Neoplasms

All Conditions

Symptoms and General Pathology

Digestive System Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Carcinoma

Recurrence

Gastrointestinal Stromal Tumors

Sarcoma

Osteosarcoma

Sarcoma, Ewing

Sarcoma, Endometrial Stromal

Chondrosarcoma

Desmoplastic Small Round Cell Tumor

Endometrial Neoplasms

Neoplasms by Histologic Type

Neoplasms, Connective and Soft Tissue

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Endometrial Stromal Tumors

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Soft Tissue Sarcoma

Ewing Sarcoma

Endometrial Stromal Sarcoma

All Drugs and Chemicals

Antineoplastic Agents

Immunomodulating Agents

Nivolumab

Ipilimumab

Antineoplastic Agents, Immunological

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

Musculoskeletal Diseases

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Bone Neoplasms

Disease Attributes

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Connective Tissue Diseases

Bone Diseases

Neuroepithelioma

Irinotecan

Vaccines

Temozolomide

Camptothecin

Topoisomerase I Inhibitors

Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Participants randomized to Group A received oral temozolomide 100 mg/m2 daily (Days 1-5), total dose 500 mg/m2/cycle) and oral irinotecan 50 mg/m2 daily (Days 1-5, total dose 250 mg/m2/cycle). Vigil immunotherapy was administered at a concentration of 1 X 10e6 cells/dose given via intradermal injection on Day 15 of each cycle. 1 cycle = 21 days

Participants continued treatment for a maximum of 12 cycles, or until disease progression, unacceptable toxicity, withdrawal of consent or other criterion is met for discontinuation from study.

Participants randomized to Group B received oral temozolomide 100 mg/m2 daily (Days 1-5), total dose 500 mg/m2/cycle) and oral irinotecan 50 mg/m2 daily (Days 1-5, total dose 250 mg/m2/cycle).

1 cycle = 21 days

Participants continued treatment for a maximum of 12 cycles, or until disease progression, unacceptable toxicity, withdrawal of consent or other criterion is met for discontinuation from study.

Participants randomized to Group B were able to receive Vigil immunotherapy at a concentration of 1 X 10e6 cells/dose given via intradermal injection on Day 15 of each cycle. Confirmation of progression by central radiologist and pre-approval from sponsor was required. 1 cycle = 21 days

Vigil is composed of autologous tumor cells harvested from the patient at the time of initial de-bulking surgery which are then transfected extracorporeally, with a plasmid encoding for the gene for GM-CSF, an immune-stimulatory cytokine, and a bifunctional, short hairpin RNA which specifically knocks down the expression of furin, the critical convertase responsible for production of the two TGβ isoforms.

Vigil

Injectable formulation of irinotecan was distributed from central supplier. 1 Cycle (5 doses of 50 mg/m2 per syringe) was drawn into provided oral syringes and dispenses to the subject with instructions to refrigerate until administration.

Dose: 100 mg/m2 daily, oral Schedule: Days 1-5, every 21 days Administered at least 1 hour before Irinotecan.

John Nemunaitis, MD

The goal of this clinical trial was to compare participants with first relapse or refractory Ewing's sarcoma when treated with investigational product (Vigil) in addition to the standard treatment of irinotecan and temozolomide compared to the standard treatment of irinotecan and temozolomide alone. The main question it aimed to answer is "Will participants who receive Vigil in addition to irinotecan and temozolomide have a prolonged time to progression and improved quality of life compared to the participants who receive irinotecan and temozolomide alone?".

This was a multicenter, Phase III study in participants with metastatic Ewing's sarcoma Family of Tumors (ESFT) refractory/intolerant or recurrent to 1 prior line of chemotherapy. Participants who agreed to participation had tumor tissue harvested from a scheduled standard surgical procedure (e.g., tumor biopsy or palliative resection). The tumor tissue removed was shipped to Gradalis, Inc. to attempt to manufacture the investigational product, Vigil.

