Tuesday, October 22, 2013

Investigational PARP inhibitor promising in BRCA-related cancers

Investigational PARP inhibitor promising in BRCA-related cancers


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22-Oct-2013



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Contact: Lauren Riley
lauren.riley@aacr.org
215-446-7155
American Association for Cancer Research






BOSTON An investigational new PARP inhibitor, BMN 673, is showing early responses in patients with heavily pretreated, advanced, BRCA-related cancers of the breast and ovary, according to phase I clinical trial results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.


When there is damage to DNA in human cells, two proteins, PARP 1 and 2, recruit proteins that can repair the damage associated with loss of BRCA proteins. Mutations in BRCA genes often result in inefficient repair of damaged DNA, which increases the risk for developing certain cancers, including cancers of the breast and ovary. Inhibiting PARP, therefore, prevents the repair of damaged DNA, leading to cell death. While some PARP inhibitors have been tested in various settings, none are approved to date.


"BMN 673 is the most potent PARP inhibitor in clinical development and has optimized pharmaceutical properties: it is well absorbed orally, has substantial single-agent antitumor activity, and has a long half-life allowing once-daily dosing," said Zev A. Wainberg, M.D., assistant professor of medicine at the Jonsson Comprehensive Cancer Center of the University of California Los Angeles School of Medicine. "The clinical data to date are promising and compare favorably with results from clinical trials with other PARP inhibitors. We observed high objective and clinical benefit response rates in BRCA-related breast and ovarian cancers at low, oral, once-daily doses.


"Based on this phase I study, we feel there's a good chance that patients with BRCA-related cancers who meet the study eligibility criteria will have disease control for a meaningful period of time with relatively few side effects. However, randomized trials are necessary to demonstrate whether this will translate into improvements in progression-free and overall survival relative to currently available therapies," said Wainberg.


He and colleagues conducted a phase I trial to evaluate the safety and efficacy of BMN 673 in a two-stage dose escalation/expansion study. So far, they have recruited 39 and 41 patients to the escalation phase and expansion phase, respectively. Patients were 18-82 years old, and they had undergone one to 13 prior therapies.


Fifty participants18 with breast cancer, 28 with ovarian cancer, three with pancreatic cancer, and one with prostate cancerhad BRCA mutations in their tumors. Wainberg reported that to date, among the patients with BRCA mutations in their tumors, 44 percent of those with ovarian cancer and 44 percent with breast cancer had an objective response. Overall, 82 percent of the ovarian cancer patients and 72 percent of the breast cancer patients had clinical benefit (measured by imaging data and/or CA 125 levels for ovarian cancers and by imaging data for breast cancers).


In patients being treated at the 1 mg dose recommended for future trials, 50 percent of the breast cancer patients with BRCA mutations had an objective response and 86 percent had clinical benefit. Of the three patients with pancreatic cancer, two have had stable disease.


Fewer than 20 percent of the patients had grade 3 adverse events including fatigue, anemia, neutropenia, and thrombocytopenia, and one patient had a grade 4 toxicity.


Given the high objective and clinical benefit response rates in breast cancer patients, the investigators have recently initiated a phase 3 trial in metastatic breast cancer with BRCA mutations, according to Wainberg.


Among those with BRCA-unrelated cancers recruited to the phase 1 trial, one of the seven currently evaluable patients with small-cell lung cancer (SCLC) has responded, according to Wainberg. This patient, whose tumor metastasized extensively, has an ongoing partial response, he explained. "A solid partial response in a patient with SCLC provides some optimism about finding indications other than BRCA-related tumors that will benefit from treatment with BMN 673," he said.


###

This study was sponsored by BioMarin Pharmaceutical. Wainberg has no conflicts of interest to declare.


The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).


