Trial of Sunitinib and/or Nivolumab Plus Chemotherapy in Advanced Soft Tissue and Bone Sarcomas

Sponsor
Grupo Espanol de Investigacion en Sarcomas
Study ID
NCT03277924
Phase
PHASE1/PHASE2
Status
Completed

Conditions

  • Bone Sarcoma
  • Soft Tissue Sarcoma

Eligibility Criteria

Sex
ALL
Age
12 Years - 80 Years
Healthy Volunteers
Not accepted

Interventions

  • Sunitinib 37.5 MG, Sunitinib 25 MG [Sutent] — DRUG
    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.
  • Nivolumab 100 MG/10 ML [Opdivo] — DRUG
    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.
  • Epirubicin — DRUG
    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.
  • Ifosfamide — DRUG
    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.
  • Doxorubicin — DRUG
    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.
  • Dacarbazine — DRUG
    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.
  • Cisplatin — DRUG
    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.
  • Methotrexate — DRUG
    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.

Study Details

Phase I-II, single-arm, non-randomized, open-label, multicenter, international clinical trial, with two stages. Stage one has two cohorts (soft tissue sarcoma and bone sarcoma) and stage two has eight cohorts (DDCS, EMC, VS, SFT, CCS, ASPS, UPS, LMS and OS). Nine sites in Spain, 3 sites in Italy and 1 site in the United Kingdom. Stage 1 (PHASE 1 and PHASE 2) Objective: To determine the recommended dose of the sunitinib plus nivolumab combination for phase II part. To evaluate the efficacy of the sunitinib plus nivolumab combination as measured by the progression-free survival rate (PFSR) at 6 months in patients with advanced soft tissue and bone sarcomas. Treatment: Adult patients will receive an initial induction phase (IP) from day 1 to day 14 of sunitinib 37.5 mg/day followed by a maintenance phase (MP) of sunitinib 37.5 mg/day continuously + nivolumab 3 mg/kg intravenous every 2 weeks infused over 1 hour. If three or more DLTs occur from day 15 to 42, for an initial set of 10 patients, sunitinib dose will be lowered to 25 mg/day or treatment schedule will be changed to 2 weeks on and one week off until recovery from toxicities. Stage 2 C1 to 6 Objective: To evaluate the efficacy of the sunitinib plus nivolumab combination as measured by PFSR at 6 months (CS/DDCS, EMC, VS, SFT, CCS cohorts) and at 12 months (ASPS cohort). Treatment: Adult patients will receive an initial induction phase (IP) from day 1 to day 14 of sunitinib 37.5 mg/day followed by a maintenance phase (MP) of sunitinib 25mg/day continuously + nivolumab 240mg every 2 weeks. Pediatric patients will receive an initial IP from day 1 to day 14 of (\<18 years) sunitinib at 25 mg/day unless the body surface area (BSA) of the patient is \>1.7. If BSA is \>1.7, then sunitinib 37.5 mg/day will be given followed by a MP of sunitinib 25 mg/day continuously + nivolumab 240 mg every 2 weeks regimen (if weight ≥40 kg) or sunitinib 25 mg/day continuously + nivolumab 3 mg/kg every 2 weeks regimen (if weight \<40kg). C 7 Objective: To determine the MTD of the epirubicin + ifosfamide + nivolumab combination in undifferentiated pleomorphic sarcoma and of the doxorubicin + dacarbazine + nivolumab combination in leiomyosarcoma. Treatment:Cohort 7a dose level 0: Patients will receive epirubicin dose of 60 mg/m2/d, d1 and d2 IV 20 minutes; followed by ifosfamide 3 g/m2/d d1-3, IV 3h with MESNA protection (40% of total dose of ifosfamide in each administration at 0, 3 and 6 h from ifosfamide initiation). Once finished Ifosfamide infusion of day 3, nivolumab is administered during 30 minutes, at dose of 360 mg IV, Q3W. GCSF support is mandatory. If three or more DLTs occur nivolumab dose will be lowered to dose level -1. Cohort 7b dose level 0: Patients will receive doxorubicin at dose of 75 mg/m2/d, d1 IV 20 minutes; followed by dacarbazine 400 mg//m2/d IV 60 minutes. Dacarbazine is administered also on day 2 of cycle. Once finished Dacarbazine infusion of day 2, nivolumab is administered for 30 minutes, at dose of 360 mg IV, Q3W. GCSF support is mandatory. If three or more DLTs occur nivolumab dose will be lowered to dose level -1 where patients will receive doxorubicin at dose of 75 mg/m2/d, d1 IV 20 minutes; followed by dacarbazine 400 mg//m2/d IV 60 minutes. Dacarbazine is administered also on day 2 of cycle. Once finished dacarbazine infusion of day 2, nivolumab is administered for 30 minutes, at dose of 240 mg IV, Q3W. GCSF support is mandatory. One-year maintenance of nivolumab is foreseen in the absence of progressive disease. C 8 Objectives:To determine the MTD of the MAP + nivolumab combination (phase I). Proportion of patients achieving good pathological response (phase II) Treatment dose level 0: In the IP, patients will receive CDDP 120 mg/m2 in 48h IV infusion (days 1-2) followed by doxorubicin 75 mg/m2 in 48h IV infusion (days 3-4). CDDP and doxorubicin will be given on days 1-4 and 36-39. Nivolumab administration will start on day 4 at flat dose 240 mg (after the end of doxorubicin), being the following doses administered on days 18, 39, and 53 (240 mg). HD methotrexate at 12 g/m2 in 2-h infusion will be administered on days 22, 29, 57, and 64. Surgery will be performed after finishing IP. Adjuvant chemotherapy will be administered after surgery. During the MP patients will receive nivolumab on day 210, every two weeks up to day 364. If three or more DLTs occur, then nivolumab dose level -1 will be activated.

Key Dates

Start date
May 31, 2017
Status verified
Aug 2024
Primary completion
Jun 30, 2024
Completion
Jun 30, 2024

Study Design

Enrollment
197 participants (actual)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: Sunitinib and/or nivolumab plus chemotherapy in advanced STS and BS
    Stage 1: IP d1-14 sunitinib 37.5mg/d then MP sunitinib 37.5mg/d+nivolumab 3mg/kg ev 2w. Stage 2: C1-6: IP d1-14 sunitinib 37.5mg/d then MP sunitinib 25mg/d+nivolumab 240mg ev 2w. C7a level 0: Epirubicin 60mg/m2/d, d1,2, ifosfamide 3g/m2/d d1-3 and nivolumab 360mg. 3 or more DLTs level -1 same treatment than in level 0, but nivolumab 240mg. C7b level 0: Doxorubicin 75mg/m2/d, d1, dacarbazine 400mg/m2/d (also on d2) and nivolumab 360mg. 3 or more DLTs level -1 same tratment than in level 0, but nivolumab 240mg. GCSF support is mandatory. 1-year maintenance of nivolumab. C8 level 0: In the IP, CDDP 120mg/m2 (d1-2), doxorubicin 75mg/m2 in (d3-4 and d36-39), nivolumab 240mg (d5), and on d18,39,53 and methotrexate 12g/m2 on d22,29,57,64, surgery and MP with nivolumab on d210, every 2 weeks up to d364. 3 or more DLTs level -1, with nivolumab 360mg on d4,36, surgery and MP with nivolumab on d210, ev 3 weeks up to d364.

Primary Outcome Measure

Stage 1 - PHASE 1 [ Time Frame: 6 months ]

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