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

Phase 2

Completed

Conditions: Soft Tissue Sarcoma

Interventions: Drug: Ipilimumab
Procedure: Cryoablation
Drug: Nivolumab

Registration Number: NCT04118166

Lead Sponsor: Kristen Ganjoo

Brief Summary: The purpose of this Phase 2 study is to

1. find out if the study drugs (ipilimumab plus nivolumab) in combination with cryotherapy will help participants with metastatic or locally advanced soft tissue sarcoma;.

2. find out how safe are ipilimumab plus nivolumab given in combination with cryotherapy, and what side effects may be related to treatment.

3. find out how do the study drugs in combination with cryotherapy work in soft tissue sarcoma.

Detailed Description: Primary Objectives:

1) Assess whether the rate of clinical benefit is sufficiently high to merit promise for further study

Secondary Objectives:

1. Characterize the 6-month progression-free survival rate

2. Assess whether the treatment yields a reasonably safe and tolerable profile

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Ipilimumab/nivolumab + cryotherapy	Cryoablation	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
Ipilimumab/nivolumab + cryotherapy	Ipilimumab	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
Ipilimumab/nivolumab + cryotherapy	Nivolumab	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

Primary Outcome Measures

Name	Time	Method
Clinical Response	14 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Related Adverse Events (Toxicity)	24 months	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.
Immune-related Clinical Response (irRECIST) Rate	16 weeks	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.
Progression-free Survival (PFS)	6 months	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.