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A preclinical evaluation of niraparib efficacy as monotherapy, maintenance and after olaparib treatment (PARP inhibitor after PARP inhibitor) in patient-derived ovarian xenograft tumor models
S96
Abstracts
713 POSTER Pharmacokinetic (PK) profile of quisinostat in combination with gemcitabine and cisplatin in patients (pts) with non-small cell lung cancer (NSCLC) or paclitaxel and carboplatin in pts with NSCLC or epithelial ovarian cancer M. Fedyanin1 , S. Tjulandin1 , S. Cheporov2 , V. Vladimirov3 , V. Moiseenko4 , S. Orlov5 , G. Manikhas6 , A. Koryakova7 , A. Cakana8 , C. Phelps8 , S. Baranovsky9 , V. Azarova10 , O. Karavaeva10 , N. Vostokova10 . 1 Russian Cancer Research Center. NN Blokhin, clinical pharmacology and chemotherapy, Moscow, Russian Federation; 2 State “Regional Clinical Oncology Hospital” health care institution of Yaroslavl region, chemotherapy, Yaroslavl, Russian Federation; 3 State Budget Institution of public health Pyatigorsk oncology dispensary, chemotherapy, Pyatigorsk, Russian Federation; 4 GBUZ Saint-Petersburg clinical scientific and practical center special kinds of medical care oncology, oncology, Saint-Petersburg, Russian Federation; 5 BioEq- LLC, BioEqLLC, Saint-Petersburg, Russian Federation; 6 Saint-Petersburg State Budget institution Healthcare Municipal Clinical Oncology Dispensary, oncology, Saint-Petersburg, Russian Federation; 7 Chemical Diversity Research Institute- JSC, Chemical Diversity Research Institute- JSC, Khimki, Russian Federation; 8 Janssen Pharmaceutica N.V., Janssen Pharmaceutica N.V., Beerse, Belgium; 9 NewVac- LLC, NewVac- LLC, Khimki, Russian Federation; 10 IPHARMA- LLC, IPHARMA- LLC, Moscow, Russian Federation Background: The purpose of this work was to determine PK parameters of multiple ascending doses of quisinostat, pan-histone deacetylase inhibitor, in combination with gemcitabine + cisplatin and paclitaxel + carboplatin within 24 hours on Day 1 and on Day 7 of the 1st cycle and evaluate potential PK interactions of quisinostat and chemotherapy (CT) drugs in pts with relapsed NSCLC and ovarian cancer within phase I study. Material and Method: quisinostat was administered at escalated doses (8, 10 and 12 mg) orally each 3 week cycle on Days 1, 3, 5, 7, 9, 11 in combination with gemcitabine + cisplatin or paclitaxel + carboplatin CT for pts with NSCLC or ovarian cancer. The infusion of CT drugs was conducted on Day 7 (relative to quisinostat administration). The PK analysis was conducted on the concentration-time data of quisinostat and CT in plasma samples of pts and this data was provided using a validated bioanalytical method Janssen R&D, J&J. PK parameters were estimated using noncompartmental analysis (Phoenix™ WinNonlin® 6.2.1. (Pharsight Corp.). Venous blood samples for the PK study were collected at 15 min before and 5, 15, 30 min, 1, 3, 4, 5, 6, 8, 24 hours after qusinostat administration on the day of administration of the first dose of quisinostat (Day 1 of Cycle 1) and on the day of CT start in combination with quisinostat (Day 7 of Cycle 1). Results: In the 12 mg cohort with paclitaxel + carboplatin (n = 13), statistically significant differences (p < 0.05) were determined for the assessed PK parameters of quisinostat on Day 1 and Day 7: Cmax of quisinostat increased 1.7-fold on average (p < 0.01), t1/2 increased 1.4-fold (p < 0.05), which led to the 2.2-fold increase of systemic exposure (AUC) (p < 0.0001). Apparent oral clearance decreased 2.7-fold. Tmax increased significantly − the median value increased from 0.5 to 3.0 h (p < 0.05). No significant changes of PK parameters were observed in the gemcitabine + cisplatin group on Day 7 compared to Day 1 (p > 0.05). Conclusions: There was a modest effect of co-adminstration of paclitaxel + carboplatin on the quisinostat disposition but not in combination with gemcitabine + cisplatin. Conflict of interest: Advisory Board: Mikhail Fedyanin is a medical adviser of NewVac, LLC. Corporate-sponsored Research: Andrew Cakana, Charles Phelps and Sergey Baranovsky.
