On June 6, 2016 GlycoMimetics, Inc. (NASDAQ:GLYC) reported dosing of the first patient with relapsed/refractory acute myeloid leukemia in the Phase 2 portion of its ongoing Phase 1/2 clinical trial evaluating its novel E-selectin antagonist, GMI-1271, combined with induction chemotherapy (Press release, GlycoMimetics, JUN 6, 2016, View Source [SID:1234513101]).

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For the study’s Phase 2 portion, the optimal dose has been determined, and clinical investigators will expand the number of patients receiving GMI-1271 to obtain additional safety and efficacy data. Study enrollment is limited to patients at least 18 years old with relapsed or refractory AML and who would be treated with mitoxantrone, etoposide, and cytarabine (‘MEC’). All patients must be eligible to receive this chemotherapy regimen, and will be given GMI-1271 in addition to this combination chemotherapy. During the Phase 1 portion of the study, patients received a single cycle of treatment including GMI-1271. During this Phase 2 portion, certain patients will be eligible to receive an additional cycle of treatment.

"The data from the first cohorts point to both the safety and potential efficacy of GMI-1271 as a treatment for AML," said Helen Thackray, M.D., Chief Medical Officer of GlycoMimetics. "In the second half of this trial, we will further assess if patients with relapsed or refractory AML respond well to this combination approach while also including those who have been newly diagnosed with the disease in a separate arm of the study. If the second half confirms our earlier preclinical and clinical findings, we believe that GMI-1271 could well address the unmet needs of AML patients, beyond what can be done with currently available therapies."

This clinical trial is a multinational open-label study evaluating endpoints for safety, pharmacokinetics (PK) and efficacy of GMI-1271 in combination with induction chemotherapy in patients with high-risk AML. This trial is being conducted at a number of academic medical institutions in the United States, Ireland, and Australia. While the primary objective is to assess safety, additional endpoints include overall response rate, biomarkers of activity, durability of response and overall survival. This Phase 2 portion of the study is expected to include approximately 25 participants.

About GMI-1271

GMI-1271 is designed to block E-selectin (an adhesion molecule on cells in the bone marrow) from binding with AML cells as a targeted approach to disrupting well-established mechanisms of leukemic cell resistance within the bone marrow microenvironment. Preclinical research points to the drug’s potential role in moving cancerous cells out of the protective environment of the bone marrow where they hide and escape the effects of chemotherapy. In preclinical studies using animal models of AML, the results of which were presented at meetings of the American Society of Hematology (ASH) (Free ASH Whitepaper), GMI-1271 was also associated with a reduction of chemotherapy-induced neutropenia and chemotherapy-induced mucositis.

On June 6, 2016 Celator Pharmaceuticals, Inc. (Nasdaq: CPXX) reported results from its Phase 3 trial of VYXEOS (cytarabine: daunorubicin) Liposome for Injection (also known as CPX-351) in patients with high-risk (secondary) acute myeloid leukemia (AML) were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2016 Annual Meeting (Press release, Celator Pharmaceuticals, JUN 6, 2016, View Source [SID:1234513035]). As previously reported, the trial met its primary endpoint demonstrating a statistically significant improvement in overall survival. The Phase 3 trial compared to the standard of care regimen of cytarabine and daunorubicin known as 7+3.

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The median overall survival for patients treated with VYXEOS in the study was 9.56 months compared to 5.95 months for patients receiving 7+3, representing a 3.61 month improvement in favor of VYXEOS. The hazard ratio (HR) was 0.69 (p=0.005) which represents a 31% reduction in the risk of death versus 7+3. The percentage of patients alive 12 months after randomization was 41.5% on the VYXEOS arm compared to 27.6% on the 7+3 arm. The percentage of patients alive 24 months after randomization was 31.1% on the VYXEOS arm compared to 12.3% on the 7+3 arm.

Event-free survival was also statistically significant in favor of VYXEOS. The HR was 0.74 (p-value=0.021). The median event-free survival was 2.53 months in the VYXEOS arm compared to 1.31 months in the 7+3 arm.

"We believe the promising primary efficacy results of CPX-351 in high risk AML, across multiple parameters, support its use as the new standard of care in a difficult-to-treat population," said Jeffrey E. Lancet, M.D., senior member and chief of the Leukemia/Myelodysplasia Program at Moffitt Cancer Center and the principal investigator for the study. "This is an important step forward in the treatment of a terrible disease, and hopefully this platform for synergistic drug delivery will continue to advance the field."

