 1-16 years old. (See Appendix I)

5. Prior Therapy: Patients may have received prior therapy including single-agent pazopanib or trabectedin. Patients may not have previously been treated with combination therapy of pazopanib and trabectedin.

   a. Patients must be fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Delayed toxicities from chemotherapy (e.g. requiring electrolyte replacement, alopecia) will be permitted as long as they are stable or improving and approved by the study PI. i. Hematopoietic growth factor: At least 7 days must have elapsed since the last administration of filgrastim, or 14 days since administration of pegfilgrastim. ii. XRT: At least 7 days since the last dose of local palliative radiation therapy. Greater than 6 months must have elapsed since the last day of treatment if given total body irradiation, craniospinal irradiation. iii. Autologous or Allogenic Stem Cell Transplant: Complete resolution of graft versus host disease and no current need for immunosuppressive medication. Greater than 3 months must have elapsed since engraftment and no longer requiring transfusion of platelets or injection of colony stimulating factors.

6. Organ Function Requirements a. Bone Marrow Function: i. Peripheral absolute neutrophil count (ANC) . 750/ƒÊL ii. Platelet count . 75,000/ƒÊL (no platelet transfusion within 7 days prior to obtaining laboratory result) b. Adequate Renal Function: i. Creatinine clearance or glomerular filtration rate . 70ml/min/1.73m2 (calculated or measured as appropriate for age and level of concern by treating MD) c. Adequate Liver Function: i. Total bilirubin . 1.5x upper limit of normal (ULN) for age ii. SGPT (ALT) . 3 x ULN iii. Serum albumin . 2gm/dL Due to the risk of hepatic injury, including fatal hepatic failure, temozolomide should not be administered if total bilirubin is >2.0 mg/dl or SGPT(ALT)> 3 x ULN.

Exclusion Criteria:

• Significant organ dysfunction, not meeting inclusion criteria.

• Pediatric subjects who are considered wards of some entity.

• Pregnancy or Breast-Feeding Pregnant or breast-feeding woman will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies.

• Concomitant Medications:

  1. Growth factor: Growth factors that support platelet or white cell number or function must not have been administered within the past 7 days.
  2. Investigational Drugs: Patients who are currently receiving another investigational drug. (Please refer to section 4.1, Prior Therapy)
  3. Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents. (Please refer to section 4.1, Prior Therapy)
  4. Medication Allergy:

  i. Allergy or intolerance to agents on this protocol: Trabectedin. Pazopanib, Ipilimumab or Nivolumab e. Infection: Patients who have uncontrolled infection, positive blood cultures within the past 48 hours, or receiving treatment for Clostridium difficile infection.

• Known history of human immunodeficiency virus (HIV) infection

• Known active infection of hepatitis B or Hepatitis C virus