SAINT:Trabectedin, Ipilimumab and Nivolumab as First Line Treatment for Advanced Soft Tissue Sarcoma
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|ClinicalTrials.gov Identifier: NCT03138161|
Recruitment Status : Recruiting
First Posted : May 3, 2017
Last Update Posted : September 6, 2018
|Condition or disease||Intervention/treatment||Phase|
|Advanced Soft Tissue Sarcoma Metastatic Soft Tissue Sarcoma||Drug: Trabectedin Drug: Ipilimumab Drug: Nivolumab||Phase 1 Phase 2|
I. Dose Escalation Phase 1 of Study: The study will employ the standard "Cohort of Three" design (Storer, 1989). Three patients are treated at each dose level with expansion to six patients per cohort if DLT is observed in one of the three initially-enrolled patients at each dose level. If no DLT occurs after 2 doses, escalation to the next dose level will be permitted. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. Patients in the dose escalation study may continue treatment at their designated dose levels until disease progression or unacceptable toxicity occurs or up to 9 six-week cycles (one year) of therapy (up 18 TRABECTEDIN doses). No intra-patient dose escalation will take place.
Dose of IPILIMUMAB: 1 mg/kg IV over 30 min. q 12 weeks, beginning 2 weeks after first dose of TRABECTEDIN, until disease progression or unacceptable toxicity, up to 5 doses
Dose of NIVOLUMAB: 3 mg/kg over 30 min. q 2 weeks, beginning 2 weeks after first dose of TRABECTEDIN, until disease progression or unacceptable toxicity, up to 26 doses
Dose of TRABECTEDIN: Escalating doses of TRABECTEDIN IV as continuous intravenous infusion (CIV) over 24 hrs) q 3 weeks:
Dose Level I: 1 mg/m2 (n = 3-6); Dose Level II: 1.2 mg/m2 (n=3-6); Dose Level III: 1.5 mg.m2 (n=3-6)
II. Expansion Phase 2 of Study: Following dose escalation, an additional 22-28 previously untreated patients will receive TRABECTEDIN at the MTD and defined doses of IPILIMUMAB and NIVOLUMAB to assess overall safety and potential efficacy in a greater number of patients. Patients in the expansion phase of the study may continue treatment until significant disease progression (see criteria for discontinuation of therapy) or unacceptable toxicity occurs up to 9 six-week cycles (one year) of therapy.
Surgical Resection: After one or more treatment cycles, the principal investigator may recommend surgical debulking, complete surgical removal or a biopsy. If residual disease is present either by histopathological examination or by CT scan/MRI, repeat treatment cycles may be given 4 weeks after surgery, if the surgical incision has healed, and if the patient has < grade I toxicity.
Resected or biopsied tumors will be analyzed for the effects of this triple therapy on response, and immune cell trafficking in the tumor microenvironment. Fresh and paraffin embedded tissue blocks will be analyzed by FACS for PD-L1 and other biomarkers, including Tregs, CD8+, CD4+ cells etc. Immunohistochemistry for cyclin G1, cyclin D1 and Ki67 will be conducted to determine the tumor's proliferative state. Histopathologic examination for tumor necrosis and mitotic index will also be determined.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||45 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||SAINT: A Phase 1/2 Study of Safe Amounts of IPLIMUMAB, NIVOLUMAB and TRABECTEDIN as First Line Treatment of Advanced Soft Tissue Sarcoma (STS)|
|Actual Study Start Date :||April 13, 2017|
|Estimated Primary Completion Date :||June 30, 2020|
|Estimated Study Completion Date :||August 31, 2020|
Experimental: Phase 1
Phase 1: 3-6 will be treated with escalating doses of Trabectedin every 3 weeks up to 18 doses. Dose Level 1 is 1.0 mg/m2; Dose Level 2,1.2 mg/m2; Dose Level 3,1.5 mg/m2. Beginning 2 weeks after the first dose of Trabectedin, all patients will be treated with Ipilimumab at 1 mg/kg every 12 weeks up to 5 doses, and Nivolumab at 3 mg/kg every 2 weeks up to 26 doses.
Phase 2: All patients will be treated with the maximum tolerated dose of Trabectedin every 3 weeks. Beginning 2 weeks after the first dose of Trabectedin, all patients will be treated with Ipilimumab at 1 mg/kg every 12 weeks up to 5 doses, and Nivolumab at 3 mg/kg every 2 weeks up to 26 doses.
Trabectedinis an alkylating drug indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.
Other Name: Yondelis
Ipilimumab is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for (1) treatment of unresectable or metastatic melanoma, and (2) adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.
Other Name: Yervoy
A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed cell death-1 (PD-1, PCD-1) with immune checkpoint inhibitory and antineoplastic activities. Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands programmed cell death ligand (PD-L1), overexpressed on certain cancer cells, and programmed cell death ligand (PD-L2), which is primarily expressed on APCs (antigen presenting cells). This results in the activation of T-cells and cell-medicated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and plays a key role in tumor evasion from host immunity.
Other Name: Opdivo
- Maximum tolerated dose [ Time Frame: 6 months ]Dose escalation study, determination of maximum tolerated dose (MTD) in previoiusly treated patients with soft tissue sarcoma followed by expansion to previously untreated patients with advanced STS
- Objective response rate (ORR), disease control rate (DCR) [ Time Frame: 24 months ]Effect of triple therapy with trabectedin, ipilimumab and nivolumab on ORR and DCR in advanced soft tissue sarcoma
- Progression free survival (PFS), 6 month PFS rate [ Time Frame: 24 months ]Effect of triple therapy with trabectedin, ipilimumab and nivolumab on progression free survival (PFS), 6 month PFS rate
- Overall survival (OS), 6 month OS rate [ Time Frame: 24 months ]Effect of triple therapy with trabectedin, ipilimumab and nivolumab on overall survival in advanced soft tissue sarcoma
- Tumor response and PD-1, PD-L1 expression in tumors [ Time Frame: 30 months ]Correlation of response with PD-L1 expression and other biomarkers in patients' tumors
- Dexamethasone and immune related events [ Time Frame: 30 months ]• Correlation of the timing and effect of dexamethasone use (necessarily given with TRABECTEDIN) on absolute lymphocyte count and the immune response, including immune related adverse events
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03138161
|Contact: Erlinda M Gordon, MDfirstname.lastname@example.org|
|Contact: Victoria Chua-Alcala, MDemail@example.com|
|United States, California|
|Sarcoma Oncology Research Center||Recruiting|
|Santa Monica, California, United States, 90403|
|Contact: Erlinda M Gordon, MD 310-552-9999 firstname.lastname@example.org|
|Contact: Victoria Chua-Alcala 310-552-9999 email@example.com|
|Principal Investigator: Erlinda M Gordon, MD|
|Sub-Investigator: Sant P Chawla, MD|
|Sub-Investigator: Kamalesh K Sankhala, MD|
|Sub-Investigator: Doris V Quon, MD|
|Sub-Investigator: William W Tseng, MD|
|Principal Investigator:||Erlinda M Gordon, MD||Sarcoma Oncology Research Center|