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D. Subramaniam
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.01 - Oncolytic Reovirus in Combination with Paclitaxel/Carboplatin in NSCLC Patients with Ras Activated Malignancies, Long Term Results (ID 500)
18:30 - 20:00 | Author(s): D. Subramaniam
- Abstract
- Presentation
Background:
Reovirus is a naturally occurring virus which preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. Cells that express high levels of EGFR are also susceptible to reovirus infection. In preclinical studies, reovirus induces host immunity and cell cycle arrest, acting synergistically with standard cytotoxic agents. Its adverse effects are mild to moderate flu-like symptoms. We have hypothesized those patients with EGFR-mutated, EGFR-amplified, or Kras-mutated NSCLC through a common downstream activated Ras pathway should be susceptible to treatment with reovirus
Methods:
We designed a Fleming, single-arm, phase II study to evaluate the objective response rate (CR + PR RECIST, or >40% PET SUV decrease) of reovirus in combination with paclitaxel-carboplatin as first-line therapy in patients with metastatic NSCLC. Secondary endpoints included progression free and overall survival. Eligible patients had ECOG PS 0-2, adequate organ function, no prior systemic chemotherapy for metastatic disease, and tumors with the specified genotype, as per CLIA certified testing. Adjuvant chemotherapy, or erlotinib/gefitinib for pts with EGFR mutant tumors was permitted.
Results:
Thirty-seven patients were enrolled. Molecular tumor demographics included 20 pts with Kras mutations; 10 with EGFR amplification alone; 3 patients with EGFR mutations and four patients with BRAF V600E mutations. Overall, 258 cycles (median 4, range 1-47) were administered. Initial doses used were C AUC 6 on day 1, and P 200 mg/m[2],on day 1 of each 21-day cycle. Due to unacceptable toxicities (grade 3 diarrhea and febrile neutropenia [1 each]) in the first two patients, doses were reduced to P 175 mg/m-m[2] and C AUC 5.. Common toxicities considered at least possibly related to the therapy included fatigue (30 pts); diarrhea (21 pts); nausea (19 pts); arthralgia-myalgia (15 pts); and anorexia (9 pts). Grade 3-4 adverse events included neutropenia (7 Gr3, 1 Gr4), anemia (2 Gr3), fatigue (9 Gr3), diarrhea (3 Gr3), nausea/vomiting (3 Gr3) and a single case of sepsis. Response evaluation showed 11 PR (5 Kras mutant), 20 SD, 4 PD and 2 NE patients by RECIST (ORR: 31%, 90% one-sided lower CI: 21%). Four of the SD patients had >40% PET SUV reductions after two cycles. Three patients opted to switch to pemetrexed maintenance after 4 cycles without disease progression or moderate/severe toxicity. Median PFS, OS and 12 month overall survival rates were: 4 months (95% CI: 2.9-6.1), 13.1 months (95% CI: 9.2-21.6) and 57% (95% CI: 39-72%), respectively. Seven patients are alive after a median follow up of 34.2 months (range: 26.9-71.5), including two patients with no evidence of disease progression to date (50 and 37 months).
Conclusion:
Oncolytic reovirus administration in combination with paclitaxel and carboplatin was well tolerated. The RECIST response rate (11/35 [31%]; 28% of Kras mutants)(15/35; 43% if PET is considered) is not conclusive, nor excludes additional benefit of the reovirus to chemotherapy. However, the number of patients surviving longer than 2 years (11; 30%) is substantial, suggesting either effect of second/third line post paclitaxel/carboplatin/reolysin treatment or perhaps the triggering of an immune response following tumor reovirus infiltration. The latter concept merits further investigation.
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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 - 17:00 | Author(s): D. Subramaniam
- 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
