A Phase II Single Arm Study Assessing Efficacy & Safety of Nivolumab Plus Ipilimumab in Nonresectable/Metastatic Sarcoma and Endometrial Carcinoma Patients With Somatic Deficient MMR as a Selection Tool
Overview
- Phase
- Phase 2
- Intervention
- Ipilimumab
- Conditions
- Soft Tissue Sarcoma
- Sponsor
- Assaf-Harofeh Medical Center
- Enrollment
- 60
- Primary Endpoint
- Response to therapy as evaluated by RECIST 1.1
- Last Updated
- 8 years ago
Overview
Brief Summary
The purpose of this study is to determine whether nivolumab plus ipilimumab are effective and safe in the treatment of sarcoma and endometrial carcinoma patients with somatic deficient MMR as a selection tool.
Detailed Description
The expected duration of this study is 36 months (18 months accrual period and 18 month follow up period). Enrollment into the screening or treatment phase of the study will be stopped when the actual subject numbers have been achieved. This single arm single institution, open label, prospective, phase II trial will evaluate the efficacy and safety of Nivolumab 240 mg IV every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks in patients with nonresectable/metastatic sarcoma or endometrial carcinoma with somatic deficient MMR as a selection tool.patients. Number of patients in the study will reflect the reconciliation between statistical requirements and incidence. Treatment will continue until disease progression, development of unacceptable toxicity, noncompliance or withdrawal of consent by the patient or investigator decision. All screening requirements must be completed within 28 days of the visit (except for Patients will be examined on cycle 1 day-1 and every 2 weeks, including complete blood count (CBC) and chemistry, until disease progression. CT/MRI imaging (contrast) will be performed every 6 weeks for response evaluation for the first 48 weeks and every 12 weeks thereafter. Clinical benefit as well as individual categories of response (complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) will be determined using Response Evaluation Criteria in Solid Tumors 1.1 (RECIST). Response duration endpoints, including median PFS, PFS at 12 and 24 weeks and OS will be assessed using the Kaplan-Meier method. Toxicity (AEs) will be recorded using the NCI- Common Toxicity Criteria for Adverse Effects v 4.03 (NCI-CTCAE). Screening procedures will include immunostaining for MLH1, MSH2, MSH6 and PMS2 all performed on formalin fixed paraffin embedded (FFPE) tissue sections. In addition tumor DNA, extracted from FFPE tissue (after choosing optimal area by a Pathologist), will be submitted to FoundationOne for a later exploratory analysis.
Investigators
Daniela Katz M.D
M.D
Assaf-Harofeh Medical Center
Eligibility Criteria
Inclusion Criteria
- •Patients will sign the informed consent form before the initiation of any study procedure.
- •Males and Females, 18 years or older
- •Patients must have a FFPE tumor block, one representative hematoxylin and eosin (H\&E) and 20 unstained sarcoma/endometrial carcinoma tissue slides available for submission to pathology review; this step is mandatory prior to registration to confirm eligibility.
- •Tumors must immune-stain negatively to one or more of the following proteins: MLH1, MSH2, MSH6 and PMS2
- •Patients must have histologically confirmed bone or soft tissue sarcoma by pathology review or a diagnosis of FIGO grade 3 endometrioid cancer, serous, clear cell, or mixed high grade endometrial cancer.
- •Measurable disease of sarcoma or endometrial carcinoma defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>10 mm with CT scan or MRI, as \>20 mm by chest x-ray, or \>10 mm with calipers by clinical exam by RECIST 1.
- •Locally advanced non-operable or metastatic disease
- •\>= 1 prior systemic therapy for sarcoma or endometrial carcinoma, including adjuvant systemic therapy
- •No treatment with biologic therapy, immunotherapy, chemotherapy, investigational agent for malignancy =\< 21 days before study registration
- •Eastern Cooperative Oncology Group ECOG performance status 0 or 1
Exclusion Criteria
- •Active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
- •Have a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
- •FIGO grade 1 or 2 endometrioid cancer.
- •Have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
- •Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to the first dose of nivolumab/ipilimumab or has not recovered (i.e., to ≤ grade 1 or baseline) from adverse events due to a previously administered agent. Note, subjects with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note, if a subject received major surgery, she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- •No known or suspected allergy to nivolumab or study drug components and no history of severe hypersensitivity reaction to any monoclonal antibody
- •Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
- •As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen.
- •Have a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
- •Have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
Arms & Interventions
Nivolumab and ipilimumab
Nivolumab 240 mg IV every 2 weeks plus Ipilimumab 1 mg/m2 IV every 6 weeks
Intervention: Ipilimumab
Nivolumab and ipilimumab
Nivolumab 240 mg IV every 2 weeks plus Ipilimumab 1 mg/m2 IV every 6 weeks
Intervention: Nivolumab
Outcomes
Primary Outcomes
Response to therapy as evaluated by RECIST 1.1
Time Frame: 36 months
complete and partial response
Secondary Outcomes
- Median Progression-free survival (PFS)(36 months)
- Progression-free survival (PFS) assessed at 12 weeks(12 weeks)
- Progression-free survival (PFS) assessed at 24 weeks(24 weeks)
- overall survival(36 months)