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

Status:	Recruiting
Conditions:	Cancer
Therapuetic Areas:	Oncology
Healthy:	No
Age Range:	8 - Any
Updated:	3/22/2019
Start Date:	October 2016
End Date:	February 2020
Contact:	Gladice Wallraven
Email:	gwallraven@gradalisinc.com
Phone:	214-442-8124

Phase I Trial of Pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex (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-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.

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 twice a week for 4 weeks (e.g. Mon and Thurs,
preferred) for a total of 8 infusions of the product per cycle followed by a 2 week washout
period. Patients will be accrued in 3-patient dose escalation cohorts using the following
escalation schema (50% to 33% to 25% to 25% to 25%) at a starting IV dose of 0.04 mg/kg.

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.

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. 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.

9. 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.

10. 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. Brain metastases unless treated with curative intent (gamma knife or surgical
resection) and without evidence of progression for ≥ 2 months.

4. 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.

5. Known HIV or chronic Hepatitis B or C infection.

We found this trial at

sites

Memorial Sloan Kettering Cancer Center

1275 York Ave
New York, New York 10021

(212) 639-2000