Ipilimumab + Nivolumab + Cryotherapy in Metastatic or Locally Advanced Soft Tissue Sarcoma

Study Overview
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Brief Summary
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The purpose of this Phase 2 study is to find out if the study drugs (ipilimumab plus nivolumab) in combination with cryotherapy will help participants with metastatic or locally advanced soft tissue sarcoma;. find out how safe are ipilimumab plus nivolumab given in combination with cryotherapy, and what side effects may be related to treatment. find out how do the study drugs in combination with cryotherapy work in soft tissue sarcoma.

Detailed Description
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Primary Objectives: 1) Assess whether the rate of clinical benefit is sufficiently high to merit promise for further study Secondary Objectives: Characterize the 6-month progression-free survival rate Assess whether the treatment yields a reasonably safe and tolerable profile

Official Title
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Phase 2 Study of Ipilimumab Plus Nivolumab in Combination With Cryotherapy in Metastatic or Locally Advanced Soft Tissue Sarcoma

Conditions
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Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Ipilimumab
* Procedure: Cryoablation
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unresectable or metastatic soft tissue sarcoma ≥ 1 prior systemic therapy for sarcoma, including adjuvant systemic therapy Age ≥ 18 years 4 Life expectancy > 3 months Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Lab values as below: Absolute neutrophil count (ANC) ≥ 1,000/mm^3 Platelet count ≥ 75,000/mm^3; Creatinine ≤ 1.5 x upper limit of normal (ULN) OR calculated (calc.); creatinine clearance > 45 mL/min using the lean body mass formula only; Total bilirubin ≤ 1.5 x ULN in absence of Gilbert disease (total bilirubin ≤ 3 x ULN with Gilbert); also, if hyperbilirubinemia is clearly attributed to liver metastases total bilirubin ≤ 3 x ULN is permitted AST/ALT ≤ 3 x ULN;Thyroid stimulating hormone (TSH) within normal limits (WNL);supplementation is acceptable to achieve a TSH WNL; in subjects with abnormal TSH if free T4 is normal and subject is clinically euthyroid, subject is eligible Any toxic effects of prior therapy (except alopecia) must be resolved to NCI CTCAE, version 5.0, Grade 1 or less Ability to understand and the willingness to sign a written informed consent Women of childbearing potential (WOCBP) receiving nivolumab must be willing to adhere to contraception for a period of 5 months after the last dose of nivolumab. Men receiving nivolumab and who are sexually active with WOCBP will be instructed and must be willing to adhere to contraception for a period of 7 months after the last dose of nivolumab. Exclusion Criteria: Prior therapy with ipilimumab or nivolumab, or any agent targeting programmed cell death 1 (PD-1), PD-L1 or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) History of the following: Active known or suspected autoimmune disease Known human immunodeficiency virus (HIV) (Subjects with lymphocytes > 350 cluster of differentiation (CD)4+ cells and no detectable viral load are eligible) Hepatitis B Hepatitis B can be defined as: Hepatitis B surface antigen (HBsAg) > 6 months Serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) 20,000 IU/mL (105 copies/mL), lower values 2,000 to 20,000 IU/mL (104 to 105 copies/mL) are often seen in hepatitis B-e antigen (HbeAg)-negative chronic hepatitis B Persistent or intermittent elevation in alanine aminotransferase (ALT)/alanine aminotransferase (AST) levels. Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation Hepatitis C Hepatitis C antibody (Ab) positive Presence of hepatitis C virus (HCV) ribonucleic acid (RNA) 3.2.2.5 Known active pulmonary disease with hypoxia defined as: Oxygen saturation < 85% on room air or Oxygen saturation < 88% despite supplemental oxygen Systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration Received any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio and measles, mumps, rubella (MMRI) within 30 days before initiation of treatment on this protocol. If female, pregnant or lactating. (Women of childbearing potential are required to have a negative pregnancy test within 24 hours prior to the initial administration of study drug)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ipilimumab/nivolumab + cryotherapy<br>1 mg/kg with nivolumab 3 mg/kg every 3 weeks x 4 doses. (One cycle of treatment is 3 weeks). Cryotherapy (cryoablation) will be performed between investigational agent treatment Cycles 1 and 2 | Drug: Ipilimumab<br>* Ipilimumab 1 mg/kg, injection<br>* Other names: MDX-CTLA4;Procedure: Cryoablation<br>* Cryoablation of the tumors occur between investigational agent treatment Cycles 1 and 2, and will be performed according to standard procedures<br>Drug: Nivolumab<br>* Nivolumab 3 mg/kg, injection<br>* Other names: ONO-4538;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response | Clinical benefit was assessed on the basis of clinical response per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria: Complete response (CR) = Disappearance of all target lesions; all lymph nodes < 10 mm on the short axis; no new lesions. Partial response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions; no new lesions. Stable disease (SD) = Small changes that do not meet any of the above criteria; no new lesions. Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s). Clinical benefit was defined as CR + PR. The primary outcome is expressed as the total number of participants who receive clinical benefit within 14 weeks, a number without dispersion. Rates of all clinical responses are reported. | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Related Adverse Events (Toxicity) | Adverse events were assessed per CTCAE version 5. The outcome is those adverse events experienced by participants that were determined to be possibly, probably, or definitely-related to study treatment. Serious adverse events are identified by the term SAE. Results are presented as the number of related adverse events by preferred term that occurred. The data are numbers without dispersion. | 24 months | 
| Immune-related Clinical Response (irRECIST) Rate | The immune-related (ir) clinical response will be assessed per the immune-related Response Evaluation Criteria in Solid Tumors (ir-RECIST) criteria, as follows: Complete response (CR) = Disappearance of all lesions, with any pathological lymph nodes having a reduction in short axis to < 10 mm; no new lesions > 5 × 5 mm in size. Partial response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions. Stable disease (SD) = Small changes that do not meet any of the these criteria; no new lesions > 5 × 5 mm in size. Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions with the sum of diameters increasing ≥ 5 mm, and/or the appearance of 1+ new lesion(s). Note that irRECIST differs from RECIST criteria. The outcome is expressed as the total number of participants who achieve a ir-clinical response (ie, CR + PR) by 16 weeks, a number without dispersion. | 16 weeks | 
| Progression-free Survival (PFS) | Progression-free survival (PFS) is a measure of participants remaining alive without disease progression. The outcome is expressed as the total number of participants remaining alive without disease progression at 6 months after consent, a number without dispersion. | 6 months |