Phase I-II Trial of Sunitinib and/or Nivolumab Plus Chemotherapy in Advanced Soft Tissue and Bone Sarcomas

Who is this study for? Adult patients with soft tissue sarcomas and bone sarcomas
What treatments are being studied? Sunitinib+Nivolumab
Status: Recruiting
Location: See all (13) locations...
Intervention Type: Drug
Study Type: Interventional
Study Phase: Phase 1/Phase 2
SUMMARY

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). Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision. 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. One-year maintenance of nivolumab is foreseen in the absence of progressive disease. If three or more DLTs occur nivolumab dose will be lowered to dose level -1 where 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 240 mg IV, Q3W. GCSF support is mandatory. One-year maintenance of nivolumab is foreseen in the absence of progressive disease. 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. One-year maintenance of nivolumab is foreseen in the absence of progressive disease. 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: o 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 where patients will receive MAP during the IP (same as described for level 0), but the dose of nivolumab will be 360 mg on days 4 and 36. 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 three weeks up to day 364.

Eligibility
Participation Requirements
Sex: All
Minimum Age: 12
Maximum Age: 80
Healthy Volunteers: No
View:

• Cohort 1-6

• Patients (or legal tutors) must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of the screening process. Procedures conducted as part of the patient's routine clinical management (e.g. blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol.

• Age: 12-80 years.

• Diagnosis of dedifferentiated chondrosarcoma, extraskeletal myxoid chondrosarcoma, vascular sarcomas (including angiosarcoma, hemangioendothelioma and intimal sarcomas), solitary fibrous tumor (excluding dedifferentiated SFT), alveolar soft part sarcoma, and clear cell sarcoma confirmed by central pathology review.

• Mandatory paraffin embedded tumor blocks must be provided for all subjects without exception for biomarker analysis before treatment.

• Metastatic/locally advanced unresectable disease in progression in the last 6 months according to RECIST 1.1. Patients with recent diagnosis of metastatic disease can be eligible (if they are not candidates to anthracycline-based treatment).

• Patients should have previously received at least anthracyclines. Patients in the cohorts of subtypes sensitive to antiangiogenic therapy (SFT, ASPS, CCS, EMC or DDCS) are eligible even if not previously treated.

• Previous therapy with antiangiogenics is allowed.

• Measurable disease according to RECIST 1.1 criteria.

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

• Adequate hepatic, renal, cardiac, and hematologic function.

• Laboratory tests as follows:

• Absolute neutrophil count ≥ 1,200/mm³

• Platelet count ≥ 100,000/mm³

• Bilirubin ≤ 1.5 mg/dL

• PT and INR ≤ 1.5 in the absence of anticoagulant therapy

• AST and ALT ≤ 2.5 times upper limit of normal

• Creatinine ≤ 1.5 mg/dL (or Cr clearance ≥ 60 ml/min)

• Calcium ≤ 12 mg/dL

• Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.

• Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment and agree to use birth control measures during study treatment and for 6 months after its completion. Patients must not be pregnant or nursing at study entry. Women/men of reproductive potential must have agreed to use an effective contraceptive method.

• Cohort 7

• The patient or his/her legal tutors must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of screening process. Procedures conducted as part of the patient's routine clinical management (e.g. blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol.

• Age: 18-80 years.

• Diagnosis of advanced/metastatic undifferentiated pleomorphic sarcoma (UPS) (cohort 7a) or leiomyosarcoma (LMS) (cohort 7b) confirmed by central pathology review.

• Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue must be provided for all subjects without exception for central pathology review and the translational study. Archive tissue can be used for diagnosis confirmation but a recent biopsy (<3 months) is mandatory for translational research. If it is not available or is older than 3 months, the patient must be willing to have a pre-treatment re-biopsy of primary or metastatic tumor (baseline biopsy) within 28 days prior to enrollment.

• Measurable disease according to RECIST v1.1 criteria.

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

• The patient must be naïve of any previous treatment with anthracyclines (not even in adjuvant chemotherapy).

• Adequate organ, hepatic, renal, cardiac, and hematologic function.