This research will be presented at a press conference entitled "Guiding Treatment for BRAF- and BRCA-related Cancers" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Monday, Oct. 22 at 9 a.m. ET in room 202 of the Hynes Convention Center in Boston, Mass. Reporters who cannot attend in person may call in using the following numbers:


  • U.S./Canada (toll-free): 800-446-2782
  • International (toll): 847-413-3235

To interview Zev Wainberg, contact Shaun Mason at smason@mednet.ucla.edu or 310-206-2805. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.



About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org. Follow the AACR on Twitter: @AACR. Follow the AACR on Facebook: http://www.facebook.com/aacr.org.


About the National Cancer Institute

The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).


About the European Organisation for Research and Treatment of Cancer

The European Organisation for the Research and Treatment of Cancer (EORTC) brings together European cancer clinical research experts from all disciplines for trans-national collaboration. Both multinational and multidisciplinary, the EORTC Network comprises more than 2,500 collaborators from all disciplines involved in cancer treatment and research in more than 300 hospitals in over 30 countries. Through translational and clinical research, the EORTC offers an integrated approach to drug development, drug evaluation programs and medical practices.

EORTC Headquarters, a unique pan European clinical research infrastructure, is based in Brussels, Belgium, from where its various activities are coordinated and run. http://www.eortc.org


Abstract Number: C295

Presenter: Zev A. Wainberg, M.D.


Title: Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors


Authors: Zev A. Wainberg1, Johann S. de Bono2, Lida Mina3, Jasgit Sachdev4, Lauren Averett Byers5, Rashmi Chugh6, Charlie Zhang7, Joshua W. Henshaw7, Andrew Dorr7, John Glaspy1, Ramesh Ramanathan4. 1David Geffen School of Medicine at UCLA, Los Angeles, CA; 2The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; 3Indiana University, Indianapolis, IN; 4Virginia G. Piper Cancer Center at Scottsdale Healthcare/Tgen, Scottsdale, AZ; 5University of Texas MD Anderson Cancer Center, Houston, TX; 6University of Michigan, Ann Arbor, MI; 7BioMarin Pharmaceutical, Novato, CA

Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage escalation/expansion study. Expansion included cohorts of pts with BRCA-related cancers, small cell lung cancer (SCLC) and Ewing sarcoma (ES).

Results: (As of July 29, 2013) In escalation, 39 pts were enrolled in 9 cohorts from 25 to 1100 g/d with 1000 g/d being the MTD related to dose-limiting hematologic toxicity. 38 pts have been enrolled in expansion including 25 patients with BRCA related cancers. For all 77 (63F/14M) pts, median age (range) is 52 (18-81), PS, 0 (0-1) and # of prior therapies 4 (1-13). Eight ES, 7 SCLC and 48 patients with deleterious BRCA mutations and breast (n=18), ovarian (n=28) or pancreatic (n=2) cancer were enrolled. BMN 673 demonstrated good oral bioavailability and a long half-life supporting daily dosing (ASCO 2013 Abstract 2580). One related grade 4 toxicity (thrombocytopenia) occurred. Related grade 3 adverse events have included fatigue, anemia, neutropenia and thrombocytopenia, all in fewer than 15% of patients. Dose-related inhibition of PARP activity in PBMC's was observed. Response, reduction in neutrophils and platelets and the need for blood transfusions and dose reductions appear to correlate with BMN 673 exposure.


^3 breast cancer responses are not yet confirmed; *CBR: clinical benefit response; **CA19-9 normalized in 1 patient

Overall, the objective response (including CA-125) and clinical benefit response rates are for all BRCA patients are 60.4% and 81%, respectively.


Treatment is ongoing in 5 of 7 SCLC patients and 2 of 8 ES patients with no objective responses observed yet.


Conclusions: BMN 673 is well tolerated with high objective and clinical benefit response rates in heavily pre-treated ovarian and breast cancer pts with deleterious germline BRCA mutations. A phase 3 trial in metastatic breast cancer is underway.


