Liu G.,Experimental Therapeutics |
Liu G.,Tianjin Medical University |
Yang D.,Experimental Therapeutics |
Rupaimoole R.,University of Houston |
And 21 more authors.
Journal of the National Cancer Institute | Year: 2015
Background: Chemoresistance is a major challenge in cancer treatment. miR-506 is a potent inhibitor of the epithelial-to-mesenchymal transition (EMT), which is also associated with chemoresistance. We characterized the role of miR-506 in chemotherapy response in high-grade serous ovarian cancers. Methods: We used Kaplan-Meier and log-rank methods to analyze the relationship between miR-506 and progression-free and overall survival in The Cancer Genome Atlas (TCGA) (n = 468) and Bagnoli (n = 130) datasets, in vitro experiments to study whether miR-506 is associated with homologous recombination, and response to chemotherapy agents. We used an orthotopic ovarian cancer mouse model (n = 10 per group) to test the effect of miR-506 on cisplatin and PARP inhibitor sensitivity. All statistical tests were two-sided. Results: MiR-506 was associated with better response to therapy and longer progression-free and overall survival in two independent epithelial ovarian cancer patient cohorts (PFS: high vs low miR-506 expression; Bagnoli: hazard ratio [HR] = 3.06, 95% confidence interval [CI] = 1.90 to 4.70, P <. 0001; TCGA: HR = 1.49, 95% CI = 1.00 to 2.25, P = 0.04). MiR-506 sensitized cells to DNA damage through directly targeting the double-strand DNA damage repair gene RAD51. Systemic delivery of miR-506 in 8-12 week old female athymic nude mice statistically significantly augmented the cisplatin and olaparib response (mean tumor weight ± SD, control miRNA plus cisplatin vs miR-506 plus cisplatin: 0.36±0.05g vs 0.07±0.02g, P <. 001; control miRNA plus olaparib vs miR-506 plus olaparib: 0.32±0.13g vs 0.05±0.02g, P =. 045, respectively), thus recapitulating the clinical observation. Conclusions: MiR-506 is a robust clinical marker for chemotherapy response and survival in serous ovarian cancers and has important therapeutic value in sensitizing cancer cells to chemotherapy. © 2015 The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: email@example.com.
ADDING MULTIMEDIA and CONFERENCE CALL DETAILS Clovis Oncology Announces FDA Accelerated Approval of RUBRACATM rucaparib for the Monotherapy Treatment of Advanced Ovarian Cancer in Women with Deleterious Germline or Somatic BRCA Mutations...
News Article | December 19, 2016
CLOVIS ONCOLOGY ANNOUNCES FDA ACCELERATED APPROVAL OF RUBRACA™ (RUCAPARIB) FOR THE MONOTHERAPY TREATMENT OF ADVANCED OVARIAN CANCER IN WOMEN WITH DELETERIOUS GERMLINE OR SOMATIC BRCA MUTATIONS TREATED WITH TWO OR MORE CHEMOTHERAPIES Clovis Oncology, Inc. (NASDAQ:CLVS) today announced that the U.S. Food and Drug Administration (FDA) has approved Rubraca™ (rucaparib) tablets as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer, who have been treated with two or more chemotherapies, and selected for therapy based on an FDA-approved companion diagnostic for Rubraca. Rubraca’s indication is approved under the FDA’s accelerated approval program, and is based on objective response rate and duration of response results from two multicenter, single-arm, open-label clinical trials, Study 10 and ARIEL2 Parts 1 and 2. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The ARIEL3 maintenance confirmatory study has completed enrollment and the ARIEL4 treatment confirmatory study is open for enrollment. Warning and precautions include Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). Please see additional warnings and precautions and Select Important Safety Information below. “Recurrent ovarian cancer remains one of the most difficult cancers to treat and for so many years, medical advances in this space have been limited,” said Robert L. Coleman, MD, Professor & Deputy Chairman, Vice Chair, Clinical Research, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Cancer Center in Houston and one of the Principal Investigators in the ARIEL clinical trial program. “Today’s approval of Rubraca for the treatment of advanced ovarian cancer demonstrates the value of treatment with PARP inhibitors and represents an important advance for women diagnosed with either germline or somatic BRCA-mutated tumors who have been treated with two or more chemotherapies.” “We believe that today’s approval of Rubraca provides an important new therapy for advanced ovarian cancer patients with a germline or somatic mutation of BRCA after two or more chemotherapies,” said Patrick J. Mahaffy, CEO and President of Clovis Oncology. “We look forward to launching Rubraca with the support of our established U.S. commercial and medical affairs organizations and bringing this much-needed precision medicine to women with advanced ovarian cancer as quickly as possible.” "NOCC commends Clovis Oncology for its commitment to bringing a new treatment option to women living with ovarian cancer, the deadliest cancer of the female reproductive