Subjects who met eligibility criteria including manufacture of a minimum of 4 doses of Vigil were randomized 1:1 to either Group A (Vigil + Irinotecan + Temozolomide (Tem/Iri)) or Group B (Irinotecan + Temozolomide). Screening for the main portion of the study occurred as early as one week but no later than 8 weeks following tumor procurement.

Subjects received repeat cycles of treatment until disease progression, unacceptable toxicity, withdrawal of consent or other criterion was met for discontinuation from study. Subjects randomized to Group A (Vigil + Tem/Iri) received up to 12 doses depending upon the quantity of Vigil manufactured from the surgical specimen. 1 cycle = 21 days. If irinotecan + temozolomide was administered beyond 12 cycles, it was administered off study. Subjects randomized to Group B (Tem/Iri) may have crossed over to receive single agent Vigil every 21 days following End of Treatment assessment and documented disease progression confirmed by central radiology vendor, for up to 12 doses of Vigil depending upon the quantity of Vigil manufactured.

Participants were managed in an outpatient setting. Hematologic function, liver enzymes, renal function and electrolytes will be monitored. Blood for immune function analyses including IFNγ-ELISPOT analysis of cytotoxic T cell activation in response to autologous tumor antigens will be collected at tissue procurement, post-procurement screening and Day 1 (prior to chemotherapy administration) at Cycles 2, 4, and 6, end of treatment (EOT), 3 months after EOT, and every 6 months thereafter. Blood for ctDNA analysis was collected at tissue procurement, prior to chemotherapy administration at baseline and on Day 1 prior to chemotherapy administration at Cycles 2, 3, 4, and 6, and EOT. After progression, participants were contacted quarterly for documentation of post study therapies and survival status information.

Participants were randomized 1:1 to either Group A (Vigil + irinotecan and temozolomide) or Group B (irinotecan and temozolomide alone). Participants randomized to Group B were able to receive Vigil (Cross-Over) after confirmation of progression by central radiologist and sponsor approval.

A Trial For Participants With Ewing's Sarcoma Treated With Vigil in Combination With Irinotecan and Temozolomide

A Multi-Center Phase III, Randomized, Open-Label Trial of Vigil (Bi-shRNAfurin and GMCSF Augmented Autologous Tumor Cell Immunotherapy) in Combination With Irinotecan and Temozolomide as a Second-Line Regimen for Ewing's Sarcoma

Progression Free Survival (PFS) is defined as the time from randomization to the event of disease recurrence/progression according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria (version 1.1) for target lesions and assessed CT/MRI by local investigator.

OS is defined as time from randomization to death or to the date of last follow-up. The date of last follow-up confirming survival will be used as the censoring date for subjects who are alive and/or do not have a known date of death.

ORR is defined as the proportion of participants who have prolonged stable disease or a partial or complete response or complete response to therapy according to RECIST 1.1.

Participants were considered eligible for treatment, if the tissue submitted to Gradalis met all criteria, including manufacturing product release criteria.

Gradalis, Inc.

Participants randomized to Group A received oral temozolomide 100 mg/m2 daily (Days 1-5), total dose 500 mg/m2/cycle) and oral irinotecan 50 mg/m2 daily (Days 1-5, total dose 250 mg/m2/cycle). Vigil immunotherapy was administered at a concentration of 1 X 10e6 cells/dose given via intradermal injection on Day 15 of each cycle. 1 cycle = 21 days

Participants continued treatment for a maximum of 12 cycles, or until disease progression, unacceptable toxicity, withdrawal of consent or other criterion was met for discontinuation from study.

Group A: Vigil in Combination With Irinotecan and Temozolomide

Participants randomized to Group B received oral temozolomide 100 mg/m2 daily (Days 1-5), total dose 500 mg/m2/cycle) and oral irinotecan 50 mg/m2 daily (Days 1-5, total dose 250 mg/m2/cycle).