VYXEOS also demonstrated a statistically significant improvement in induction response rate (CR+CRi of 47.7% versus 33.3%; p=0.016) and this significance was maintained for the analysis of CR alone (CR of 37.3% versus 25.6%, p=0.040).

Thirty-four percent of VYXEOS treated patients received a stem cell transplant (SCT) compared to 25% of 7+3 treated patients. In a landmark survival analysis of patients receiving a SCT, VYXEOS patients had significantly improved survival post-transplant (HR was 0.46 (p-value=0.0046)). The median overall survival had not been reached in the VYXEOS treated patients compared to 10.25 months in the 7+3 treated patients.

Thirty-day and sixty-day all-cause mortality favored VYXEOS. Thirty-day mortality was 5.9% compared to 10.6% and sixty-day mortality was 13.7% versus 21.2%.

Grade 3-5 non-hematologic and hematologic adverse events were similar between the VYXEOS and 7+3 arms.

The company expects to submit a New Drug Application (NDA) for VYXEOS with the U.S. Food and Drug Administration (FDA) by the end of the third quarter of 2016 and submit a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) in the first quarter of 2017.

"We are very pleased to have this opportunity to share the data from our Phase 3 trial with the oncology community. This successful outcome represents an important advance for AML patients, their families and clinicians," said Scott Jackson, Chief Executive Officer of Celator Pharmaceuticals. "We thank the patients and investigators who participated in this study and we will work closely with regulatory authorities to make this new treatment available to the AML community as soon as possible."

The clinical trial was conducted in partnership with The Leukemia & Lymphoma Society (LLS) through its Therapy Acceleration Program (TAP), which has supported the clinical development of VYXEOS beginning in Phase 2.

Phase 3 Trial Design

The randomized, controlled, Phase 3 trial (Protocol NCT01696084), enrolled 309 patients at 39 sites in the United States and Canada, and compared VYXEOS to the conventional cytarabine and daunorubicin treatment regimen (commonly referred to as 7+3) as first-line therapy in older (60-75 years of age) patients with high-risk (secondary) AML. Patients were stratified for age (60 to 69 and 70 to 75 years of age) and AML type; treatment-related AML, AML with documented history of myelodysplastic syndrome (MDS) with prior treatment with hypomethylating agent therapy, AML with documented history of MDS without prior hypomethlyating agent therapy, AML with a documented history of chronic myelomonocytic leukemia (CMMoL), and de novo AML with a karyotype characteristic of MDS.

Patients were randomized 1:1 to receive either VYXEOS or 7+3. Patients could receive one or two inductions, and responding patients could receive one or two consolidations. First induction for VYXEOS was 100u/m2; days 1, 3, and 5 by 90-minute infusion and for the control arm was cytarabine 100mg/m2/day by continuous infusion for 7 days and daunorubicin 60mg/m2 on days 1, 2, and 3 (7+3). Second induction for VYXEOS-treated patients was 100u/m2 on days 1 and 3, and the control arm was cytarabine 100mg/m2/day by continuous infusion for 5 days and daunorubicin 60mg/m2 on days 1 and 2 (5+2).

Only patients with documented CR or CRi were eligible to receive chemotherapy consolidation. Consolidation for VYXEOS-treated patients was 65u/m2 on days 1 and 3 and the control arm was cytarabine 100mg/m2/day by continuous infusion for 5 days and daunorubicin 60mg/m2 on days 1 and 2 (5+2).

About VYXEOS

VYXEOS (cytarabine:daunorubicin) Liposome for Injection, also known as CPX-351, is a nano-scale co-formulation of cytarabine and daunorubicin at a synergistic 5:1 molar ration. VYXEOS represents a novel approach to developing combinations of drugs in which molar ratios of two drugs with synergistic anti-tumor activity are encapsulated in a nano-scale liposome in order to maintain the desired ratio following administration. The FDA granted Breakthrough Therapy designation to VYXEOS for the treatment of adults with therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). VYXEOS was granted orphan drug status for the treatment of AML by the FDA and the European Commission. VYXEOS was also granted Fast Track designation for the treatment of elderly patients with secondary AML by the FDA.

