Soft Tissue Sarcoma
Conditions
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
Interventions
DRUGIpilimumab
Ipilimumab 1 mg/kg, injection
PROCEDURECryoablation
Cryoablation of the tumors occur between investigational agent treatment Cycles 1 and 2, and will be performed according to standard procedures
DRUGNivolumab
Nivolumab 3 mg/kg, injection
Sponsors
Bristol-Myers Squibb
Kristen Ganjoo
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ipilimumab/Nivolumab + Cryotherapy 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: Ipilimumab 1 mg/kg, injection
Cryoablation: Cryoablation of the tumors occur between investigational agent treatment Cycles 1 and 2, and will be performed according to standard procedures
Nivolumab: Nivolumab 3 mg/kg, injection | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Ipilimumab/Nivolumab + Cryotherapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Age, Continuous | 55.0 years STANDARD_DEVIATION 14.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 15 / 30 |
| other Total, other adverse events | 30 / 30 |
| serious Total, serious adverse events | 30 / 30 |
Outcome results
Primary
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.
Time frame: 14 weeks
Population: Does not include participants taken off-study, and not evaluated for the outcome.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ipilimumab/Nivolumab + Cryotherapy | Clinical Response | Complete Response (CR) | 0 Participants |
| Ipilimumab/Nivolumab + Cryotherapy | Clinical Response | Partial Response (PR) | 3 Participants |
| Ipilimumab/Nivolumab + Cryotherapy | Clinical Response | Stable Disease (SD) | 7 Participants |
| Ipilimumab/Nivolumab + Cryotherapy | Clinical Response | Progressive disease (PD) | 19 Participants |
Secondary
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.
Time frame: 16 weeks
Population: Immune-related Response Evaluation Criteria in Solid Tumors (ir-RECIST) was not assessed/collected for some subjects, and cannot be reported. Reasons that ir-RECIST was not assessed included death, adverse event, and withdrawal/lost-to-follow-up subsequent to PD determination per RECIST at 14 weeks.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ipilimumab/Nivolumab + Cryotherapy | Immune-related Clinical Response (irRECIST) Rate | Complete response (CR) | 0 Participants |
| Ipilimumab/Nivolumab + Cryotherapy | Immune-related Clinical Response (irRECIST) Rate | Partial response (PR) | 3 Participants |
| Ipilimumab/Nivolumab + Cryotherapy | Immune-related Clinical Response (irRECIST) Rate | Stable disease (SD) | 7 Participants |
| Ipilimumab/Nivolumab + Cryotherapy | Immune-related Clinical Response (irRECIST) Rate | Progressive disease (PD) | 15 Participants |
Secondary
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.
Time frame: 6 months
Population: Does not include participants taken off-study, and not evaluated for the outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ipilimumab/Nivolumab + Cryotherapy | Progression-free Survival (PFS) | 3 Participants |
Secondary
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.
Time frame: 24 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Pain, neuropathic | 1 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Dry mouth | 2 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Allergic reaction | 1 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Ringing in the ears (tinnitus) | 1 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Adrenal insufficiency | 1 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Hyperthyroidism (excess levels of thyroxine hormone) | 3 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Hypothyroidism (diminished levels of thyroxine hormone) | 4 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Hypophysitis (inflammation of the pituitary gland) | 1 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Diarrhea | 4 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Diarrhea (intermittent) | 1 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Thyroid stimulating hormone (TSH) elevated | 2 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Alanine aminotransferase (ALT) elevated | 1 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Hyponatremia (blood sodium level decreased) | 2 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Neuropathy, peripheral sensory | 1 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Numbness, bilateral hand, intermittent | 1 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Cough, all descriptions | 4 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Dyspnea (shortness of breath) | 3 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Hoarse voice | 1 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Pneumonitis (lung inflammation) | 1 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Pneumonitis (lung inflammation) (SAE) | 1 Related adverse events |
| Ipilimumab/Nivolumab + Cryotherapy | Related Adverse Events (Toxicity) | Rash, all descriptions | 12 Related adverse events |