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J.A. Bacha
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-084 - Post-Market Clinical Trial of Dianhydrogalactitol in the Treatment of Relapsed or Refractory Non-Small Cell Lung Cancer (ID 998)
09:30 - 09:30 | Author(s): J.A. Bacha
- Abstract
Background:
The median overall survival time for patients with stage IV non-small cell lung cancer (NSCLC) is 4 months, and 1- and 5-year survival is less than 16% and 2%, respectively. NSCLC is usually treated with surgery followed by radiation and treatment with platinum-based regimens or in some cases Tyrosine Kinase Inhibitors (TKIs). Unfortunately, long-term prognosis with platinum-based therapies is poor, and TKI resistance has emerged as a significant unmet medical need. Dianhydrogalactitol (VAL-083) is a structurally unique bi-functional alkylating agent mediating interstrand DNA crosslinks at N[7] of guanine. It has previously demonstrated activity against NSCLC in NCI-sponsored preclinical and clinical trials and is approved for treatment of lung cancer in China (Approval No. Guoyao Zhunzi H45021133); however, it is currently not widely known or used for the treatment of NSCLC.
Methods:
not applicable
Results:
Recent preclinical data suggest that VAL-083 may be a therapeutic option for drug-resistant NSCLC. VAL-083 has superior activity to cisplatin in both in vitro and in vivo models of NSCLC, including TKI-resistant NSCLC. When combined with either cisplatin or oxaliplatin in vitro, VAL-083 demonstrates significant superadditivity (p<0.05) and synergism (CI < 1) for both combinations in NSCLC cell lines A549, H1975 and H460. When tested in a standard syngeneic mouse fibrosarcoma model (RIF-1 cell-line in C3H mice), VAL-083 (10 mg/kg) was superior to cisplatin (4 mg/kg) in tumor growth delay. Mice were treated with a single IP injection of either cisplatin, VAL-083 or VAL-083 followed immediately by cisplatin. Combination treatment of with cisplatin produced a more than additive effect by delaying growth 8.65 days. In another in vivo model using NSCLC cell-line A549 in Rag2mice, VAL-083 was given as part of a combination treatment with cisplatin. Tumour growth delays of 11, 18 and 25 days were observed for 2 mg/kg cisplatin in combination with 2, 2.5 or 3 mg/kg VAL-083, respectively, while no significant tumour growth delay was observed between untreated and Cisplatin (2 mg/kg). The median survival time was increased by 2 days for cisplatin alone, while the combination of VAL-083 (2 mg/kg, 2.5 mg/kg and 3 mg/kg) with cisplatin (2 mg/kg) increased survival by 17 days, 17 days, and 14 days, respectively.
Conclusion:
The preclinical data strongly suggest VAL-083 as a potential treatment for drug-resistant NSCLC. A planned open-label phase IV (post market) clinical trial will investigate the activity of VAL-083 in relapsed or refractory NSCLC assessed by objective response rates, complete and partial response rates and stable disease. VAL-083 will be dosed in accordance with the approved label (40 mg/day) and the results will provide guidance to treating physicians under the context of VAL-083’s current approval in China, as well as serve as proof of concept for expanded development in the rest of the world.