About AML

Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood characterized by the uncontrolled proliferation of immature blast cells in the bone marrow. AML is generally a disease of older adults, and the median age of a patient diagnosed with AML is about 67 years. The American Cancer Society estimates that there will be 19,950 new cases of AML and 10,430 deaths from AML in the U.S. in 2016. In Europe the number of new cases is estimated to be 18,000 and in Japan the number is 5,500. The Company estimates that nearly 70 percent of AML patients are over the age of 60, and approximately 75% are intermediate or high risk. Furthermore, approximately half of those patients are considered suitable for intensive treatment.

Even with current treatment, overall survival for AML is poor. In patients over 60 years of age, the 5 year survival rate is less than 10%. In high-risk (secondary) AML, overall survival is lower, resulting in an acute need for new treatment options for these patients.

On June 6, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported longer-term follow-up results from Phase 3 studies of IMBRUVICA (ibrutinib) in chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) (Press release, AbbVie, JUN 6, 2016, View Source [SID:1234513058]). Findings include an analysis of outcomes from the RESONATETM (PCYC-1112) and RESONATETM-2 (PCYC-1115) trials, which showed IMBRUVICA was associated with favorable progression-free survival (PFS) and overall survival (OS) regardless of line of therapy (previously treated or treatment-naïve; abstract 7520). Other data include first-ever presentation of longer-term follow-up data from the HELIOS (CLL3001) trial showing IMBRUVICA in combination with bendamustine and rituximab (BR) continued to demonstrate superiority over time versus placebo plus BR in relapsed/refractory CLL/SLL patients (abstract 7525), along with improvements in quality of response.

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These data showcasing additional clinical evidence of IMBRUVICA in CLL/SLL will be presented today in a poster session at the Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago from 8:00 – 11:30 a.m. CDT. The RESONATE and RESONATE-2 analysis will also be featured as a poster discussion today from 1:15 – 2:45 p.m. CDT. IMBRUVICA is jointly developed and commercialized in the U.S. by Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc.

"Our clinical data presented at this year’s ASCO (Free ASCO Whitepaper) from several randomized studies demonstrate solid durability of response with IMBRUVICA in patients with CLL/SLL with additional follow-up of up to three years," said Danelle James, M.D., M.S., Head of Oncology at Pharmacyclics. "This evidence of deepening responses with continued therapy and long-term survival with IMBRUVICA over time, used either as a single agent or in combination, positions this therapy as a potentially beneficial treatment option for a variety of patients with CLL or SLL, regardless of when it is prescribed in the treatment journey."

An analysis of the RESONATE and RESONATE-2 trials showed IMBRUVICA was associated with favorable PFS and OS outcomes, as well as a high overall response rate (ORR) in previously treated and treatment-naïve patients with CLL/SLL, regardless of line of therapy. The median PFS and OS were not reached in treatment-naïve or previously-treated patients; 89-92% of patients treated with ibrutinib at first or second line of therapy remained progression-free at two years. Additionally, ORR was high in both previously treated and treatment-naïve patients (92% and 91%, respectively). The safety profile was similar for both patient groups1 and was consistent with previously-reported outcomes. Data from the RESONATE and RESONATE-2 studies served as the basis for the 2014 and 2016 FDA approvals of IMBRUVICA for patients with CLL/SLL.

The most commonly occurring adverse reactions (? 20%) in studies that supported the FDA approvals for patients with CLL/SLL were neutropenia, thrombocytopenia, anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, pyrexia and hemorrhage. Four to 10% of patients receiving IMBRUVICA discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each). Adverse reactions leading to dose reduction occurred in approximately 6% of patients.

Additionally, after a median follow-up of 25.4 months, data from the HELIOS trial showed the combination of IMBRUVICA plus BR continued to demonstrate a significant improvement in investigator-assessed PFS (the primary endpoint) (74.8%) versus placebo plus BR (20.9%) in patients with relapsed/refractory CLL/SLL (median not reached versus 14.2 months, respectively; HR [95% CI]: 0.199 [0.15, 0.26], P<0.0001). The updated investigator-assessed ORR for IMBRUVICA plus BR was 87.2%, as compared with 66.1% for placebo plus BR (P<0.0001) and the rate of complete responses (CRs) and CRs with incomplete bone marrow recovery (CRi) improved in the IMBRUVICA plus BR arm (33.9% versus 7.2% in the placebo plus BR arm). OS was not reached in either arm (HR [95% CI]: 0.670 [0.44, 1.02], P=0.587). Safety was consistent with the first analysis.2 Notably, positive results from the initial analysis (median follow-up: 17 months) supported the May 2016 update to the IMBRUVICA U.S. Prescribing Information.

