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

NCT03495921 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: CL-PTL-130
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 15

Brief Summary

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?".

Conditions

Ewing Sarcoma; Ewing Family of Tumors; Ewing's Tumor Metastatic; Ewing's Sarcoma Metastatic; Ewing's Tumor Recurrent; Rare Diseases; Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma, Ewing; Neoplasms

Keywords

ESFT; Immunotherapy; Phase 3; irinotecan; temozolomide; First Relapse; Second Line; Vigil; vaccine; orphan drug; soft bone; pediatric; FLI; EWS; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS)

  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.

  From date of randomization until the date of first documented progression (assessed up to 3 years).

Secondary Outcomes (3)

• Overall Survival (OS)

  From date of randomization until date of death from any cause, whichever came first (assessed up to 3 years).

• Overall Response Rate (ORR)

  6 months after treatment with Vigil.

• Vigil Manufacture Success Rate: Number of Participants Eligible for Treatment on the Main Study.

  From manufacturing start date until 4 weeks post manufacturing for each tissue procurement (assessed up to 17 months).

Study Arms (3)

Group A: Vigil + Irinotecan and Temozolomide

EXPERIMENTAL

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.

Biological: Vigil; Drug: Irinotecan; Drug: Temozolomide

Group B: Irinotecan and Temozolomide

ACTIVE COMPARATOR

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.

Drug: Irinotecan; Drug: Temozolomide

Cross-Over: Vigil monotherapy

OTHER

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

Biological: Vigil

Interventions

Vigil BIOLOGICAL

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.

Also known as: Bi-shRNAfurin and GMCSF Augmented Autologous Tumor Cell Immunotherapy, FANG vaccine

Cross-Over: Vigil monotherapy; Group A: Vigil + Irinotecan and Temozolomide

Irinotecan DRUG

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.

Also known as: Camptosar, Camptothecin-11, CPT-11

Group A: Vigil + Irinotecan and Temozolomide; Group B: Irinotecan and Temozolomide

Temozolomide DRUG

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

Also known as: Temodar

Group A: Vigil + Irinotecan and Temozolomide; Group B: Irinotecan and Temozolomide

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed Ewing's Sarcoma Family of Tumors (ESFT).
• Age greater than or equal to 2 years.
• Estimated survival greater than or equal to 6 months.
• Evidence of EWS translocation by FISH or RT-PCR or Next Generation Sequencing (NGS). If available, NGS sequencing report should be submitted to Gradalis.
• Recurrence or refractory to 1 line of systemic chemotherapy, including but not limited to doxorubicin, vincristine, and ifosfamide.
• Planned standard of care surgical procedure (e.g., tumor biopsy or palliative resection or thoracentesis) and expected availability of a cumulative soft-tissue mass of \~10-30 grams tissue ("grape" to "golf-ball" size / approximately 2 cm total diameter on imaging) or pleural fluid estimated volume ≥ 500mL (from a primary or secondary thoracentesis, yielding in a high volume of tumor cells) for immunotherapy manufacture.
• Tumor intended for immunotherapy manufacture is not embedded in bone and does not contain luminal tissue (e.g. bowel, ureter, bile duct).
• Ability to understand and the willingness to sign a written protocol specific informed consent for tissue harvest or a parental/guardian informed consent and pediatric assent when appropriate.

You may not qualify if:

• Medical condition requiring any form of chronic systemic immunosuppressive therapy (steroid or other) except physiologic replacement doses of hydrocortisone or equivalent (no more than 30 mg hydrocortisone or 10 mg prednisone equivalent daily) for \< 30 days duration.
• Known history of other malignancy unless having undergone curative intent therapy without evidence of that disease for ≥ 3 years except cutaneous squamous cell and basal cell skin cancer, superficial bladder cancer, in situ cervical cancer or other in situ cancers are allowed if definitively resected.
• Brain metastases unless treated with curative intent (gamma knife or surgical resection) and without evidence of progression for ≥ 2 months.
• Any documented history of autoimmune disease with exception of Type 1 diabetes on stable insulin regimen, hypothyroidism on stable dose of replacement thyroid medication, vitiligo, or asthma not requiring systemic steroids.
• Known HIV or chronic Hepatitis B or C infection.
• Known hypersensitivity to any temozolomide component or to dacarbazine (DTIC).
• Known hypersensitivity to irinotecan or its excipients.
• Known history of allergies or sensitivities to gentamicin.
• History of or current evidence of any condition (including medical, psychiatric or substance abuse disorder), therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
• Completed manufacture of at least 4 vials of Vigil.
• Karnofsky performance status (KPS) / Lansky performance status (LS) ≥80 percent.
• Normal organ and marrow function as defined below:
• Absolute granulocyte count ≥1,000/mm3, Absolute lymphocyte count ≥400/mm3, Platelets ≥75,000/mm3, Hemoglobin ≥ 8.0 mg/dL, Total bilirubin ≤ institutional upper limit of normal\*, AST(SGOT)/ALT(SGPT) ≤2x institutional upper limit of normal, Creatinine \<1.5 mg/dL
• \* documented Gilbert's syndrome may be considered after medical monitor review
• Subject has recovered to CTCAE Grade 1 (except for parameters noted in Item 3, above) or better from all adverse events associated with prior therapy or surgery. Pre-existing motor or sensory neurologic pathology or symptoms, or dermatologic must be recovered to CTCAE Grade 2 or better.

