Abstract CT314: “Multi-metronomic” algorithms for targeted therapy to improve value of response and “failed drugs” for “resistant” women's cancers
Authors: Bruckner Howard W. , Hirschfeld Azriel , Stega Jeanetta , Dottino Peter 
Published: May 2015

Abstract
The use of Bevacizumab (Bev) for ovarian cancer (OC) has been impeded by adverse events (AEs), long maintenance therapy (T) and tumor rebound. Eligibility, requirements and limits, as well as ideal time(s) and length of use remain unknowns. Drug interactions and algorithms offer testable solutions. Multi-metronomic Ts provide Bev with 5-6 synergistic integrated partners. Bruckner HW ASCO 06 gastric ca, ASCO 01,04,08,12 pancreatic ca; Hirschfeld A ASCO 12 cholangioca and Loupakis F ASCO GI 2013 colon ca
Methods: For resistant OC Bev 10mg/kg day 1, Cyclophosphamide 250 150mg/m2 day 1 day 2 were combined with GFLIC - (D); Gemzar ° 500mg/m2, Fluorouracil ° 1500mg/m2, Irinotecan ° 80mg/m2, day1 , (Docetaxel (D) 25mg/m2) and Carboplatin ° AUC 2, day 2. (° reduced 20% on addition of D and then increased). D was added at complete response, plateau or any Bev stop. When Bev was resumed the use of D continued. GFLIC, core drugs were never stopped. Bev was briefly held for Gr 1-2 GI and other Gr 2-3 AEs. Exclusions: Helsinki criteria PS4 urgent surgery or 4 weeks survival. Sequential T at best response (CR or plateau) was evaluated for rapid response, and potential value for research, low tumor volume, Ts.
Results: 30 OC patients pts had no severe clinical AEs, Bev could be resumed, stop-go (all but once) after Gr 2-3 AEs. None had rebound. RECIST response rates were &gt; 80% and 12% SD after 3-8, median 5, lines had failed, 5 had failed Bev. Primary PACLITAXEL and carboplatin resistant ROC, had 5 of 5 CRs p 0.03-0.008 after either early- plateau or 2nd line retreatment recurrence, Multi line ROC &gt; 4cm, size reduction was 60% to less than 2cm, 40% to less than 0.5cm; &lt;4cm ROCs were “all” downsized, p 0.03. Post neuropathy resumption of D was safe and improved responses for half the pts. PFS for PS 0-2 multi-line ROC was not reached at 1 year; for performance status 3 pts it was 6 mos.
Conclusions: The sequential multi drug cores give cytotoxic and targeted drugs second chances to help achieve symptom free small tumor status and, in high risk subsets, improve survival: 1, a second time after AEs ; 2, 6-24 mos after Bev failed; 3, as a possible multimetronomic T ; with unconventional low doses for Gemzar, Irinotecan, Docetaxel and Carboplatin; 4, replace maintenance, T to progression with either 4a, neoadjuvant or 4b, stop-go Ts. T creates 5, many ideal pts for research; 6, testable algorithms to reduce Bev's duration of use, 7, cost and 8, AEs by 50-75% and 9, selectively expand eligibility to PS3 pts. It is safer to use 5-6 drug cores than to use many 1-2 drug Ts. Cores are suitable for integration algorithms and drug development. Rapid sequential T to low volume OC, creates ideal pts for crossover immunoT and other targeted Ts for stable disease. These add value to response and biochemical modulation and second chances for both used drugs and “unnecessary” failures due to one Phase III, all or none, single drug survival tests of $50 million investments.
Citation Format: Howard W. Bruckner, Azriel Hirschfeld, Jeanetta Stega, Peter Dottino. “Multi-metronomic” algorithms for targeted therapy to improve value of response and “failed drugs” for “resistant” women's cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT314. doi:10.1158/1538-7445.AM2014-CT314