The prevalence of CLL is approximately 115,000 patients in the U.S.3 with approximately 15,000 newly diagnosed patients every year.4 SLL is a slow-growing lymphoma biologically similar to CLL in which too many immature white blood cells cause lymph nodes to become larger than normal.5 CLL and SLL are predominately diseases of the elderly, with a median age of 71 at diagnosis.3

About the RESONATE Study
RESONATE is a Pharmacyclics-sponsored randomized, multi-center, open-label, international Phase 3 study that examined ibrutinib versus ofatumumab in relapsed/refractory patients with CLL/SLL who had received at least one prior therapy and were not considered appropriate candidates for treatment with a purine analog (n=391). Patients were administered either 420 mg oral ibrutinib (n=195) once-daily until progression or unacceptable toxicity or intravenous ofatumumab for up to 24 weeks (n=196, initial dose of 300 mg followed by 11 doses at 2,000 mg per dose and schedule consistent with local labeling). The study met its primary endpoint, demonstrating improved PFS.

Results from RESONATE were featured in the official press program at ASCO (Free ASCO Whitepaper) in Chicago in June 2014 and simultaneously published in The New England Journal of Medicine.

About the RESONATE-2 Study
RESONATE-2 is a Pharmacyclics-sponsored, randomized, multi-center, open-label, Phase 3 study which enrolled 269 treatment-naïve patients with CLL/SLL aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive either IMBRUVICA 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg. The study met its primary endpoint, demonstrating improved PFS, as assessed by an independent review committee (IRC).

Results from RESONATE-2 were first presented in an oral session at the American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in Orlando, FL in December 2015 and simultaneously published in The New England Journal of Medicine. The results were also part of the official press program at ASH (Free ASH Whitepaper) 2015.

About the HELIOS Study
HELIOS is a Janssen-sponsored, randomized, multi-center, double-blind, placebo-controlled, Phase 3 study which enrolled 578 CLL/SLL patients who had received at least one prior systemic therapy. Patients were randomized to receive IMBRUVICA or placebo, once daily continuing until disease progression or unacceptable toxicity with six cycles of BR. The study met its primary endpoint, demonstrating improved IRC assessed PFS.

Data from an interim analysis of HELIOS were first presented during the official press program at ASCO (Free ASCO Whitepaper) in Chicago in May 2015. The results were also published in The Lancet Oncology in December 2015.

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK).6 BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.7 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably. 7

IMBRUVICA is approved to treat patients with CLL/SLL, patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.7

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers. More than 6,000 patients have been treated with IMBRUVICA in clinical trials. Currently, 14 Phase 3 trials have been initiated with IMBRUVICA and more than 90 trials are registered on www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.

Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension – Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies – Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).

Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS

The most common adverse reactions (?20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia* (64%), thrombocytopenia* (63%), diarrhea (43%), anemia* (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia (21%).

*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

The most common Grade 3 or 4 non-hematologic adverse reactions (?5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

Please see Full Prescribing Information: View Source

On June 6, 2016 Stemline Therapeutics, Inc. (Nasdaq:STML) reported that Ivan Bergstein, M.D., Stemline’s CEO, will present at the Jefferies 2016 Healthcare Conference on Wednesday, June 8, 2016 at 10:00 AM ET (Press release, Stemline Therapeutics, JUN 6, 2016, View Source [SID:1234513078]). During the presentation, Dr. Bergstein will discuss the SL-401 Phase 2 blastic plasmacytoid dendritic cell neoplasm (BPDCN) data presented on June 4th at the 2016 ASCO (Free ASCO Whitepaper) conference. He will also review next steps for the SL-401 program as well as provide updates on the company’s overall pipeline. A live webcast of the presentation can be viewed on the company’s website at www.stemline.com.

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On June 6, 2016 Clovis Oncology (NASDAQ:CLVS) reported updated phase 2 results from Part 1 of the ongoing ARIEL2 study in patients with advanced ovarian cancer as well as the final results of the RUCAPANC study of rucaparib in pancreatic cancer at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Clovis Oncology, JUN 6, 2016, View Source;p=RssLanding&cat=news&id=2175294 [SID:1234513036]). Rucaparib is the Company’s oral, potent, small molecule inhibitor of PARP1, PARP2 and PARP3 currently being developed for the treatment of ovarian cancer, specifically in patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA, including those with high genomic loss of heterozygosity (LOH) also known as "BRCA-like."