Clinicaltrial.gov ID: NCT01286987




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Investigational PARP inhibitor promising in BRCA-related cancers


[ Back to EurekAlert! ]

PUBLIC RELEASE DATE:

22-Oct-2013



[


| E-mail

]


Share Share

Contact: Lauren Riley
lauren.riley@aacr.org
215-446-7155
American Association for Cancer Research






BOSTON An investigational new PARP inhibitor, BMN 673, is showing early responses in patients with heavily pretreated, advanced, BRCA-related cancers of the breast and ovary, according to phase I clinical trial results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.


When there is damage to DNA in human cells, two proteins, PARP 1 and 2, recruit proteins that can repair the damage associated with loss of BRCA proteins. Mutations in BRCA genes often result in inefficient repair of damaged DNA, which increases the risk for developing certain cancers, including cancers of the breast and ovary. Inhibiting PARP, therefore, prevents the repair of damaged DNA, leading to cell death. While some PARP inhibitors have been tested in various settings, none are approved to date.


"BMN 673 is the most potent PARP inhibitor in clinical development and has optimized pharmaceutical properties: it is well absorbed orally, has substantial single-agent antitumor activity, and has a long half-life allowing once-daily dosing," said Zev A. Wainberg, M.D., assistant professor of medicine at the Jonsson Comprehensive Cancer Center of the University of California Los Angeles School of Medicine. "The clinical data to date are promising and compare favorably with results from clinical trials with other PARP inhibitors. We observed high objective and clinical benefit response rates in BRCA-related breast and ovarian cancers at low, oral, once-daily doses.


"Based on this phase I study, we feel there's a good chance that patients with BRCA-related cancers who meet the study eligibility criteria will have disease control for a meaningful period of time with relatively few side effects. However, randomized trials are necessary to demonstrate whether this will translate into improvements in progression-free and overall survival relative to currently available therapies," said Wainberg.


He and colleagues conducted a phase I trial to evaluate the safety and efficacy of BMN 673 in a two-stage dose escalation/expansion study. So far, they have recruited 39 and 41 patients to the escalation phase and expansion phase, respectively. Patients were 18-82 years old, and they had undergone one to 13 prior therapies.


Fifty participants18 with breast cancer, 28 with ovarian cancer, three with pancreatic cancer, and one with prostate cancerhad BRCA mutations in their tumors. Wainberg reported that to date, among the patients with BRCA mutations in their tumors, 44 percent of those with ovarian cancer and 44 percent with breast cancer had an objective response. Overall, 82 percent of the ovarian cancer patients and 72 percent of the breast cancer patients had clinical benefit (measured by imaging data and/or CA 125 levels for ovarian cancers and by imaging data for breast cancers).


In patients being treated at the 1 mg dose recommended for future trials, 50 percent of the breast cancer patients with BRCA mutations had an objective response and 86 percent had clinical benefit. Of the three patients with pancreatic cancer, two have had stable disease.


Fewer than 20 percent of the patients had grade 3 adverse events including fatigue, anemia, neutropenia, and thrombocytopenia, and one patient had a grade 4 toxicity.


Given the high objective and clinical benefit response rates in breast cancer patients, the investigators have recently initiated a phase 3 trial in metastatic breast cancer with BRCA mutations, according to Wainberg.


Among those with BRCA-unrelated cancers recruited to the phase 1 trial, one of the seven currently evaluable patients with small-cell lung cancer (SCLC) has responded, according to Wainberg. This patient, whose tumor metastasized extensively, has an ongoing partial response, he explained. "A solid partial response in a patient with SCLC provides some optimism about finding indications other than BRCA-related tumors that will benefit from treatment with BMN 673," he said.


###

This study was sponsored by BioMarin Pharmaceutical. Wainberg has no conflicts of interest to declare.


The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).


