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A phase 1 study of niraparib in Japanese patients with advanced solid tumors
abstracts
Annals of Oncology
P1 190
L-Lysine increased the cytotoxicity effect of doxorubicin in MDAMB-231 and MDA-MB-468 breast cancer cell lines
Javad Chehri1,2, Mozhgan Jahani1, Hadis Tahmasebi1, Reza Yarani1,3, Kamran Mansouri1 1 Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran, Islamic Republic of, 2Moscow State Academy of Veterinary Medicine, Biotechnology (K.I. Skryabin), Russia, 3Department of Clinical Research, Type 1 Diabetes Biology, Steno Diabetes Center, Copenhagen, Denmark Background: Breast cancer is the first cause of death among Women. Chemoresistance is believed to be responsible for most of the mortalities, thus using new therapeutic strategies are needed. Autophagy has been shown as a critical player in cancer cells response to chemotherapeutic drugs such as doxorubicin. However, autophagy effect on cancer cell can be viewed as a pro-death or a pro-survival role. Thus, increase or decrease of this process in cells relative to its baseline can induce cancer cell death. Thus, we investigated if L-Lysine can increase doxorubicin effectiveness in combination therapy through autophagy modulation. Methods: MDA-MB-231 and MDA-MB-468 were used as two breast cancer cell lines. Cells were treated with various concentrations of doxorubicin and L-Lysine. Cell viability was assessed using MTT assay 24 and 48h after treatment. ROS and NO level was examined and the expression of various autophagy and apoptosis related proteins/ genes were evaluated with western blotting and real-time PCR respectively. Results: L-Lysine increased cytotoxicity effect of doxorubicin in both MDA-MB-231 and MDA-MB-468 by autophagy enhancement. L-Lysine reduced cell viability and increased apoptosis in combination with doxorubicin. Real-time PCR analysis indicated that the combination of these two drugs resulted in increased autophagy as well as apoptosis-related genes. Moreover, reactive oxygen species (ROS) and nitric oxide (NO) production increased 30min after treatment with both drugs. However, the amount of these molecules decreased after 24h which can be results of autophagy induction. These results were further confirmed at protein levels of LC-3 and mTOR by western blotting. Conclusion: Our findings indicated that L-Lysine can reduce the resistance to doxorubicin in triple negative breast cancer cells, MDA-MB-231 and MDA-MB-468. Therefore combination therapy with L-Lysine and doxorubicin could be consider an effective strategy in breast cancer therapy.
P1 195
Development of new treatment using CMG for oxaliplatin-resistant colorectal cancer with KRAS mutation
Masashi Kanai1, Mitsuhiro Kishimoto2, Hitomi Umeda2, Atsushi Imaizumi2, Hideaki Kakeya3 1 Department of Medical Oncology, Kyoto University Hospital, 2TheraBioPharma. Inc, 3 Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University Background: KRAS mutations are known as poor prognostic factor for patients with colon cancer who receive chemotherapy. KRAS mutations have been shown to activate NF-kappa B (NF-kB) signaling pathway, that plays a pivotal role in cancer progression or chemoresistance. In this study, we tested whether KRAS mutations could confer chemoresistance to oxaliplatin (L-OHP) in vitro. In addition, we tested the efficacy of the newly developed water-soluble injectable type of curcumin monoglucuronide (CMG) in vivo, that is transformed into an active form of curcumin after the injection and potentially suppresses NF-kB activation. Methods: Sensitivity of L-OHP was tested using HCT116/DLD1 colon cancer cell lines with/without KRAS mutations (KRASþ/- cells). Efficacy of CMG was tested using xenograft mouse models. Results: IC50 of L-OHP was significantly higher in KRASþ cells compared to KRAScells. Addition of p53 deletion in KRASþ HCT 116 cells (KRASþp53- cells) significantly increased chemoresistance to L-OHP compared to KRASþ cells. Curcumin showed the similar anti-tumor effects regardless of KRAS/p53 mutation status in vitro. Higher NF-kB activity in KRASþ cells compared to KRAS- cells was detected by using a reporter gene assay and NF-kB activation was suppressed by curcumin in vitro. In
Volume 30 | Supplement 6 | October 2019
xenograft models using KRASþp53- HCT116 cell line, intraperitoneal administration of CMG demonstrated significantly superior anti-tumor effects compared to L-OHP monotherapy. Notably, no adverse events were noted in the CMG group, whereas bodyweight loss, severe myelosuppression, and liver damage were observed in the LOHP group. Combination of CMG and L-OHP showed synergic anti-tumor effects. Conclusion: These results indicate that CMG could be a novel anti-cancer drug with minimal toxicities for colorectal cancer patients with KRAS mutations.
