Phase I/II Study of SBRT and GC4711 for Centrally Located or Large NSCLC

GRECO-1: Phase I/II, Randomized, Placebo-Controlled Study of Stereotactic Body Radiation Therapy (SBRT) and GC4711 for Centrally Located or Large, Node-Negative Non-Small Cell Lung Cancer (NSCLC)

GTI-4711-101 is a Phase I/II study of the safety of GC4711, its effect on in-field tumor response and its potential to reduce radiation-related pulmonary injury due to SBRT for lymph node negative (T1 to T3N0M0) peripheral or central localized (within 2cm of the proximal bronchial tree) NSCLC.

After an open-label, Phase 1, safety cohort of 5 subjects has been completed, a randomized, placebo-controlled Phase 2 portion of 66 subjects will be conducted.

Subjects must be referred for SBRT with large peripheral lesions (>1cm-7cm) and/or central localized, node negative, non-metastatic NSCLC, and have an ECOG PS score of 0-3. Feasibility of SBRT is judged by the treating physician.

SBRT is planned for the tumor location as a dose of or 3 fractions of 18-20 Gy (Phase 2 only) or 5 fractions of 10-12 Gy. SBRT fractions will be given within 180 minutes from the end of the GC4711 or placebo infusion.

After completion of Phase I, a Phase II, randomized, placebo-controlled study will be initiated, wherein approximately 66 subjects referred for SBRT with early stage large and/or central localized NSCLC will be randomized in a 1:1 ratio to receive either GC4711 or placebo given intravenously (IV) over 15 minutes before each fraction of SBRT, beginning the day of the first fraction of SBRT and ending the last day of SBRT.

Subjects will be monitored for treatment emergent adverse events for 30 days post SBRT completion. Additionally, subjects will be monitored 90 days post-SBRT for all adverse events to evaluate acute toxicities, and monitored for 1-year post-SBRT completion for specific late toxicities.

In-field tumor response and overall survival will be evaluated through 24 months post SBRT completion.

Inclusion Criteria:

1. Male or female subjects at least 18 years of age.

2. Ability to understand and the willingness to sign a written informed consent.

3. Histological or biopsy proven NSCLC.

4. ECOG performance status of 0-3.

5. Node negative (T1 to T3N0M0), centrally located (within 2cm in all directions around the proximal bronchial tree, including ultra-central tumors, abutting the bronchial tree or trachea) or large (>1-7cm) Non-Small Cell Lung Cancer (NSCLC), judged acceptable for SBRT by the treating Investigator

6. Adequate end-organ function, based on routine clinical and laboratory workup:

   1. ANC >1,000 cells/µl, Platelets ≥ 75,000 cells/µl, Hemoglobin ≥ 7.0 g/dl
   2. Serum creatinine ≤ 2 x ULN or calculated creatinine clearance ≥ 30 ml/min
   3. Total bilirubin ≤ 1.5 x ULN (or direct bilirubin below the ULN), AST and ALT ≤ 2.5 x ULN

7. Males and females of must agree to use effective contraception starting prior to the first day of treatment and continuing after the last dose of GC4711/Placebo for 30 days (females) and 90 days (males).

Exclusion Criteria:

1. Subjects with confirmed nodal and/or distant disease(including brain), according standard workup by local investigator
2. Subjects with peripheral lesions 1cm or smaller
3. Prior treatment with immunotherapy within 3 months prior to Day 1 dosing.
4. Prior intra-thoracic radiotherapy or surgery with substantial overlap to planned radiation fields as determined by the treating radiation oncologist.
5. Subjects not recovered/controlled from prior treatment-related (chemotherapy or targeted therapy) toxicities judged by treating physician.
6. Uncontrolled malignancy other than lung cancer that requires active treatment or is deemed by the treating physicians to be likely to affect the subject's survival duration.
7. History of allergic reactions attributed to compounds of similar chemical or biologic composition to GC4711.
8. 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, in the opinion of the investigator, would limit compliance with study requirements.
9. Participation in other clinical trials actively testing new anti-cancer treatments, unless previously written approval is provided by the Sponsor.
10. Requirement for concurrent treatment with nitrates or other drugs that may, in the judgment of the treating investigator, create a risk for a precipitous decrease in blood pressure.
11. Female subjects who are pregnant or breastfeeding.
12. Any other conditions that, in the Investigator's opinion, might indicate the subject to be unsuitable for the study.