Phase I Intratumoral Pbi-shRNA STMN1 LP in Advanced and/or Metastatic Cancer
| Status: | Completed |
|---|---|
| Conditions: | Cancer, Cancer, Cancer, Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 2/24/2018 |
| Start Date: | February 2012 |
| End Date: | April 13, 2017 |
Phase I Trial of Intratumoral Bi-functional shRNA Stathmin 1-knockdown Lipoplex in Patients With Advanced and/or Metastatic Cancer
This is a Phase I safety trial of bifunctional shRNA-STMN1 (pbi-shRNA™STMN1) BIV (bilamellar
invaginated vesicle) lipoplex (LP), pbi-shRNA™ STMN1 LP administered by a single intratumoral
(IT) injection. Patients with superficially accessible advanced cancer following prior
therapies will be entered into the study following a modified dose escalation design based on
the demonstrated safety of our previous clinical experience (BB-IND 13744) with the same
liposome and vector DNA backbone expressing a different transgene (of which doses up to 7 mg
DNA IV/single dose have been administered). Patients will accrue in 4-patient escalation
cohorts using a modified Fibronacci escalation schema (100%-50%-33%-33%) at a starting
intratumoral dose of 0.010 mg/kg of DNA through a dose of 0.053 mg/kg DNA intratumoral /
single dose. Should a single, but not more than two (2), ≥ Grade 3 Dose Limiting Toxicity
(DLT) occur in any cohort, following mandated review (see below) an additional two (2)
patients will be accrued at that dose (total of six). If more than one ≥ Grade 3 toxicity
occurs in any cohort, the preceding dose cohort will be expanded to six (from four) and if <
2/6 patients experience ≥ Grade 3 toxicity, that dose will be the Phase II recommended dose.
Should no ≥ Grade 3 toxicity occur in any cohort (other than Grade 3 local injection site
reaction), an additional two (2) patients will be treated at 0.053 mg/kg DNA intratumoral /
single dose.
invaginated vesicle) lipoplex (LP), pbi-shRNA™ STMN1 LP administered by a single intratumoral
(IT) injection. Patients with superficially accessible advanced cancer following prior
therapies will be entered into the study following a modified dose escalation design based on
the demonstrated safety of our previous clinical experience (BB-IND 13744) with the same
liposome and vector DNA backbone expressing a different transgene (of which doses up to 7 mg
DNA IV/single dose have been administered). Patients will accrue in 4-patient escalation
cohorts using a modified Fibronacci escalation schema (100%-50%-33%-33%) at a starting
intratumoral dose of 0.010 mg/kg of DNA through a dose of 0.053 mg/kg DNA intratumoral /
single dose. Should a single, but not more than two (2), ≥ Grade 3 Dose Limiting Toxicity
(DLT) occur in any cohort, following mandated review (see below) an additional two (2)
patients will be accrued at that dose (total of six). If more than one ≥ Grade 3 toxicity
occurs in any cohort, the preceding dose cohort will be expanded to six (from four) and if <
2/6 patients experience ≥ Grade 3 toxicity, that dose will be the Phase II recommended dose.
Should no ≥ Grade 3 toxicity occur in any cohort (other than Grade 3 local injection site
reaction), an additional two (2) patients will be treated at 0.053 mg/kg DNA intratumoral /
single dose.
Inclusion Criteria:
1. Histologically confirmed advanced and/or metastatic cancer, and, if limited to a
single lesion, not considered a candidate for curative surgery or radiation therapy).
2. Biopsy accessible lesion.
3. Per cohort dose/volume, the volume of the lesion to be injected must be 3x volume of
the injectate.
4. Subjects that have completed all acceptable therapies with curative potential that are
the current standard of care for their respective diseases.
5. Recovered from all toxicities (≤ Grade 1) related to prior therapies except for
alopecia.
6. 1 measurable or evaluable lesion; ≥ 1.8 cm diameter for cohort 1 (see Table 10);
injection and biopsy accessible.
7. Age ≥18 years.
8. ECOG performance status (PS) 0-2.
9. Organ and marrow function as defined below:
Absolute granulocyte count ≥ 1,500/mm^3 Platelets ≥ 100,000/mm^3 Total bilirubin ≤
1.5x institutional ULN Creatinine ≤ 2.0 mg/dL
10. Ability to understand and the willingness to sign a written informed consent document
including permission for pre- and Days 1 and 2 post- injection biopsy and Day 8
injected lesion excision.
11. Negative pregnancy test.
Exclusion Criteria:
1. Surgery involving general anesthesia, chemotherapy, radiotherapy, or immunotherapy
within 3 weeks prior to entering the study.
2. Patient must not have received any other investigational agents within 4 weeks prior
to study entry.
3. Patients with known brain metastases unless treated with whole brain radiation and
stable for >/= 2 months or treated with stereotactic radiotherapy only and stable for
>/=1 month.
4. Short term (<30 days) concurrent systemic steroids ≤0.125 mg/kg prednisone per day
(maximum 7.5 mg/day) and bronchodilators (inhaled steroids) are permitted; other
steroid regimens and/or immunosuppressives are excluded.
5. Prior malignancy (excluding nonmelanoma carcinomas of the skin) unless in remission
for >/= 2 years.
6. Kaposi's Sarcoma.
7. Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.
8. Patients who are pregnant or nursing.
9. Patients with known HIV.
10. Patients with chronic Hepatitis B and C infection.
11. Patients with uncontrolled diseases.
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