P1 198
A phase 1 study of niraparib in Japanese patients with advanced solid tumors
Ryota Shibaki1, Toshio Shimizu1, Shunsuke Kondo1, Satoru Iwasa1, Takafumi Koyama1, Shigehisa Kitano1, Jun Sato1,2, Akihiko Shimomura1, Ajit Suri3, Yoichi Kase4, Shuuji Sumino5, Kenji Tamura6, Noboru Yamamoto1, Kan Yonemori1 1 Department of Experimental Therapeutics, National Cancer Center Hospital, 2 Department of Thoracic Oncology, National Cancer Center Hospital, 3Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 4Oncology Clinical Research Department, Oncology Therapeutic Area Unit for Japan and Asia, Takeda Pharmaceutical Company Limited, 5Biostatistics, Japan Development Center, Takeda Pharmaceutical Company Limited, 6Department of Breast and Medical Oncology, National Cancer Center Hospital Background: Niraparib is an oral, potent, highly selective poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) -1 and -2 inhibitor, and approved in US and Europe for the maintenance treatment of patients with recurrent ovarian cancer. Safety, tolerability and pharmacokinetics (PK) of niraparib were investigated in Japanese patients with advanced solid tumors. Methods: This Phase 1 study followed a standard 3 þ 3 dose escalation design with two dose levels. Niraparib was administered orally once daily (QD) continuously for 21days in a cycle until treatment discontinuation. Intensive PK was evaluated on day 1 and day 21 during cycle 1. Results: Total of 9 subjects were enrolled, 3 in cohort 1 (200 mg) and 6 in cohort 2 (300 mg). No DLT was observed in cohort 1 whereas one DLT was observed in 1 of 6 subjects in cohort 2. The observed DLT was grade 4 thrombocytopenia. According to the preliminary data, the treatment-emergent adverse events reported in more than 1 subject were vomiting and thrombocytopenia/platelet count decreased (4 subjects each), nausea and anorexia (3 subjects each), and diarrhoea, alkaline phosphatase increased, creatinine increased, leukopenia/white blood cell count decreased, neutropenia-related events (including neutrophil count decreased and febrile neutropenia) and fatigue/malaise (2 subjects each). Cmax and AUC24 of niraparib after a single and multiple dose (QD) administration were increased generally in dose-proportional manner between dose of 200 mg and 300 mg. The PK profiles were generally comparable across Western and Japanese patients. Three subjects stay on treatment at the timing of cutoff date (February 21, 2019) Conclusion: Niraparib was well tolerated and MTD was considered 300 mg or higher with recommended phase 2 dose as 300 mg in Japanese patients with advanced solid tumors. No unknown safety concerns were identified. No obvious PK difference was observed between Japanese and non-Japanese patients.
