Pbi-shRNA™ EWS/FLI1 Type 1 LPX in Subjects With Advanced Ewing's Sarcoma

NCT02736565 | Completed Phase 1 FDA Drug

• 1 other identifier: CL-PTL-001
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to determine the safety and the maximum tolerated dose of of pbi-shRNA™ EWS/FLI1 Type 1 lipoplex in patients with advanced Ewing's sarcoma.

Conditions

Ewing's Sarcoma; Ewing Family of Tumors; Ewing's Tumor Metastatic; Ewing's Sarcoma Metastatic; Ewing's Tumor Recurrent; Rare Diseases; Sarcoma

Keywords

bone cancer; EWS gene; neuroectodermal tumor; pNET; sarcoma; soft tissue; ESFT; Immunotherapy

Outcome Measures

Primary Outcomes (2)

• Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v4.0

  Adverse events(AEs) will be recorded for the duration of the participant's study treatment (following the first dose of the investigational product), and for up to 60 days following the last study treatment. AEs will be graded and reported using the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03. The relationship of each event to the investigational product will be assessed by the Treating Physician.

  From first dose and up to 60 days following the last treatment, up to approximately 13 months.

• Determine the maximum tolerated dose of intravenous administration of lipoplex

  By observing the Dose Limiting Toxicities, including ≥ Grade 3 toxicity encountered within the four weeks following the first administration of the investigational product the MTD will be determined.

  From first subject, first dose and after an additional 6 subjects have been treated at the MTD, up to 4 weeks.

Secondary Outcomes (3)

• To assess disease response for different cohorts following pbi-shRNA™ EWS/FLI1 Type 1 lipoplex administration at different dose(s).

  From Baseline and quarterly thereafter until progressive disease is noted, up to approximately 12 months.

• To assess the pharmacokinetics of pbi-shRNA™ EWS/FLI1 Type 1 plasmid.

  From Cycle 1 Week 1 Day 1 and until Cycle 2 Week 1 Day 1, approximately 8 weeks.

• To assess ctDNA (EWSR-FLI1) levels and compare to tumor burden and disease response prior to and following pbi-shRNA™ EWS/FLI1 Type 1 lipoplex administration.

  From Cycle 1 Week 1 Day 1 and until the last even cycle where product was administered, up to approximately 1 year.

Study Arms (8)

Cohort -1

EXPERIMENTAL

0.02mg/kg pbi-shRNA™ EWS/FL/I1 Type 1 Lipoplex

Biological: pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex

Cohort 0

EXPERIMENTAL

0.03mg/kg pbi-shRNA™ EWS/FL/I1 Type 1 Lipoplex

Biological: pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex

Cohort 1

EXPERIMENTAL

0.04mg/kg pbi-shRNA™ EWS/FL/I1 Type 1 Lipoplex

Biological: pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex

Cohort 2

EXPERIMENTAL

0.06mg/kg pbi-shRNA™ EWS/FL/I1 Type 1 Lipoplex

Biological: pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex

Cohort 3

EXPERIMENTAL

0.08mg/kg pbi-shRNA™ EWS/FL/I1 Type 1 Lipoplex

Biological: pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex

Cohort 4

EXPERIMENTAL

0.10mg/kg pbi-shRNA™ EWS/FL/I1 Type 1 Lipoplex

Biological: pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex

Cohort 5

EXPERIMENTAL

0.125mg/kg pbi-shRNA™ EWS/FL/I1 Type 1 Lipoplex

Biological: pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex

Cohort 6

EXPERIMENTAL

0.156mg/kg pbi-shRNA™ EWS/FL/I1 Type 1 Lipoplex

Biological: pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex

Interventions

pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex BIOLOGICAL

Lipoplex is given intravenously as a single administration twice a week for 4 weeks for a total of 8 infusions per cycle followed by 2 weeks of rest. Treatment may continue as long as there is clinical benefit, no evidence of disease progression, and no other withdrawal criteria are met. First dose started on Cycle 1 Week 1 Day 1 followed by observation and safety assessment for 13 days. If no toxicity was observed, then another single administration of study agent was given at Cycle 1 Week 3 Day 1 followed by observation and safety for 6 days. If no toxicity was observed, then study agent was given twice a week on Days 1 and 4 over 3 weeks, for a total of 8 infusions per cycle, followed by a 2-week washout before starting each subsequent cycle. Cycle 1 = 8 weeks. Each subsequent cycles = 6 weeks.