1 cycle = 21 days

Participants continued treatment for a maximum of 12 cycles, or until disease progression, unacceptable toxicity, withdrawal of consent or other criterion was met for discontinuation from study.

Group B: Irinotecan and Temozolomide

Participants assigned to Group B crossed-over to received Vigil monotherapy at a concentration of 1 X 10e6 cells//dose via intradermal injection every 21 days following End of Treatment assessment.

Participants received up to 12 doses of Vigil depending upon the quantity of Vigil manufactured.

Cross-over to Vigil Alone

Participants randomized to Group A received oral temozolomide 100 mg/m\^2 daily (Days 1-5), total dose 500 mg/m\^2/cycle) and oral irinotecan 50 mg/m\^2 daily (Days 1-5, total dose 250 mg/m\^2/cycle). Vigil immunotherapy was administered at a concentration of 1 X 10e6 cells/dose given via intradermal injection on Day 15 of each cycle. 1 cycle = 21 days

Participants continued treatment for a maximum of 12 cycles, or until disease progression, unacceptable toxicity, withdrawal of consent or other criterion is met for discontinuation from study.

Participants randomized to Group B received oral temozolomide 100 mg/m\^2 daily (Days 1-5), total dose 500 mg/m\^2/cycle) and oral irinotecan 50 mg/m\^2 daily (Days 1-5, total dose 250 mg/m\^2/cycle).

1 cycle = 21 days

Participants continued treatment for a maximum of 12 cycles, or until disease progression, unacceptable toxicity, withdrawal of consent or other criterion is met for discontinuation from study.

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

An assessment of Performance Status (PS) on the Karnofsky or Lansky scale is standard way of measuring the ability of cancer patients to perform ordinary tasks. The PS scores range from 0 to 100. A higher score means the patient is better able to carry out daily activities. The assessment is made by an investigator during the physical exam of the subject.

Baseline Performance Status

Only 1 subject randomized to Group B was eligible to Cross-over to receive Vigil.

Early termination of trial leading to small numbers of subjects analyzed. Technical problems with measurement leading to unreliable or uninterpretable data.

Clinical and Regulatory Operations

Participants randomized to Group B received oral temozolomide 100 mg/m2 daily (Days 1-5), total dose 500 mg/m2/cycle) and oral irinotecan 50 mg/m2 daily (Days 1-5, total dose 250 mg/m2/cycle). 1 cycle = 21 days

Participants continued treatment for a maximum of 12 cycles, or until disease progression, unacceptable toxicity, withdrawal of consent or other criterion is met for discontinuation from study.

PFS is not adequately assessable for difference between cohorts given only 5 participants were enrolled and received treatment.

Progression Free Survival (PFS)

OS is not adequately assessable for difference between cohorts given only 5 participants were enrolled and received treatment.

Overall Survival (OS)

No subjects on trial achieved a partial or complete response, therefore the ORR was not determined.

Overall Response Rate (ORR)

Participants who underwent tissue procurement and the processed tissue samples were successfully shipped to Gradalis whereby Vigil production was attempted.

Total Number of Tissue Procurements

All enrolled subjects who completed tissue procurement and the tissue was received by Gradalis for Vigil Manufacture. Any subjects whose tissue was not submitted to Gradalis was excluded in the analysis.

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
A Trial For Participants With Ewing's Sarcoma Treated With Vigil in Combination With Irinotecan and Temozolomide	NCT03495921	Ewing Sarcoma Ewing Family of... Ewing's Tumor M... Ewing's Sarcoma... Ewing's Tumor R... Rare Diseases Sarcoma Neoplasms, Conn... Neoplasms by Hi... Neoplasms, Bone... Neoplasms, Conn... Sarcoma, Ewing Neoplasms	Vigil Irinotecan Temozolomide	2 Years -	Gradalis, Inc.

Spots Global Cancer Trial Database for ewing's tumor recurrent