P1 210
Fluoropyrimidine-based chemotherapy for gastrointestinal cancer in patients with direct oral anticoagulants or warfarin
Yuki Matsubara1, Takayuki Ando2, Miho Sakumura2, Hiroki Yoshita2, Sohachi Nanjo2, Hiroshi Mihara2, Haruka Fujinami2, Kenichiro Tsukada1, Kajiura Shinya2, Kohei Ogawa1, Ayumu Hosokawa2, Mitsuhiro Terada1, Ichiro Yasuda2 1 Kouseiren Takaoka Hospital, 2University of Toyama Background: The warfarin is known to enhance its activity by interaction with fluoropyrimidine. On the other hands, direct oral anticoagulants (DOACs) have several advantages compared with warfarin such as the unnecessity of dose monitoring and their few drug interactions. Therefore, the aim of this study is to assess the dose intensity and safety of fluoropyrimidine-based chemotherapy for gastrointestinal cancer in patients with DOACs or warfarin. Methods: Between January 2006 to June 2018, a total of 1,413 patients with esophageal, gastric, colorectal, and pancreatic cancer received fluoropyrimidine-based chemotherapy at two institutions. Among all patients, 49 patients with anticoagulant therapy were enrolled in this study. They were further divided into the warfarin group (27 patients) and the DOACs group (22 patients). We retrospectively analyzed their Relative Dose Intensity (RDI) of fluoropyrimidine, Time in Therapeutic Range (TTR) of warfarin, and bleeding or thrombosis events. Results: In the warfarin group, the median RDI of fluoropyrimidne and TTR of warfarin was 80.0% (0-100%) and 37.5% (0-100%), respectively. The proportion of patients with prolonged PT-NR values (cut off value of 3.00) was 51.9% (14/27). In the DOACs group, the median RDI was 72.9% (0-100%). There was no significant difference in RDI (p ¼ 0.88), although TTR of warfarin was relatively low. The bleeding or thrombosis events occurred only in the warfarin group (3.7% and 7.4%, respectively).
doi:10.1093/annonc/mdz343 | vi127
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz343.044/5582877 by guest on 25 October 2019
dinnerin dividing dosage. The primary endpoint of this study was to assess the adverse eventsin the breast cancer patients and the treatment outcome. Results: Out of 62 patients enrolled, hormonal (ER/PR) positive patients 27, 21 TNBC and 14 Her2 positive patients were enrolled. 32 were locally advanced breast cancer (LABC patients while 30 were Stage IV patients. Results indicate that hormonal positive and Her2 positive patients have significantly better outcomes when compared with TNBC group (66.12% vs 33.87%, P ¼ <0.001). These patients have lesser toxicity and very less adverse events when Curcumin group was compared with non Curcumin group. The toxicities assessed were nausea, diarrhea, pain, weakness, mucositis, fatigue, alopecia, anemia and we found significant reduction in nausea, pain, mucositis, weakness and diarrhea toxicity. Conclusions: Curcumin in combination with a standard dose of chemotherapy show less toxicity and better outcome in breast cancer.
Annals of Oncology
P1 190
L-Lysine increased the cytotoxicity effect of doxorubicin in MDAMB-231 and MDA-MB-468 breast cancer cell lines
Javad Chehri1,2, Mozhgan Jahani1, Hadis Tahmasebi1, Reza Yarani1,3, Kamran Mansouri1 1 Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran, Islamic Republic of, 2Moscow State Academy of Veterinary Medicine, Biotechnology (K.I. Skryabin), Russia, 3Department of Clinical Research, Type 1 Diabetes Biology, Steno Diabetes Center, Copenhagen, Denmark Background: Breast cancer is the first cause of death among Women. Chemoresistance is believed to be responsible for most of the mortalities, thus using new therapeutic strategies are needed. Autophagy has been shown as a critical player in cancer cells response to chemotherapeutic drugs such as doxorubicin. However, autophagy effect on cancer cell can be viewed as a pro-death or a pro-survival role. Thus, increase or decrease of this process in cells relative to its baseline can induce cancer cell death. Thus, we investigated if L-Lysine can increase doxorubicin effectiveness in combination therapy through autophagy modulation. Methods: MDA-MB-231 and MDA-MB-468 were used as two breast cancer cell lines. Cells were treated with various concentrations of doxorubicin and L-Lysine. Cell viability was assessed using MTT assay 24 and 48h after treatment. ROS and NO level was examined and the expression of various autophagy and apoptosis related proteins/ genes were evaluated with western blotting and real-time PCR respectively. Results: L-Lysine increased cytotoxicity effect of doxorubicin in both MDA-MB-231 and MDA-MB-468 by autophagy enhancement. L-Lysine reduced cell viability and increased apoptosis in combination with doxorubicin. Real-time PCR analysis indicated that the combination of these two drugs resulted in increased autophagy as well as apoptosis-related genes. Moreover, reactive oxygen species (ROS) and nitric oxide (NO) production increased 30min after treatment with both drugs. However, the amount of these molecules decreased after 24h which can be results of autophagy induction. These results were further confirmed at protein levels of LC-3 and mTOR by western blotting. Conclusion: Our findings indicated that L-Lysine can reduce the resistance to doxorubicin in triple negative breast cancer cells, MDA-MB-231 and MDA-MB-468. Therefore combination therapy with L-Lysine and doxorubicin could be consider an effective strategy in breast cancer therapy.