system. All too often, women are diagnosed when the disease is far advanced, leaving them with few viable treatment options,” said David Barley, Chief Executive Officer, National Ovarian Cancer Coalition. “The development and FDA approval of therapies for use in third-line is a promising step forward for the tens of thousands of women who will battle ovarian cancer in their lifetime." “Ovarian cancer is one of the most difficult cancers to detect. For this reason, most women who develop ovarian cancer are diagnosed with advanced disease," said Sue Friedman, DVM, Executive Director of Facing Our Risk of Cancer Empowered. "There is a tremendous need for new ways to treat women with advanced ovarian cancer and ways to find those women who will respond to therapies such as PARP inhibitors. PARP inhibitors, like Rubraca, represent an exciting advancement for appropriate patients." The Rubraca NDA filing received Priority Review and was reviewed and approved under FDA’s Accelerated Approval program. These programs allow for earlier approval of drugs that treat serious conditions and that fill an unmet medical need. The application was based on objective response rate and duration of response results from two multicenter, single-arm, open-label clinical trials, Study 1 (Study 10, NCT01482715) and Study 2 (ARIEL2 Parts 1 and 2, NCT01891344), in women with advanced BRCA-mutant ovarian cancer who had progressed after two or more prior chemotherapies. All 106 patients received Rubraca orally 600 mg twice daily as monotherapy until disease progression or unacceptable toxicity. Objective response rate (ORR) and duration of response (DOR) were assessed by the investigator and independent radiology review (IRR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Clovis partnered with Foundation Medicine, Inc. to co-develop a companion diagnostic test, the FDA approved FoundationFocusTM CDx , to select patients for Rubraca treatment. FoundationFocus CDx is a tissue-based, genomic assay that detects tumor BRCA1 and BRCA2 mutations (germline and/or somatic) in ovarian cancer. Efficacy and safety results from the U.S. Prescribing Information are summarized below: Overall Response and Duration of Response in Patients with BRCA-mutant Ovarian Cancer Who Received 2 or More Chemotherapies in Study 1 and Study 2 Response assessment by IRR was 42% (95% CI: 32, 52), with a median DOR of 6.7 months (95% CI: 5.5, 11.1). Investigator-assessed ORR was 66% (52/79; 95% CI: 54, 76) in platinum-sensitive patients, 25% (5/20; 95% CI: 9, 49) in platinum-resistant patients, and 0% (0/7; 95% CI: 0, 41) in platinum-refractory patients. ORR was similar for patients with a BRCA1 gene mutation or BRCA2 gene mutation. The overall safety evaluation of Rubraca 600 mg twice daily as monotherapy is based on data from 377 patients with ovarian cancer treated in two open-label, single arm trials. The most common adverse reactions (≥ 20% of patients; Grade 1-4) were nausea, asthenia/fatigue, vomiting, anemia, constipation, dysgeusia, decreased appetite, diarrhea, abdominal pain, thrombocytopenia and dyspnea. The most common laboratory abnormalities (≥ 35% of patients; Grade 1-4) were increase in creatinine, increase in ALT, increase in AST, decrease in hemoglobin, decrease in lymphocytes, increase in cholesterol, decrease in platelets and decrease in absolute neutrophil count. Rubraca will be available in the United States immediately. For those who are eligible, Clovis Oncology plans to offer programs through Rubraca Connections to support patients taking Rubraca. More information about Rubraca Connections is available at RubracaConnections.com or by calling 1-844-779-7707 between 8 am and 8 pm Eastern, Monday through Friday. Rubraca is a PARP inhibitor indicated as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer, who have been treated with two or more chemotherapies, and selected for therapy based on an FDA-approved companion diagnostic for Rubraca. Rubraca’s indication is approved under the FDA’s accelerated approval program based on objective response rate and duration of response, and is based on results from two multicenter, single-arm, open-label clinical trials. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. There are no contraindications with Rubraca. Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) was reported in 2 of 377 (0.5%) patients with ovarian cancer treated with Rubraca. The duration of Rubraca treatment prior to the diagnosis of MDS/AML was 57 days and 539 days. Both patients received prior treatment with platinum and other DNA damaging agents. AML was reported in 2 (<1%) patients with ovarian cancer enrolled in ARIEL3, a blinded, randomized trial evaluating Rubraca versus placebo. One case of AML was fatal. The duration of treatment prior to the diagnosis of AML was 107 days and 427 days. Both patients had received prior treatment with platinum and other DNA damaging agents. Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood count testing at baseline and monthly thereafter. For prolonged hematological toxicities, interrupt Rubraca and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca. Rubraca can cause fetal harm when administered to pregnant women based on its mechanism of action and findings from animal studies. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca. Most common adverse reactions (≥ 20%; Grade 1-4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%), and thrombocytopenia (21%). Most common laboratory abnormalities (≥ 35%; Grade 1-4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%), and decrease in absolute neutrophil count (35%). Because of the potential for serious adverse reactions in breast-fed infants from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the final dose. Please see the U.S. Prescribing Information for full safety and efficacy or visit www.Rubraca.com for more information. Clovis will hold an investor/analyst conference call to discuss the Rubraca approval this afternoon, Monday, December 19, at 4:15pm ET. The conference call will be simultaneously webcast on the Company’s web site at www.clovisoncology.com, and archived for future review. Dial-in numbers for the conference call are as follows: US participants 866.489.9022, International participants 678.509.7575, conference ID: 42678403. Clovis Oncology, Inc. is a biopharmaceutical company focused on acquiring, developing and commercializing innovative anti-cancer agents in the U.S., Europe and additional international markets. Clovis Oncology targets development programs at specific subsets of cancer populations, and simultaneously develops diagnostic tools that direct a compound in development to the population that is most likely to benefit from its use. Clovis Oncology is headquartered in Boulder, Colorado. This press release contains forward-looking statements (as defined under the Private Securities Litigation Reform Act of 1995) about the potential of RubracaTM (rucaparib) as a treatment for BRCA-mutated advanced ovarian cancer after two or more prior chemotherapies, and reflects Clovis Oncology’s current beliefs. As with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization that could cause actual results to differ materially from those expressed or implied by the forward-looking statements. In particular, there are no guarantees that future study results and patient experience will be consistent with the study findings to date, that Rubraca will receive regulatory approval for any future indications, or that it will prove to be commercially successful. A further description of risks and uncertainties can be found in Clovis Oncology’s filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K and its reports on Form 10-Q and Form 8-K. All forward-looking statements are based on information currently available to the company, and Clovis Oncology does not undertake to update or revise any forward-looking statements.
News Article | February 21, 2017
For women with a rare subtype of epithelial ovarian or peritoneum cancer, known as low-grade serous carcinoma (LGSC), hormone maintenance therapy (HMT) may significantly improve survival, according to a new study from researchers at The University of Texas MD Anderson Cancer Center. The research is published in the Journal of Clinical Oncology and has been updated since it was first presented at the 2016 Annual Meeting of the American Society of Clinical Oncology. According to the researchers, LGSC accounts for just 10 percent of serous carcinomas of the ovary/peritoneum. It is typically diagnosed in women, as early as in their 40s and 50s (however, teenagers and women in their 20s and 30s also may be diagnosed). Patients usually present with advanced disease. MD Anderson has a long history of discovery in this field of rare ovarian cancer -- publishing a study in 2004 that changed the way serous carcinomas were graded and thereby identifying LGSC. MD Anderson research also showed that LGSC is relatively chemo-resistant compared with high-grade serous carcinoma, said David M. Gershenson, M.D., professor, Gynecologic Oncology and Reproductive Medicine. Should this new retrospective data be validated in a randomized study, the findings could one day represent a significant improvement to frontline standard of care. "There is a true unmet need for these patients -- roughly 70 percent of women with this disease will experience a recurrence of the cancer at some point," said Gershenson, the study's corresponding author. "Our group published research demonstrating that hormonal therapy showed promise in the recurrent setting, with most patients responding or having stable disease. It was a natural progression over time that we began to study this up front, after women received their primary chemotherapy." In this retrospective cohort study, researchers analyzed data from 203 women with Stage II-IV LGSC treated at MD Anderson between 1981 and 2013 to evaluate the effect of HMT, compared with