Poster Session, Sunday 29 January 2017 BEP chemo treatment, patients received 3−6 cycles regimen every three weeks per cycle. The safety of BEP was evaluated by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 and efficacy were determined overall survival (OS) by the Kaplan–Meier method. Results: Moderate adverse events with BEP chemotherapy was observed 37.6% (n = 58). Severe to life-threatening was reported 22.1% (n = 34). Mean frequency in the moderate adverse event was 1.12 times. Severe adverse events mean frequency was 1.12 times, and life threatening was one time. About 1% (n = 14) patients recurred and disease-free survival was 10.3 months. Overall survival rate was evaluated 94.8%. Conclusions: BEP regimen has good activity and acceptable toxicity in patients with MOGCT. The updated and expanded results confirm a low relapse rate following BEP chemotherapy in MOGCT. Fertility-sparing surgery was possible in the early stage of cases. No conflict of interest. 716 POSTER A preclinical evaluation of niraparib efficacy as monotherapy, maintenance and after olaparib treatment (PARP inhibitor after PARP inhibitor) in patient-derived ovarian xenograft tumor models K. Mikule1 , S. Wang1 , S.J. Weroha2 , J. Nakashima3 , K. Wilcoxen1 . 1 Tesaro- Inc., Research and Development, Waltham- MA, USA; 2 Mayo Clinic, Medical Oncology, Rochester- MN, USA; 3 Crown Bioscience Inc., Research, San Diego- CA, USA Background: Niraparib is an investigational oral, once daily, highlyselective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor being developed for use in ovarian and other cancers. Preclinical efficacy of niraparib was evaluated as monotherapy in ovarian cancer patient-derived xenograft (PDX) models and as maintenance therapy after platinum treatment. This preclinical study also assessed the relative efficacy and exposure of niraparib and olaparib in tumor bearing mice. Materials and Methods: Mice bearing PDX tumors were administered test articles after tumors initiated growth and were monitored biweekly. For monotherapy studies niraparib or olaparib was dosed daily at 50 mg/kg or 75 mg/kg, respectively. For maintenance treatment, a single 30 mg/kg carboplatin dose was given on day one, followed on day eight by daily niraparib at 50 mg/kg. Some mice receiving olaparib were switched to niraparib on day 44 of treatment. Each tumor was tested for homologous recombination DNA repair deficiency using the Myriad myChoice® HRD test to evaluate the potential utility of using this tumor classifier to identify patients that may benefit from niraparib therapy. The concentrations of niraparib and olaparib in tumors and plasma were determined at steady state in tumor bearing mice. Terminal blood samples were collected via cardiac puncture at 6 hours post final dose. After euthanasia, the tumor was collected from each animal. Plasma, tumor, and dose formulation samples were analyzed for niraparib and olaparib by LC-MS/MS. Results: Single-agent niraparib caused tumor regression in 9 of 30 ovarian PDX tumor models overall (30%), and in 9 of 19 HRD positive models (47%). In addition, five (four HRD negative) models responded with 50% or greater tumor growth inhibition. Niraparib maintenance therapy resulted in complete regressions in 2 of 3 models evaluated, including one model that was refractory to platinum. In one BRCA2 mutant platinum-sensitive PDX model niraparib caused tumor regression, while olaparib achieved only tumor growth inhibition. In addition, when the olaparib treatment was switched to niraparib, tumors regressed. Plasma and tumor exposures of niraparib at the 50 mg/kg dose were >12-fold higher than those of olaparib at the 75 mg/kg dose (Table). Table: Plasma and tumor exposures 6 h post final dose