Also known as: Lipoplex

Cohort -1; Cohort 0; Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5; Cohort 6

Eligibility Criteria

• Age: 8 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 ≥8 years.
• Evidence of EWS translocation fusion by FISH or RT-PCR or NGS.
• Evidence of Type 1 fusion by molecular diagnostics.
• Refractory or intolerant to standard of care. Subjects must have failed surgery (if resectable), radiation (if no function-preserving surgical approach at primary site, unresectable primary following induction chemotherapy, residual microscopic or gross disease after surgery or inadequate margins), and the following chemotherapy agents: doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide.
• ECOG performance status (PS) = 0-2, or Karnofsky PS ≥60% or Lansky PS ≥60%.
• Normal organ and marrow function as defined below:
• Absolute granulocyte count ≥1,000/mm3 Absolute lymphocyte count ≥400/mm3 Platelets ≥100,000/mm3 Total bilirubin ≤ institutional upper limit of normal AST(SGOT)/ALT(SGPT) ≤2x institutional upper limit of normal Creatinine \<1.5 mg/dL
• Normal pulmonary function as defined as FEV1/FVC greater than 70% in adults or greater than 80% in individuals between 8 and 18 years of age.
• Subject has recovered to CTCAE Grade 1 or better from all adverse events associated with prior therapy or surgery. Pre-existing motor or sensory neurologic pathology or symptoms must be recovered to CTCAE Grade 2 or better.
• If female of childbearing potential, has a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a negative serum test will be required for study entry.
• Ability to understand and the willingness to sign a written informed protocol specific consent. Pediatric patients must sign an assent with a parent or legal guardian sign a written informed consent, per institutional guidelines.
• Subjects will NOT be eligible for study registration and enrollment if meeting any of the following criteria:

You may not qualify if:

• Anti-cancer chemotherapy, biologic therapy or immunotherapy within 3 weeks or radiation therapy within 2 weeks of first infusion.
• 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.
• Patients with PET avid disease only will be excluded.
• Brain metastases unless treated with curative intent (gamma knife or surgical resection) and without evidence of progression for ≥ 2 months.
• History of or current evidence of thrombosis.
• 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 subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the Investigator.
• Known HIV or chronic Hepatitis B or C infection.
• Have signs and symptoms consistent with an active infection.
• Live vaccination for the prevention of infectious disease administered \<30 days prior to the start of study therapy or inactivated vaccination \<14 days prior to the start of study therapy.

Sponsors & Collaborators

• Gradalis, Inc.: lead

Study Sites (2)

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Mary Crowley Cancer Research Centers

Dallas, Texas, 75230, United States

Location

Related Publications (4)

• Barve M, Wang Z, Kumar P, Jay CM, Luo X, Bedell C, Mennel RG, Wallraven G, Brunicardi FC, Senzer N, Nemunaitis J, Rao DD. Phase 1 Trial of Bi-shRNA STMN1 BIV in Refractory Cancer. Mol Ther. 2015 Jun;23(6):1123-1130. doi: 10.1038/mt.2015.14. Epub 2015 Jan 26.

  PMID: 25619726 BACKGROUND

• Wang Z, Rao DD, Senzer N, Nemunaitis J. RNA interference and cancer therapy. Pharm Res. 2011 Dec;28(12):2983-95. doi: 10.1007/s11095-011-0604-5. Epub 2011 Oct 19.

  PMID: 22009588 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

• Rao DD, Jay C, Wang Z, Luo X, Kumar P, Eysenbach H, Ghisoli M, Senzer N, Nemunaitis J. Preclinical Justification of pbi-shRNA EWS/FLI1 Lipoplex (LPX) Treatment for Ewing's Sarcoma. Mol Ther. 2016 Aug;24(8):1412-22. doi: 10.1038/mt.2016.93. Epub 2016 May 11.

  PMID: 27166877 BACKGROUND

MeSH Terms

Conditions

Sarcoma, Ewing; Neuroectodermal Tumors, Primitive, Peripheral; Rare Diseases; Sarcoma; Bone Neoplasms; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive

Condition Hierarchy (Ancestors)

Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Neuroepithelial; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms by Site; Bone Diseases; Musculoskeletal Diseases

Study Officials

• John Nemunaitis, MD

  Gradalis, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 4, 2016
• First Posted: April 13, 2016
• Study Start: October 1, 2016
• Primary Completion: August 12, 2019
• Study Completion: August 4, 2020
• Last Updated: November 13, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)