Pbi-shRNA™ EWS / FLI1 Type 1 LPX in Subjects With Advanced Ewing's Sarcoma
Ewing's sarcoma characterized by the t(11; 22) (q24; q12) translocation at several but prioritized breakpoint sites, resulting in the EWS / FLI1 fusion gene is the second most frequently diagnosed primary malignant bone tumor in the US with an annual incidence, from birth to age 20, of 2.9 cases per million population. The survival rate for patients with high-risk recurrent disease (relapse < 2 years) is < 10% at 5 years. Moreover, of patients who progress after second line treatment, eighty percent do not achieve a second complete response and of these patients < 10% survive one year. Refractory patients to both frontline and second line therapy have even worse prognosis. The EWS / FLI1 gene is well known as the driver gene of Ewing's sarcoma. We designed a novel pbi-shRNA™ EWS / FLI1 Type 1 LPX which has demonstrated sufficient specificity, safety and efficacy in animal testing to justify Phase I testing. Clinical safety (no ≥ grade 3 product related toxic effect) and target specific activity has been observed with other bi-shRNA products involving 147 cancer patients (698 separate dose administrations) (BB-Investigational New Drug (IND) 14205; BB-IND 14938). Moreover, safety has been observed with IV delivery of pbi-shRNA™ EWS / FLI1 Type 1 LPX in murine and swine testing via multidose IV administration.
- 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.
- 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.
Locations & Contacts
Contact: Morgan J Coleman
Trial Objectives and Outline
Study testing of pbi-shRNA™ EWS/FLI1 Type 1 LPX will involve patients (≥age 8) with advanced Ewing's sarcoma. The first 3 subjects enrolled onto the study as well as the first subject enrolled into each dose cohort must be 16 years of age or older. pbi-shRNA™ EWS/FLI1 Type 1 LPX will be given via intravenous infusion. Patients will be accrued in 3- patient dose escalation cohorts using the following escalation schema (50%→33%→25%→25%→25%) at a starting IV dose of 0.04 mg/kg. If 1 of 3 subjects within a dose cohort experiences a Dose Limiting Toxicity (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 maximum tolerated dose (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. Serum for pharmacokinetics (PK) analysis will be collected on Cycle 1, Week 1, Day 1 (C1W1D1), Cycle 1, Week 6, Day 4; and Cycle 2, Week 1, Day 1 at following time points (±10%):30 minutes prior to administration and at the following time points after initiation of study agent administration: 5 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours. Serum for cytokine analysis will be collected on Cycle 1, Week 1, Day 1 at following time points (±10%): 2 hours, 6 hours, and 24 hours. Serum for cytokine analysis will also be collected on Cycle 2, Week 1, Day 1 and Cycle 3, Week 1, Day 1, at following time points (±10%): 30 minutes prior to administration and at 6 hours after initiation of study agent administration. Blood for analysis of RNA mechanism will be collected prior to administration of the study agent and 48 hours after study agent administration (with a 10% window). Blood for RNA will be collected at the first and last dose of each cycle (e.g. C1W1D1, C1W6D4). Blood for circulating tumor DNA (ctDNA) analysis will be collected at Cycle 1 Week 1 Day 1, Cycle 1 Week 3 Day 1, Cycle 2 Week 1 Day 1 prior to product infusion and every even cycle thereafter at Week 1 Day 1 prior to product infusion. If available, a biopsy or pleural fluid will be collected 1 to 3 weeks prior to Cycle 1 Week 1 Day 1 and 72 hours after the last dose of Cycle 1.
Trial Phase & Type
Secondary IDs NCI-2019-02149
Clinicaltrials.gov ID NCT02736565