This research will be presented at a press conference entitled "Guiding Treatment for BRAF- and BRCA-related Cancers" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Monday, Oct. 22 at 9 a.m. ET in room 202 of the Hynes Convention Center in Boston, Mass. Reporters who cannot attend in person may call in using the following numbers:


  • U.S./Canada (toll-free): 800-446-2782
  • International (toll): 847-413-3235

To interview Zev Wainberg, contact Shaun Mason at smason@mednet.ucla.edu or 310-206-2805. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.



About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org. Follow the AACR on Twitter: @AACR. Follow the AACR on Facebook: http://www.facebook.com/aacr.org.


About the National Cancer Institute

The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).


About the European Organisation for Research and Treatment of Cancer

The European Organisation for the Research and Treatment of Cancer (EORTC) brings together European cancer clinical research experts from all disciplines for trans-national collaboration. Both multinational and multidisciplinary, the EORTC Network comprises more than 2,500 collaborators from all disciplines involved in cancer treatment and research in more than 300 hospitals in over 30 countries. Through translational and clinical research, the EORTC offers an integrated approach to drug development, drug evaluation programs and medical practices.

EORTC Headquarters, a unique pan European clinical research infrastructure, is based in Brussels, Belgium, from where its various activities are coordinated and run. http://www.eortc.org


Abstract Number: C295

Presenter: Zev A. Wainberg, M.D.


Title: Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors


Authors: Zev A. Wainberg1, Johann S. de Bono2, Lida Mina3, Jasgit Sachdev4, Lauren Averett Byers5, Rashmi Chugh6, Charlie Zhang7, Joshua W. Henshaw7, Andrew Dorr7, John Glaspy1, Ramesh Ramanathan4. 1David Geffen School of Medicine at UCLA, Los Angeles, CA; 2The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; 3Indiana University, Indianapolis, IN; 4Virginia G. Piper Cancer Center at Scottsdale Healthcare/Tgen, Scottsdale, AZ; 5University of Texas MD Anderson Cancer Center, Houston, TX; 6University of Michigan, Ann Arbor, MI; 7BioMarin Pharmaceutical, Novato, CA

Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage escalation/expansion study. Expansion included cohorts of pts with BRCA-related cancers, small cell lung cancer (SCLC) and Ewing sarcoma (ES).

Results: (As of July 29, 2013) In escalation, 39 pts were enrolled in 9 cohorts from 25 to 1100 g/d with 1000 g/d being the MTD related to dose-limiting hematologic toxicity. 38 pts have been enrolled in expansion including 25 patients with BRCA related cancers. For all 77 (63F/14M) pts, median age (range) is 52 (18-81), PS, 0 (0-1) and # of prior therapies 4 (1-13). Eight ES, 7 SCLC and 48 patients with deleterious BRCA mutations and breast (n=18), ovarian (n=28) or pancreatic (n=2) cancer were enrolled. BMN 673 demonstrated good oral bioavailability and a long half-life supporting daily dosing (ASCO 2013 Abstract 2580). One related grade 4 toxicity (thrombocytopenia) occurred. Related grade 3 adverse events have included fatigue, anemia, neutropenia and thrombocytopenia, all in fewer than 15% of patients. Dose-related inhibition of PARP activity in PBMC's was observed. Response, reduction in neutrophils and platelets and the need for blood transfusions and dose reductions appear to correlate with BMN 673 exposure.


^3 breast cancer responses are not yet confirmed; *CBR: clinical benefit response; **CA19-9 normalized in 1 patient

Overall, the objective response (including CA-125) and clinical benefit response rates are for all BRCA patients are 60.4% and 81%, respectively.


Treatment is ongoing in 5 of 7 SCLC patients and 2 of 8 ES patients with no objective responses observed yet.


Conclusions: BMN 673 is well tolerated with high objective and clinical benefit response rates in heavily pre-treated ovarian and breast cancer pts with deleterious germline BRCA mutations. A phase 3 trial in metastatic breast cancer is underway.


Clinicaltrial.gov ID: NCT01286987




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]

 


AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.




Source: http://www.eurekalert.org/pub_releases/2013-10/aafc-ipi101513.php
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