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"We are pleased to present our mature dataset from Part 1 of the ARIEL2 study for rucaparib in ovarian cancer at ASCO (Free ASCO Whitepaper), which demonstrates its encouraging clinical activity in selected patients and its potential in the treatment of advanced ovarian cancer," said Patrick J. Mahaffy, CEO and President of Clovis Oncology. "We are also encouraged by the results of the RUCAPANC study of rucaparib in advanced pancreatic cancer patients with mutations of BRCA, and look forward to exploring rucaparib in additional tumor types in which mutations in BRCA and other DNA repair deficiencies play a significant role."

Study objectives of the global, two-part single-arm open-label ARIEL2 trial in patients with advanced ovarian cancer include determining rucaparib activity in prospectively defined molecular subgroups through the assessment of progression-free survival (PFS) in patients with tumors that have germline and somatic BRCA mutations, those with a BRCA-like signature (patients whose tumors have other DNA repair deficiencies, including those with high genomic LOH but with normal BRCA genes (BRCAwt/LOHhigh)), and patients whose tumors are biomarker negative (those with low genomic LOH, or BRCAwt/LOHlow). Objective response rate (ORR), safety and pharmacokinetics were also analyzed. Patients in ARIEL2 were treated with the recommended phase 2 dose (RP2D) of 600mg twice daily (BID). ARIEL2 Part 1 was initiated in October 2013 and completed enrollment in 2014. At the data cutoff date of January 18, 2016, 28 of the 204 patients enrolled in ARIEL2 Part 1 remained on study. These patients were required to be platinum-sensitive for enrollment and received a median of one prior treatment regimen and a median of one prior platinum-based chemotherapy regimen. Enrollment continues for ARIEL2 Part 2, which expanded the ARIEL2 study in early 2015 into up to 300 additional patients with recurrent disease after at least three prior lines of chemotherapy. Enrollment into ARIEL2 Part 2 is not limited to platinum-sensitive disease, but also includes patients with platinum-resistant or platinum-refractory disease. Presentation of ARIEL2 Part 2 data will follow at a future medical meeting.

A NGS-based assay developed with Foundation Medicine, Inc. was used to determine the percentage of genomic LOH, mutations in BRCA, and other homologous recombination genes in archival tumor tissue and pretreatment biopsies for patients enrolled in ARIEL2. A prespecified cutoff of ≥14% for LOHhigh was determined through analysis of microarray and survival data for patients in The Cancer Genome Atlas who had ovarian carcinoma and had received platinum-based chemotherapy. A planned post hoc analysis using outcome data from ARIEL2 Part 1 was performed to refine the genomic cutoff. The data for both the prespecified and refined cutoff percentages are presented in today’s poster presentation.

Updated Results of ARIEL2 Part 1
Data presented from the ARIEL2 Part 1 study demonstrated clinical activity in patients with tumors with germline and somatic BRCA mutations as well as those with tumors classified as BRCAwt/LOHhigh.

Using the prespecified ≥14% cutoff, patients in the BRCAmut subgroup demonstrated a 73 percent reduction in the risk of progression, and patients in the BRCAwt/LOHhigh subgroup demonstrated a 38 percent reduction in the risk of progression, both compared to the BRCAwt/LOHlow subgroup (hazard ratio: 0.27 [95% CI: 0.16, 0.44; p<0.001] and hazard ratio: 0.62 [95% CI: 0.42, 0.90; p=0.01], respectively). Median PFS for the BRCAmut, BRCAwt/LOHhigh, and BRCAwt/LOHlow subgroups was 12.8 months, 5.7 months and 5.2 months, respectively.

An analysis of platinum-sensitive patients from ARIEL2 Part 1 identified a refined LOH cutoff of ≥16% that provided further discrimination of PFS, objective response rate and duration of response in patients with LOHhigh and LOHlow tumors who received a median of one prior treatment regimen. Using the refined LOH cutoff of ≥16%, patients in the BRCAmut subgroup demonstrated a 75 percent reduction in the risk of progression, and patients in the BRCAwt/LOHhigh subgroup demonstrated a 49 percent reduction in the risk of progression, both compared to the BRCAwt/LOHlow subgroup (hazard ratio: 0.25 [95% CI: 0.15, 0.42; p<0.001] and hazard ratio: 0.51 [95% CI: 0.34, 0.74; p<0.001], respectively). Median PFS for the BRCAmut, BRCAwt/LOHhigh, and BRCAwt/LOHlow subgroups was 12.8 months, 7.2 months and 5.0 months, respectively.