P1 195
Development of new treatment using CMG for oxaliplatin-resistant colorectal cancer with KRAS mutation
Masashi Kanai1, Mitsuhiro Kishimoto2, Hitomi Umeda2, Atsushi Imaizumi2, Hideaki Kakeya3 1 Department of Medical Oncology, Kyoto University Hospital, 2TheraBioPharma. Inc, 3 Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University Background: KRAS mutations are known as poor prognostic factor for patients with colon cancer who receive chemotherapy. KRAS mutations have been shown to activate NF-kappa B (NF-kB) signaling pathway, that plays a pivotal role in cancer progression or chemoresistance. In this study, we tested whether KRAS mutations could confer chemoresistance to oxaliplatin (L-OHP) in vitro. In addition, we tested the efficacy of the newly developed water-soluble injectable type of curcumin monoglucuronide (CMG) in vivo, that is transformed into an active form of curcumin after the injection and potentially suppresses NF-kB activation. Methods: Sensitivity of L-OHP was tested using HCT116/DLD1 colon cancer cell lines with/without KRAS mutations (KRASþ/- cells). Efficacy of CMG was tested using xenograft mouse models. Results: IC50 of L-OHP was significantly higher in KRASþ cells compared to KRAScells. Addition of p53 deletion in KRASþ HCT 116 cells (KRASþp53- cells) significantly increased chemoresistance to L-OHP compared to KRASþ cells. Curcumin showed the similar anti-tumor effects regardless of KRAS/p53 mutation status in vitro. Higher NF-kB activity in KRASþ cells compared to KRAS- cells was detected by using a reporter gene assay and NF-kB activation was suppressed by curcumin in vitro. In
Volume 30 | Supplement 6 | October 2019
xenograft models using KRASþp53- HCT116 cell line, intraperitoneal administration of CMG demonstrated significantly superior anti-tumor effects compared to L-OHP monotherapy. Notably, no adverse events were noted in the CMG group, whereas bodyweight loss, severe myelosuppression, and liver damage were observed in the LOHP group. Combination of CMG and L-OHP showed synergic anti-tumor effects. Conclusion: These results indicate that CMG could be a novel anti-cancer drug with minimal toxicities for colorectal cancer patients with KRAS mutations.
P1 198
A phase 1 study of niraparib in Japanese patients with advanced solid tumors
Ryota Shibaki1, Toshio Shimizu1, Shunsuke Kondo1, Satoru Iwasa1, Takafumi Koyama1, Shigehisa Kitano1, Jun Sato1,2, Akihiko Shimomura1, Ajit Suri3, Yoichi Kase4, Shuuji Sumino5, Kenji Tamura6, Noboru Yamamoto1, Kan Yonemori1 1 Department of Experimental Therapeutics, National Cancer Center Hospital, 2 Department of Thoracic Oncology, National Cancer Center Hospital, 3Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 4Oncology Clinical Research Department, Oncology Therapeutic Area Unit for Japan and Asia, Takeda Pharmaceutical Company Limited, 5Biostatistics, Japan Development Center, Takeda Pharmaceutical Company Limited, 6Department of Breast and Medical Oncology, National Cancer Center Hospital Background: Niraparib is an oral, potent, highly selective poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) -1 and -2 inhibitor, and approved in US and Europe for the maintenance treatment of patients with recurrent ovarian cancer. Safety, tolerability and pharmacokinetics (PK) of niraparib were investigated in Japanese patients with advanced solid tumors. Methods: This Phase 1 study followed a standard 3 þ 3 dose escalation design with two dose levels. Niraparib was administered orally once daily (QD) continuously for 21days in a cycle until treatment discontinuation. Intensive PK was evaluated on day 1 and day 21 during cycle 1. Results: Total of 9 subjects were enrolled, 3 in cohort 1 (200 mg) and 6 in cohort 2 (300 mg). No DLT was observed in cohort 1 whereas one DLT was observed in 1 of 6 subjects in cohort 2. The observed DLT was grade 4 thrombocytopenia. According to the preliminary data, the treatment-emergent adverse events reported in more than 1 subject were vomiting and thrombocytopenia/platelet count decreased (4 subjects each), nausea and anorexia (3 subjects each), and diarrhoea, alkaline phosphatase increased, creatinine increased, leukopenia/white blood cell count decreased, neutropenia-related events (including neutrophil count decreased and febrile neutropenia) and fatigue/malaise (2 subjects each). Cmax and AUC24 of niraparib after a single and multiple dose (QD) administration were increased generally in dose-proportional manner between dose of 200 mg and 300 mg. The PK profiles were generally comparable across Western and Japanese patients. Three subjects stay on treatment at the timing of cutoff date (February 21, 2019) Conclusion: Niraparib was well tolerated and MTD was considered 300 mg or higher with recommended phase 2 dose as 300 mg in Japanese patients with advanced solid tumors. No unknown safety concerns were identified. No obvious PK difference was observed between Japanese and non-Japanese patients.