• Laboratory tests as follows:

• Absolute neutrophil count ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Hg > 9 g/dL

• Bilirubin ≤ 1.5 mg/dL

• PT and INR ≤ 1.5

• AST and ALT ≤ 2.5 times upper limit of normal

• Creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 60 mL/min

• Blood glucose < 150 mg/dL

• Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.

• Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment. Patients must not be pregnant or nursing at study entry.

• Women and men of reproductive potential must have agreed to use an effective contraceptive method during study treatment and for 6 months after the last dose of study drug.

• Cohort 8

• The patient or his/her legal tutors must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of screening process. Procedures conducted as part of the patient's routine clinical management (e.g. blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol.

• Age: 12-40 years.

• Diagnosis of resectable primary metastatic high-grade osteosarcoma confirmed by central pathology review. Resection of primary tumor +/- metastatic disease has to be feasible and planned.

• Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue must be provided for all subjects without exception for central pathology review and the translational study. The patient must be willing to have a pre-treatment re-biopsy of primary or metastatic tumor (baseline biopsy) within 28 days prior to enrollment if diagnosis biopsy does not have enough remaining tissue for translational purposes.

• Measurable disease according to RECIST v1.1 criteria.

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

• The patient must be naïve of any previous treatment.

• Adequate organ, hepatic, renal, cardiac, and hematologic function.

• Laboratory tests as follows:

• Absolute neutrophil count ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Hg > 9 g/dL

• Bilirubin ≤ 1.5 mg/dL

• PT and INR ≤ 1.5

• AST and ALT ≤ 2.5 times upper limit of normal

• Creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 60 mL/min

• Blood glucose < 150 mg/dL

• Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.

• Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment. Patients must not be pregnant or nursing at study entry.

• Women and men of reproductive potential must have agreed to use an effective contraceptive method during study treatment and for 6 months after the last dose of study drug.

Locations
Other Locations
Italy
Istituto Ortopedico Rizzoli
Recruiting
Bologna
Candiolo Cancer Institute - FPO, IRCCS
Recruiting
Candiolo
Istituto Nazionale dei Tumori
Recruiting
Milano
Spain
Hospital de la Santa Creu i Sant Pau
Recruiting
Barcelona
Hospital Universitari Vall d'Hebrón
Recruiting
Barcelona
Complejo Hospitalario Universitario de Canarias
Recruiting
La Laguna
Hospital Universitario 12 de Octubre
Recruiting
Madrid
Hospital Universitario Fundación Jiménez Díaz
Recruiting
Madrid
Hospital Universitario La Paz
Recruiting
Madrid
Hospital Universitario Virgen del Rocío
Recruiting
Sevilla
Hospital Universitari i Politècnic La Fe
Recruiting
Valencia
Hospital Universitario Miguel Servet
Recruiting
Zaragoza
United Kingdom
University College London Hospitals NHS Foundation Trust
Not yet recruiting
London
Contact Information
Primary
Patricio Ledesma
ensayos@sofpromed.com
+34 971439900
Time Frame
Start Date: May 31, 2017
Estimated Completion Date: September 30, 2022
Participants
Target number of participants: 270
Treatments
Experimental: Sunitinib and/or nivolumab plus chemotherapy in advanced STS and BS
C1-6: Adults, IP d1-14 sunitinib 37.5mg/d then MP sunitinib 25mg/d+nivolumab 240mg ev 2 weeks. Pediatrics, IP d1-14 sunitinib 25mg/d, if BSA>1.7 sunitinib 37.5mg/d and MP sunitinib 25mg/d+nivolumab (dose weight dependent). 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.
Authors
Sandra Strauss, Roberto Diaz de Beveridge, Irene Carrasco, Enrique González, Josefina Cruz, Giovanni Grignani, Claudia Valverde, Silvia Stacchiotti, Emanuela Palmerini, Antonio López Pousa, Andrés Redondo, Javier Martínez Trufero
Sponsors
Leads: Grupo Espanol de Investigacion en Sarcomas

This content was sourced from clinicaltrials.gov

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