714 POSTER The safety and efficacy of bleomycin, etoposide and cisplatin (BEP) chemotherapy in patients with malignant ovarian germ cell tumor G. Lee1 , J.Y. Park1 , D.Y. Kim1 , D.S. Suh1 , J.H. Kim1 , Y.M. Kim1 , Y.T. Kim1 , J.H. Nam1 . 1 Asan Medical Center, Obstetrics & Gynecology, Seoul, South Korea Background: Malignant ovarian germ cell tumor (MOGCT) is the rare malignancy and occurs in young or adolescent patients. Standard treatment is made of surgery followed by bleomycin, etoposide, and cisplatin (BEP) chemotherapy. It is sensitive to platinum-based chemotherapy with excellent cure rate. However, it needs skillful experience in administration and toxicity management to maintain optimal dose. The aim of our study was to evaluate safety and efficacy of BEP chemotherapy in MOGCT patients. Material and Methods: This report is retrospectively recorded cases that were treated at Asan Medical Center (Seoul, Korea). From 1992 to 2015, 154 patients with I to IV MOGCTs underwent BEP chemotherapy. In the
Olaparib Niraparib
Exposure ±SD Plasma (ng/mL)
Tumor (ng/mg)
168±87 2150±881
123±32 4567±2050
Conclusions: In a preclinical evaluation, niraparib is highly efficacious as monotherapy causing tumor regression in HRD+ ovarian PDX models. In addition, niraparib shows significant growth inhibition in tumor models regardless of HRD status. Niraparib demonstrated durable complete remissions as maintenance therapy in both platinum-sensitive and platinum-refractory tumor models. Finally, niraparib caused complete tumor regression in a PDX model whose best response to olaparib was stable disease. Conflict of interest: Corporate-sponsored Research: S.J. Weroha reports grants from Tesaro, Inc. and AstraZeneca. Other Substantive Relationships: K. Mikule, S. Wang, and K. Wilcoxen are employees of Tesaro, Inc.; S.J. Weroha has a patent with Mayo Medical Ventures with royalties paid.
Abstracts
713 POSTER Pharmacokinetic (PK) profile of quisinostat in combination with gemcitabine and cisplatin in patients (pts) with non-small cell lung cancer (NSCLC) or paclitaxel and carboplatin in pts with NSCLC or epithelial ovarian cancer M. Fedyanin1 , S. Tjulandin1 , S. Cheporov2 , V. Vladimirov3 , V. Moiseenko4 , S. Orlov5 , G. Manikhas6 , A. Koryakova7 , A. Cakana8 , C. Phelps8 , S. Baranovsky9 , V. Azarova10 , O. Karavaeva10 , N. Vostokova10 . 1 Russian Cancer Research Center. NN Blokhin, clinical pharmacology and chemotherapy, Moscow, Russian Federation; 2 State “Regional Clinical Oncology Hospital” health care institution of Yaroslavl region, chemotherapy, Yaroslavl, Russian Federation; 3 State Budget Institution of public health Pyatigorsk oncology dispensary, chemotherapy, Pyatigorsk, Russian Federation; 4 GBUZ Saint-Petersburg clinical scientific and practical center special kinds of medical care oncology, oncology, Saint-Petersburg, Russian Federation; 5 BioEq- LLC, BioEqLLC, Saint-Petersburg, Russian Federation; 6 Saint-Petersburg State Budget institution Healthcare Municipal Clinical Oncology Dispensary, oncology, Saint-Petersburg, Russian Federation; 7 Chemical Diversity Research Institute- JSC, Chemical Diversity Research Institute- JSC, Khimki, Russian Federation; 8 Janssen Pharmaceutica N.V., Janssen Pharmaceutica N.V., Beerse, Belgium; 9 NewVac- LLC, NewVac- LLC, Khimki, Russian Federation; 10 IPHARMA- LLC, IPHARMA- LLC, Moscow, Russian Federation Background: The purpose of this work was to determine PK parameters of multiple ascending doses of quisinostat, pan-histone deacetylase inhibitor, in combination with gemcitabine + cisplatin and paclitaxel + carboplatin within 24 hours on Day 1 and on Day 7 of the 1st cycle and evaluate potential PK interactions of quisinostat and chemotherapy (CT) drugs in pts with relapsed NSCLC and ovarian cancer within phase I study. Material