Sponsors & Collaborators

• Gradalis, Inc.: lead

Study Sites (15)

Arkansas Children's Hospital

Little Rock, Arkansas, 72202, United States

Location

Southern California Permanente Medical Group

Los Angeles, California, 90027, United States

Location

Mayo Clinic Florida

Jacksonville, Florida, 32224, United States

Location

Nicklaus Children's Hospital

Miami, Florida, 33155, United States

Location

Dana-Farber/Boston Children's Cancer and Blood Disorders

Boston, Massachusetts, 02215, United States

Location

Washington University Siteman Cancer Center

St Louis, Missouri, 63110, United States

Location

Nebraska Methodist Hospital

Omaha, Nebraska, 68114, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Duke Children's Hospital and Health Center; Duke Cancer Institute

Durham, North Carolina, 27710, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

Texas Oncology - Pediatrics

Dallas, Texas, 75230, United States

Location

Cook Children's Medical Center

Fort Worth, Texas, 76104, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

Related Publications (4)

• Ghisoli M, Rutledge M, Stephens PJ, Mennel R, Barve M, Manley M, Oliai BR, Murphy KM, Manning L, Gutierrez B, Rangadass P, Walker A, Wang Z, Rao D, Adams N, Wallraven G, Senzer N, Nemunaitis J. Case Report: Immune-mediated Complete Response in a Patient With Recurrent Advanced Ewing Sarcoma (EWS) After Vigil Immunotherapy. J Pediatr Hematol Oncol. 2017 May;39(4):e183-e186. doi: 10.1097/MPH.0000000000000822.

  PMID: 28338569 BACKGROUND

• Ghisoli M, Barve M, Mennel R, Lenarsky C, Horvath S, Wallraven G, Pappen BO, Whiting S, Rao D, Senzer N, Nemunaitis J. Three-year Follow up of GMCSF/bi-shRNA(furin) DNA-transfected Autologous Tumor Immunotherapy (Vigil) in Metastatic Advanced Ewing's Sarcoma. Mol Ther. 2016 Aug;24(8):1478-83. doi: 10.1038/mt.2016.86. Epub 2016 Apr 25.

  PMID: 27109631 BACKGROUND

• Ghisoli M, Barve M, Schneider R, Mennel R, Lenarsky C, Wallraven G, Pappen BO, LaNoue J, Kumar P, Nemunaitis D, Roth A, Nemunaitis J, Whiting S, Senzer N, Fletcher FA, Nemunaitis J. Pilot Trial of FANG Immunotherapy in Ewing's Sarcoma. Mol Ther. 2015 Jun;23(6):1103-1109. doi: 10.1038/mt.2015.43. Epub 2015 Mar 19.

  PMID: 25917459 BACKGROUND

• Senzer N, Barve M, Kuhn J, Melnyk A, Beitsch P, Lazar M, Lifshitz S, Magee M, Oh J, Mill SW, Bedell C, Higgs C, Kumar P, Yu Y, Norvell F, Phalon C, Taquet N, Rao DD, Wang Z, Jay CM, Pappen BO, Wallraven G, Brunicardi FC, Shanahan DM, Maples PB, Nemunaitis J. Phase I trial of "bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell" vaccine (FANG) in advanced cancer. Mol Ther. 2012 Mar;20(3):679-86. doi: 10.1038/mt.2011.269. Epub 2011 Dec 20.

  PMID: 22186789 BACKGROUND

MeSH Terms

Conditions

Sarcoma, Ewing; Neuroectodermal Tumors, Primitive, Peripheral; Rare Diseases; Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms

Interventions

FANG vaccine; Irinotecan; Temozolomide

Condition Hierarchy (Ancestors)

Osteosarcoma; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Connective Tissue Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Limitations and Caveats

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

Results Point of Contact

• Title: Clinical and Regulatory Operations
• Organization: Gradalis, Inc.

info@gradalisinc.com

(214) 442-8100

Study Officials

• John Nemunaitis, MD

  Gradalis, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Model Details: 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.

Study Record Dates

• First Submitted: February 15, 2018
• First Posted: April 12, 2018
• Study Start: August 21, 2018
• Primary Completion: January 20, 2022
• Study Completion: January 20, 2022
• Last Updated: April 26, 2023
• Results First Posted: April 26, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (15)