P1 210
Fluoropyrimidine-based chemotherapy for gastrointestinal cancer in patients with direct oral anticoagulants or warfarin
Yuki Matsubara1, Takayuki Ando2, Miho Sakumura2, Hiroki Yoshita2, Sohachi Nanjo2, Hiroshi Mihara2, Haruka Fujinami2, Kenichiro Tsukada1, Kajiura Shinya2, Kohei Ogawa1, Ayumu Hosokawa2, Mitsuhiro Terada1, Ichiro Yasuda2 1 Kouseiren Takaoka Hospital, 2University of Toyama Background: The warfarin is known to enhance its activity by interaction with fluoropyrimidine. On the other hands, direct oral anticoagulants (DOACs) have several advantages compared with warfarin such as the unnecessity of dose monitoring and their few drug interactions. Therefore, the aim of this study is to assess the dose intensity and safety of fluoropyrimidine-based chemotherapy for gastrointestinal cancer in patients with DOACs or warfarin. Methods: Between January 2006 to June 2018, a total of 1,413 patients with esophageal, gastric, colorectal, and pancreatic cancer received fluoropyrimidine-based chemotherapy at two institutions. Among all patients, 49 patients with anticoagulant therapy were enrolled in this study. They were further divided into the warfarin group (27 patients) and the DOACs group (22 patients). We retrospectively analyzed their Relative Dose Intensity (RDI) of fluoropyrimidine, Time in Therapeutic Range (TTR) of warfarin, and bleeding or thrombosis events. Results: In the warfarin group, the median RDI of fluoropyrimidne and TTR of warfarin was 80.0% (0-100%) and 37.5% (0-100%), respectively. The proportion of patients with prolonged PT-NR values (cut off value of 3.00) was 51.9% (14/27). In the DOACs group, the median RDI was 72.9% (0-100%). There was no significant difference in RDI (p ¼ 0.88), although TTR of warfarin was relatively low. The bleeding or thrombosis events occurred only in the warfarin group (3.7% and 7.4%, respectively).
doi:10.1093/annonc/mdz343 | vi127
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz343.044/5582877 by guest on 25 October 2019
dinnerin dividing dosage. The primary endpoint of this study was to assess the adverse eventsin the breast cancer patients and the treatment outcome. Results: Out of 62 patients enrolled, hormonal (ER/PR) positive patients 27, 21 TNBC and 14 Her2 positive patients were enrolled. 32 were locally advanced breast cancer (LABC patients while 30 were Stage IV patients. Results indicate that hormonal positive and Her2 positive patients have significantly better outcomes when compared with TNBC group (66.12% vs 33.87%, P ¼ <0.001). These patients have lesser toxicity and very less adverse events when Curcumin group was compared with non Curcumin group. The toxicities assessed were nausea, diarrhea, pain, weakness, mucositis, fatigue, alopecia, anemia and we found significant reduction in nausea, pain, mucositis, weakness and diarrhea toxicity. Conclusions: Curcumin in combination with a standard dose of chemotherapy show less toxicity and better outcome in breast cancer.