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

Phase I Trial of Pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex (LPX) in Subjects With Advanced Ewing's Sarcoma

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.

Eligible participants with advanced Ewing's sarcoma will be accrued in 3-subject dose escalation cohorts using the following escalation schema (50%→33%→25%→25%→25%) at a starting IV dose of 0.04 mg/kg and up to a dose of 0.156mg/kg.

For this first in class study of pbi-shRNA™ EWS/FLI1 Type 1 lipoplex, Dose Limiting Toxicity (DLT) will be defined as any ≥ Grade 3 toxicity reported within the four weeks following the first administration of the investigational product, regardless of attribution. Any other ≥ Grade 3 toxicity encountered after the first four weeks post Dose 1 on Cycle 1 will be reported according to the CTCAE Version 4.0 but not defined as DLTs.

If 1 of 3 subjects within a dose cohort experiences a DLT, that dose cohort will be expanded to six subjects provided no further subjects experience a DLT. If no further subjects experience a DLT, dose-escalation may continue. If ≥2 subjects within a dose cohort experiences a DLT, this will define the DLT dose level and the Maximum Tolerated Dose (MTD) will have been exceeded.

The preceding dose level will be expanded to a total of 6 subjects and, if ≤1 subject experiences a DLT, that dose level will be considered the MTD. If no further subjects experience a DLT, dose-escalation may resume per escalation schema. Once the presumptive MTD is reached, an additional 6 subjects will be treated at that dose, designated the expanded MTD dose cohort.

Participants who experience an unrelated Grade ≥3 toxicity that normalizes within 1 week may continue study treatment when the adverse event returns to Grade 1 or better at 50% of their assigned cohort dose. Delay in dosing of >24 hours will require that the next dose is skipped.

As of protocol Amendment No. 5, two subjects met the definition of dose limiting toxicity at Cohort 1, 0.04mg/kg, therefore the dose reduced by 50% and subsequent lipoplex administrations were given at 0.02mg/kg. Administration of 0.02mg/kg is defined as Cohort -1. An additional 6 subjects will be treated at Cohort -1, designated the expanded MTD dose cohort. If no further subjects experience a DLT at Cohort -1, dose re-escalation may continue to Cohort 0. The dose administered for subjects in Cohort 0 is 0.03mg/kg and would be defined as the optimal dose.

All study agent administrations will cease for the occurrence of any of the following events at any time point over the four weeks following the first study agent dose administration to a participant: death, hospitalization for reasons other than those related to the participant's malignancy (excluding preplanned hospitalization and/or hospitalization for observation during the participant's first infusion), or any Grade ≥3 liver toxicity or Grade ≥4 pulmonary toxicity. All Grade ≥3 liver toxicities or Grade ≥4 pulmonary toxicities will be considered Adverse Events of Special Interest (AESI).

Participants will receive an intravenous infusion twice a week for 4 weeks for a total of 8 infusions per cycle followed by 2 weeks of rest. Treatment with investigational product may continue as long as there is clinical benefit, no evidence of disease progression, and no other withdrawal criteria are met.

Safety assessments will include physical examinations, performance status, laboratory assessments, and vital signs. Toxicity (Adverse Events) will be recorded for the duration of the participant's study treatment (following the first dose), and for up to 60 days following the last study treatment. Toxicities and AEs will be graded and reported using the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.0.

Efficacy assessments (response and progression) will be evaluated by local investigators using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

Subjects will be eligible for registration if they meet all of the following inclusion criteria:

Inclusion Criteria:

1. Histologically confirmed Ewing's Sarcoma Family of Tumors (ESFT).

2. Age ≥8 years.

3. Evidence of EWS translocation fusion by FISH or RT-PCR or NGS.

4. Evidence of Type 1 fusion by molecular diagnostics.

5. 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.

6. ECOG performance status (PS) = 0-2, or Karnofsky PS ≥60% or Lansky PS ≥60%.

7. 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

8. 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.

9. 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.

10. 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.

11. 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:

Exclusion Criteria:

1. Anti-cancer chemotherapy, biologic therapy or immunotherapy within 3 weeks or radiation therapy within 2 weeks of first infusion.
2. 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.
3. Patients with PET avid disease only will be excluded.
4. Brain metastases unless treated with curative intent (gamma knife or surgical resection) and without evidence of progression for ≥ 2 months.
5. History of or current evidence of thrombosis.
6. 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.
7. Known HIV or chronic Hepatitis B or C infection.
8. Have signs and symptoms consistent with an active infection.
9. 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.