A Phase 1b/2a Study Evaluating the Pharmacokinetics, Safety, and Efficacy of Nanogenistein in Combination with Chemoradiotherapy for Non-small Cell Lung Cancer
Simone CB, Movsas B, Gore EM, Mohindra P, Vujaskovic Z, Wang D, Ajlouni M, Menon S, Thompson J, Brown SL, Kurman M, Dykstra JC, Rillo L, Ingram M, Serebrenik A, and Kaytor MD. A Phase 1b/2a Study Evaluating the Pharmacokinetics, Safety, and Efficacy of Nanogenistein in Combination with Chemoradiotherapy for Non-small Cell Lung Cancer. International Journal of Radiation Oncology Biology Physics 2020; 108(3):S103.
International Journal of Radiation Oncology Biology Physics
Purpose/Objective(s): Radiation therapy (RT) remains a critical component of locally advanced (LA) and limited metastatic non-small cell lung cancer (NSCLC) but is associated with significant risks of pneumonitis, esophagitis, and major cardiac events. Nanogenistein (NG) is a radioprotectant that promotes DNA repair, cell cycle arrest and anti-inflammatory signaling to mitigate RT-associated toxicities. The objective of this phase 1b/2a trial is to evaluate the safety, pharmacokinetics (PK), and efficacy of NG in combination with concurrent chemoradiotherapy for NSCLC.
Materials/Methods: Patients with newly diagnosed stage II, III or IV (oligometastatic) NSCLC planned for 60-70/1.8-2.0 Gy RT and concurrent weekly paclitaxel/carboplatin were eligible. Patients were treated daily with a self-administered, oral suspension of NG at one of three dose levels (500, 1000, or 1500 mg) starting prior to and continuing during the entire course of chemoradiotherapy (up to 8 weeks). Three cohorts (n = 7/cohort) were enrolled sequentially. PK analysis was completed for NG, paclitaxel and carboplatin. Tumor response was defined per RECIST 1.1 criteria. CT scans were obtained during chemoradiotherapy, consolidation, and every 2-3 months following RT completion. Adverse events (AEs) were reported using the NCI CTCAEv4 and used to monitor dose-limiting toxicities (DLTs). Quality of life measurements included UCSD-SOBQ, FACT-L TOI and a swallowing diary.
Results: Enrolled patients (n = 21) were a median of 69 years (range 50-84), predominantly Caucasian (n = 19) and female (n = 11), and had stage II (n = 5), III (n = 14) or IV (n = 2) disease. NG was well tolerated and no DLTs were identified. NG PK did not interfere with chemotherapeutic PK. AEs were not dose dependent and those possibly (n = 10), probably (n = 1) or definitely (n = 0) attributable to NG treatment were mild GI events (n = 8, all grade 1), fatigue (n = 1, grade 2), anorexia (n = 1, grade 2), and dysgeusia (n = 1, grade 1). Overall, 1 major cardiac event, 1 grade 3 esophagitis, and 2 cases of grade ≥2 pneumonitis occurred. Patient weight loss was ≤ 5%, pulmonary function (0, 9- and 13-months post-RT), and FACT-L TOI (0, 3, 6- and 13-months post-RT) remained stable across all cohorts (all p>0.05). Tumor response rate was 70%, with a complete response rate of 15%. The median progression-free survival across cohorts was 15.6 months, and the median overall survival was not reached at a median of 15.9 months follow-up.
Conclusion: In this study, NG was found to be safe and well tolerated, with an incidence of Grade ≥2 hematological and normal tissue toxicities both less than that observed in RTOG 0617. These encouraging safety and efficacy data support advancing the drug to an adequately powered, randomized, double-blind, placebo-controlled phase 2b study that is planned in LA-NSCLC patients.