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Nivolumab

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Immune Checkpoint Inhibitors

Nivolumab 240 mg IV every 2 weeks plus Ipilimumab 1 mg/m2 IV every 6 weeks

Daniela Katz, MD

Sharona Ben Ami

Daniela Katz, M.D

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.

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.

A Phase II of Nivolumab Plus Ipilimumab in Non-resectable Sarcoma and Endometrial Carcinoma

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

PFS will be computed from the date of start of treatment to the first documented date of progression or the date of death, due to any cause assessed by investigator.

PFS will be computed from the date of start of treatment to week 12 as assessed by investigator.

PFS will be computed from the date of start of treatment to week 24 as assessed by investigator

will be computed from the date of start of treatment to the date of death, due to any cause. Patients alive or lost for follow-up at the time of the analysis will be censored at the date of last follow-up.

Assaf-Harofeh Medical Center

Nervous System Diseases

Heart and Blood Diseases

Wounds and Injuries

Stomach Neoplasms

Hematoma, Subdural

Stomach Diseases

Stomach Cancer

Amino Acids

Tyrosine Kinase Inhibitors

Tyrosine

Patients with histologically confirmed or clinical presentation suspicious of GIST

Audra A Satterwhite, R.N.

Andrew M Blakely, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Objective:

To follow people with GISTs and collect tumor tissue so that it can be studied in the lab.

Eligibility:

People age 6 and older who have a GIST.

Design:

Participants will be screened with a review of their medical records and samples.

Participants will enroll in 1 other NIH study, and may be asked to enroll in 2 other optional NIH studies.

Participants will have a medical history and physical exam. Data about how they function in their daily activities will be obtained.

Participants may speak with a genetic counselor. They may have genetic testing.

Participants will give blood samples. They may have a cheek swab. For this, small brush will be rubbed against the inside of the cheek.

Participants may have a computed tomography (CT) scan of the chest, abdomen, and pelvis. Or they may have a CT scan of the chest and magnetic resonance imaging (MRI) of the abdomen and pelvis.

Participants will be monitored every 6-12 months at the NIH Clinical Center, for up to 10 years before having surgery. If they need surgery, it will be performed at the NIH. Then, they will be monitored every 6-12 months, for up to 5 years after surgery.

If a participant has surgery, tumor tissue samples will be taken.

If a participant does not need surgery, their participation will end after 10 years. If they have surgery, the 5-year monitoring period will restart after each surgery.

Background:

Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal soft tissue sarcoma, but remain a rare disease entity.

Most GISTs are characterized by KIT or PDGFRA mutations, making them susceptible to tyrosine kinase inhibitor (TKI) therapy.

Wild-type (WT) GISTs are rarer tumors, usually characterized by SDH mutations and/or lack of KIT or PDGFRA mutations; paragangliomas are frequently associated with WT GISTs.

Non-WT GISTs may become refractory to TKI therapy, whereas WT GISTs are generally resistant to TKI therapy.

The primary treatment modality for GISTs is surgical resection, which may involve the stomach, liver, and/or peritoneal surfaces; most patients will require multiple operations to remove disease not responsive to systemic agents.

Investigational systemic therapies are limited by toxicity and/or lack of efficacy, resulting in an unmet need for novel treatment options.

Obtaining fresh tumor tissue is critical to the successful development of GIST models for drug research, as well as for next generation tumor genomic sequencing, and to help identify novel targets and/or agents for the treatment of WT and TKI-resistant non-WT GISTs.

Objective:

Evaluate and follow patients with GISTs, particularly WT and treatment-refractory non-WT, to support translational research for this rare disease

Assess disease-free intervals (DFIs) between surgical resection of disease for at least 5 years

Eligibility:

Participants with histologically confirmed or clinical presentation suspicious of GIST.

Design:

Prospective cohort study

Participants with histologically confirmed or clinical presentation suspicious of GIST will enroll on study and will have active surveillance every 9-15 months for up to 10 years prior to and up to 5 years after surgical resection and/or cytoreduction. As participants may have multiple resections during the course of the study, 5-year surveillance post-surgery may be initiated multiple times, relative to the last resection performed.

All participants enrolled will be evaluated for tumor resection or cytoreduction at the start of study and if appropriate, will be offered surgery, otherwise they will be on active surveillance until surgical resection or cytoreduction is clinically indicated.

It is expected that approximately 30-40 patients per year may enroll on this trial; the accrual ceiling will be set at 400 to permit accrual over a 10-year period.

Surgery in Gastrointestinal Stromal Tumors (GISTs) for Treatment, Tumor Modeling, and Genomic Analysis

Prospective Study of Surgery in Gastrointestinal Stromal Tumors (GISTs) for Treatment, Tumor Modeling, and Genomic Analysis

.All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

Patients with non-WT GIST and WT GIST will have the durations of the DFIs described both within each patient as their own control and across patients. Analyses will be done separately for those with WT GIST and those with non-WT GIST as well as for all patients combined.

Surveillance every 6-12 months and time of surgery, by tumor measurement and imaging studies, to assess disease-free intervals (DFIs) between surgical resection of disease for at least 5 years.

Characterization of the genomic and clinicopathologic features associated with GISTs.

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase II of Nivolumab Plus Ipilimumab in Non-resectable Sarcoma and Endometrial Carcinoma	NCT02982486	Soft Tissue Sar... Bone Sarcoma Chondrosarcoma Gastrointestina... Ewing's Tumor M... Ewing's Tumor R... Osteosarcoma Desmoplastic Sm...	Ipilimumab Nivolumab	18 Years -	Assaf-Harofeh Medical Center
A Phase II of Nivolumab Plus Ipilimumab in Non-resectable Sarcoma and Endometrial Carcinoma	NCT02982486	Soft Tissue Sar... Bone Sarcoma Chondrosarcoma Gastrointestina... Ewing's Tumor M... Ewing's Tumor R... Osteosarcoma Desmoplastic Sm...	Ipilimumab Nivolumab	18 Years -	Assaf-Harofeh Medical Center
Surgery in Gastrointestinal Stromal Tumors (GISTs) for Treatment, Tumor Modeling, and Genomic Analysis	NCT04557969	Gastric Cancer Gastric Neoplas... Gastrointestina... Gastrointestina... Gastrointestina...		6 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for gastrointestinal stromal sarcoma