and Method: quisinostat was administered at escalated doses (8, 10 and 12 mg) orally each 3 week cycle on Days 1, 3, 5, 7, 9, 11 in combination with gemcitabine + cisplatin or paclitaxel + carboplatin CT for pts with NSCLC or ovarian cancer. The infusion of CT drugs was conducted on Day 7 (relative to quisinostat administration). The PK analysis was conducted on the concentration-time data of quisinostat and CT in plasma samples of pts and this data was provided using a validated bioanalytical method Janssen R&D, J&J. PK parameters were estimated using noncompartmental analysis (Phoenix™ WinNonlin® 6.2.1. (Pharsight Corp.). Venous blood samples for the PK study were collected at 15 min before and 5, 15, 30 min, 1, 3, 4, 5, 6, 8, 24 hours after qusinostat administration on the day of administration of the first dose of quisinostat (Day 1 of Cycle 1) and on the day of CT start in combination with quisinostat (Day 7 of Cycle 1). Results: In the 12 mg cohort with paclitaxel + carboplatin (n = 13), statistically significant differences (p < 0.05) were determined for the assessed PK parameters of quisinostat on Day 1 and Day 7: Cmax of quisinostat increased 1.7-fold on average (p < 0.01), t1/2 increased 1.4-fold (p < 0.05), which led to the 2.2-fold increase of systemic exposure (AUC) (p < 0.0001). Apparent oral clearance decreased 2.7-fold. Tmax increased significantly − the median value increased from 0.5 to 3.0 h (p < 0.05). No significant changes of PK parameters were observed in the gemcitabine + cisplatin group on Day 7 compared to Day 1 (p > 0.05). Conclusions: There was a modest effect of co-adminstration of paclitaxel + carboplatin on the quisinostat disposition but not in combination with gemcitabine + cisplatin. Conflict of interest: Advisory Board: Mikhail Fedyanin is a medical adviser of NewVac, LLC. Corporate-sponsored Research: Andrew Cakana, Charles Phelps and Sergey Baranovsky.
Poster Session, Sunday 29 January 2017 BEP chemo treatment, patients received 3−6 cycles regimen every three weeks per cycle. The safety of BEP was evaluated by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 and efficacy were determined overall survival (OS) by the Kaplan–Meier method. Results: Moderate adverse events with BEP chemotherapy was observed 37.6% (n = 58). Severe to life-threatening was reported 22.1% (n = 34). Mean frequency in the moderate adverse event was 1.12 times. Severe adverse events mean frequency was 1.12 times, and life threatening was one time. About 1% (n = 14) patients recurred and disease-free survival was 10.3 months. Overall survival rate was evaluated 94.8%. Conclusions: BEP regimen has good activity and acceptable toxicity in patients with MOGCT. The updated and expanded results confirm a low relapse rate following BEP chemotherapy in MOGCT. Fertility-sparing surgery was possible in the early stage of cases. No conflict of interest. 716 POSTER A preclinical evaluation of niraparib efficacy as monotherapy, maintenance and after olaparib treatment (PARP inhibitor after PARP inhibitor) in patient-derived ovarian xenograft tumor models K. Mikule1 , S. Wang1 , S.J. Weroha2 , J. Nakashima3 , K. Wilcoxen1 . 1 Tesaro- Inc., Research and Development, Waltham- MA, USA; 2 Mayo Clinic, Medical Oncology, Rochester- MN, USA; 3 Crown Bioscience Inc., Research, San Diego- CA, USA Background: Niraparib is an investigational oral, once daily, highlyselective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor being developed for use in ovarian and other cancers. Preclinical efficacy of niraparib was evaluated as monotherapy in ovarian cancer patient-derived xenograft (PDX) models and as maintenance therapy after platinum treatment. This preclinical study also assessed the relative efficacy and exposure of niraparib