surveillance, after surgery and chemotherapy. Women who received HMT (70 patients) showed an average progression-free survival (PFS) of 64.9 months compared with 26.4 months for those in the surveillance group (133 patients). Overall survival (OS) was 115.7 months following HMT, versus 102.7 months for the surveillance group. Further, among 149 women who showed no evidence of disease following completion of primary chemotherapy, HMT appears to have resulted in even greater survival: 81.1 vs. 30 months PFS; and 191.3 vs.106.8 months OS. "Hormonal therapy has shown promising results in reducing cancer recurrence, and there is increasing interest in integrating this approach into first-line therapy," said Gershenson. "If confirmatory research in a clinical trial setting shows hormonal maintenance therapy can prevent or delay recurrence of this cancer subtype, it would be practice changing." Though recruitment for this patient population is challenging given the rarity of the disease, Gershenson noted that a prospective international Phase III clinical trial has been designed. The study will compare: chemotherapy and observation; chemotherapy and HMT; and hormonal therapy alone, which also has shown early promise in other studies. In addition to Gershenson, authors on the all-MD Anderson study include: Diane Bodurka, M.D., Robert L. Coleman, M.D., Karen H. Lu, M.D., chair; and Charlotte Sun, all of the Department of Gynecologic Oncology and Reproductive Medicine; and Anais Malpica, M.D., of Pathology. The study was supported by the Sara Brown Musselman Fund for Serous Ovarian Cancer Research and the MD Anderson Cancer Center Support Grant from the National Cancer Institute (No. P30 CA016672).
Hou M.-M.,University of Houston |
Hou M.-M.,Chang Gung University |
Liu X.,University of Houston |
Wheler J.,University of Houston |
And 12 more authors.
Anticancer Research | Year: 2014
Background: We evaluated clinical outcomes of patients with metastatic cervical cancer referred to a Phase I Clinical Trials Program. Patients and Methods: We reviewed the electronic medical records of 54 consecutive phase I patients with metastatic cervical cancer over 6.5 years and analyzed the correlation between clinical outcome and potential predictors. Results: All patients had received at least one systemic therapy for metastatic disease before referral. Only two patients declined phase I trial therapy. The median progression-free (PFS) and overall (OS) survivals were 3.6 and 10.6 months, respectively. Patients harboring phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations or phosphatase and tensin homolog loss, and those with more than two sites of metastasis who received more than one prior systemic chemotherapy before the referral had median PFS of 6.7 and 1.8 months, and median OS of 12.6 and 2.9 months, respectively. Conclusion: Patients with more than two metastatic sites who had received more than one prior system therapy had dismal outcomes. An aberrant PI3K pathway was frequently identified and associated with favorable outcome, providing a promising target.
Okoye E.I.,Houston Methodist Hospital |
Bruegl A.S.,Gynecologic Oncology and Reproductive Medicine |
Fellman B.,Biostatistics |
Luthra R.,University of Texas |
Broaddus R.R.,Houston Methodist Hospital
International Journal of Gynecological Pathology | Year: 2016
Endometrial endometrioid carcinomas are related to estrogen excess and express estrogen and progesterone receptors. However, hormone receptor expression can be variable from tumor to tumor, and this variability is not always explained by differences in tumor grade. Variable expression of other biomarkers that may be used in the diagnostic work-up of endometrial cancer has also been noted. We hypothesized that mismatch repair (MMR) defects may contribute to this variability. A total of 411 unselected endometrial carcinomas were evaluated for immunohistochemical expression of DNA MMR proteins and MLH1 methylation. Loss of immunohistochemical expression of MLH1, MSH2, MSH6, or PMS2 was defined as MMR deficient; positive expression was defined as MMR intact. A case-control cohort of 80 Grade 2 endometrioid carcinomas was selected from this set (40 MMR deficient, 40 MMR intact). Cases were matched for histotype, grade, and age. Estrogen receptor, progesterone receptor, CK7, CK20, and Pax-8 immunohistochemistry was evaluated. The median percentage of CK7 + tumor cells was significantly lower in the MMR deficient group compared with the MMR intact group. The mean percentage of tumor cells exhibiting estrogen receptor expression was similar in both the MMR-deficient and MMR intact groups. However, there was greater variability in the MMR-deficient group. Our study shows that MMR defects influence the expression of clinically important biomarkers for endometrioid-type endometrial carcinoma as decreased cytokeratin 7 expression is more commonly associated with MMR deficiency. © 2015 International Society of Gynecological Pathologists.