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J. Kramer
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P3.07 - Poster Session/ Small Cell Lung Cancer (ID 223)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.07-003 - A Phase Ib/II Trial of Doxorubicin with Ganetespib, a Novel Hsp90 Inhibitor, in Advanced Solid Tumors, with Dose Expansion in Small Cell Lung Cancer (ID 3105)
09:30 - 09:30 | Author(s): J. Kramer
- Abstract
Background:
Relapsed/refractory small cell lung cancer (RR-SCLC) has a poor prognosis with median overall survival of only 2-3 months. Objective responses to single agent newer chemotherapy agents range from 14-29%. One of the key mechanisms for the development of acquired resistance of cancer cells to chemotherapy is the induction of a heat shock response. Over-expression of Hsp90 and its co-chaperones in tumor cells results in up-regulation of ATP-dependent transporters such as ABCG2 and RLIP76. Such transporters act as drug-efflux pumps for chemotherapeutic agents including doxorubicin, thus mediating drug resistance. Ganetespib, a next generation Hsp90 inhibitor devoid of liver and ocular toxicities that limit other agents in its class, is now in phase 3 evaluation in NSCLC. Targeting Hsp90, ganetespib affects multiple drug resistance pathways. We recently demonstrated in vitro and in vivo that the addition of ganetespib (G) to doxorubicin (D) can indeed overcome drug resistance (Lai et al., Oncogene 2014). The primary objective of this clinical study is to determine the maximum tolerated dose and the recommended Phase II dose (RP2D) of G + D in subjects with advanced solid tumors. The secondary objectives are to determine the dose limiting toxicities (DLTs) and to assess if there is preliminary evidence of activity for the combination of G + D in RR- SCLC by determining the objective response rate and response duration. We will also aim to establish conditionally reprogrammed cancer cell lines from tumor tissue in subjects with RR-SCLC to allow ex-vivo molecular characterization and drug sensitivity testing.
Methods:
The dose escalation phase will follow a standard 3+3 dose escalation scheme with 2 dose levels of G administered weekly on Days 1, 8 of a 21-day cycle, in combination with fixed dose D at 50 mg/m[2] on Day 1. After 4-6 cycles of the combination, continuation of single agent G is permitted in patients deriving clinical benefit. The RP2D determined at the end of the dose escalation phase will be used to conduct a dose expansion study in subjects with RR-SCLC. Key inclusion criteria are refractory solid tumors (in dose escalation phase) and RR-SCLC (in dose expansion phase), age >18 years, ECOG PS 0-1, adequate organ/marrow function. Key exclusion criteria include LVEF < 50%, lifetime cumulative doxorubicin dose >150 mg/m[2], untreated, symptomatic brain metastases, serious cardiac illness, QTc >470 msec, strong inhibitors or inducers of CYP 3A4 or 2C19. DLTs are defined as grade 4 hematologic toxicities or > grade 3 non-hematologic toxicities including hypersensitivity reactions despite pre-medication and nausea, vomiting and diarrhea despite maximal medical therapy. Response assessment will be done using RECIST 1.1.
Results:
Clinical Trial Status: A total of 6 subjects have been enrolled thus far. With no DLTs observed in 5 subjects who have crossed the DLT evaluation period, the trial continues enrollment.
Conclusion:
Not applicable