and olaparib in tumor bearing mice. Materials and Methods: Mice bearing PDX tumors were administered test articles after tumors initiated growth and were monitored biweekly. For monotherapy studies niraparib or olaparib was dosed daily at 50 mg/kg or 75 mg/kg, respectively. For maintenance treatment, a single 30 mg/kg carboplatin dose was given on day one, followed on day eight by daily niraparib at 50 mg/kg. Some mice receiving olaparib were switched to niraparib on day 44 of treatment. Each tumor was tested for homologous recombination DNA repair deficiency using the Myriad myChoice® HRD test to evaluate the potential utility of using this tumor classifier to identify patients that may benefit from niraparib therapy. The concentrations of niraparib and olaparib in tumors and plasma were determined at steady state in tumor bearing mice. Terminal blood samples were collected via cardiac puncture at 6 hours post final dose. After euthanasia, the tumor was collected from each animal. Plasma, tumor, and dose formulation samples were analyzed for niraparib and olaparib by LC-MS/MS. Results: Single-agent niraparib caused tumor regression in 9 of 30 ovarian PDX tumor models overall (30%), and in 9 of 19 HRD positive models (47%). In addition, five (four HRD negative) models responded with 50% or greater tumor growth inhibition. Niraparib maintenance therapy resulted in complete regressions in 2 of 3 models evaluated, including one model that was refractory to platinum. In one BRCA2 mutant platinum-sensitive PDX model niraparib caused tumor regression, while olaparib achieved only tumor growth inhibition. In addition, when the olaparib treatment was switched to niraparib, tumors regressed. Plasma and tumor exposures of niraparib at the 50 mg/kg dose were >12-fold higher than those of olaparib at the 75 mg/kg dose (Table). Table: Plasma and tumor exposures 6 h post final dose
714 POSTER The safety and efficacy of bleomycin, etoposide and cisplatin (BEP) chemotherapy in patients with malignant ovarian germ cell tumor G. Lee1 , J.Y. Park1 , D.Y. Kim1 , D.S. Suh1 , J.H. Kim1 , Y.M. Kim1 , Y.T. Kim1 , J.H. Nam1 . 1 Asan Medical Center, Obstetrics & Gynecology, Seoul, South Korea Background: Malignant ovarian germ cell tumor (MOGCT) is the rare malignancy and occurs in young or adolescent patients. Standard treatment is made of surgery followed by bleomycin, etoposide, and cisplatin (BEP) chemotherapy. It is sensitive to platinum-based chemotherapy with excellent cure rate. However, it needs skillful experience in administration and toxicity management to maintain optimal dose. The aim of our study was to evaluate safety and efficacy of BEP chemotherapy in MOGCT patients. Material and Methods: This report is retrospectively recorded cases that were treated at Asan Medical Center (Seoul, Korea). From 1992 to 2015, 154 patients with I to IV MOGCTs underwent BEP chemotherapy. In the
Olaparib Niraparib
Exposure ±SD Plasma (ng/mL)
Tumor (ng/mg)
168±87 2150±881
123±32 4567±2050
Conclusions: In a preclinical evaluation, niraparib is highly efficacious as monotherapy causing tumor regression in HRD+ ovarian PDX models. In addition, niraparib shows significant growth inhibition in tumor models regardless of HRD status. Niraparib demonstrated durable complete remissions as maintenance therapy in both platinum-sensitive and platinum-refractory tumor models. Finally, niraparib caused complete tumor regression in a PDX model whose best response to olaparib was stable disease. Conflict of interest: Corporate-sponsored Research: S.J. Weroha reports grants from Tesaro, Inc. and AstraZeneca. Other Substantive Relationships: K. Mikule, S. Wang, and K. Wilcoxen are employees of Tesaro, Inc.; S.J. Weroha has a patent with Mayo Medical Ventures with royalties paid.