The confirmed investigator-assessed ORR based on RECIST criteria was significantly higher in the BRCAmut subgroup than in the BRCAwt/LOHlow with the prespecified LOH cutoff. As expected, the most robust clinical responses were observed in patients with tumor (germline and somatic) BRCA mutations: 80 percent (32/40) of BRCAmut patients achieved a response. Responses were observed in both germline and somatic BRCAmut tumors, including 85 percent (17/20) of patients with a gBRCA mutation and 74 percent (14/19) of patients with a sBRCA mutation. One patient with a BRCA mutation was indeterminate for mutation type. In the BRCAwt/LOHhigh subgroup, the ORR was 29 percent (24/82) and 33 percent (23/69) based on the prespecified and refined cutoff, respectively. In the BRCAwt/LOHlow subgroup, the ORR was 10 percent for both the prespecified and refined cutoffs, representing responses in 7 of 70 and 8 of 83 patients, respectively. Median duration of response for the prespecified and refined LOH cutoffs for the BRCAmut and BRCAwt/LOHhigh subgroups were the same at 9.2 months and 10.8 months, respectively, and highly similar for the BRCAwt/LOHlow subgroup at 5.6 months and 5.5 months, respectively.

The most common treatment-emergent AEs reported in ≥20 percent of all patients included nausea (80%), asthenia/fatigue (78%), constipation (46%), vomiting (44%) and dysgeusia (43%). These events were mostly Grade 1/2. The most common Grade 3/4 treatment-emergent AEs were anemia/decreased hemoglobin (21%) and ALT/AST elevations (12%). No treatment-related deaths were reported. Nineteen patients (9%) discontinued treatment because of an adverse event.

These results support the predictive utility of an HRD signature to identify patients with platinum-sensitive ovarian cancer who may benefit from rucaparib treatment. The NGS-based HRD assay will be prospectively applied to assess the utility of a rucaparib treatment-based LOHhigh cutoff in predicting response to rucaparib in the phase 3 ARIEL3 study investigating rucaparib in the maintenance setting in platinum-sensitive ovarian cancer.

Feasibility of Monitoring Response to Rucaparib with ctDNA
A study at the University of Cambridge was conducted to assess TP53 mutant allele fraction (MAF) in circulating tumor DNA (ctDNA) from a subset of 18 patients in ARIEL2 Part 1 and will be presented in a poster session this afternoon. Plasma samples were collected from 18 patients in the ARIEL2 Part 1 study during screening, on day 1 of each cycle, and at the end of rucaparib treatment. The objective was to assess monitoring responses to rucaparib with targeted amplicon deep sequencing (TADS) of ctDNA. Seven of 9 patients with a >50% reduction of TP53 MAF in ctDNA at cycle 2 achieved a RECIST PR; this included 5/6 patients with either a germline or somatic BRCA mutation. No patients with a <50% reduction at cycle 2 (n=5) achieved a RECIST response. TADS detected different types of TP53 mutation in plasma including substitutions (n=12) and indels (n=6) across a wide spectrum of allele fractions (0.01–42.3%) with 100% concordance for TP53 mutation status in matched tumor-plasma samples. ctDNA is a potential biomarker for monitoring responses to the PARP inhibitor rucaparib.

Final Results of RUCAPANC
The open-label phase 2 RUCAPANC study investigated the safety and efficacy of rucaparib in patients with advanced pancreatic cancer and a known deleterious germline or somatic BRCA mutation and final results were presented in a poster session on June 4. A total of 19 patients were enrolled and received one or more doses of rucaparib, with a median of three cycles (range 1-18) of treatment started. The confirmed investigator-assessed ORR based on RECIST criteria was 16%, in which two partial responses (PR) and one complete response (CR) were observed. The disease control rate was 32% for all patients (6/19) and 50% for patients with one prior chemotherapy (3/6). All three patients with a confirmed response received only one prior line of therapy. Common treatment-emergent AEs included nausea (63%) and anemia (47%). These findings are expected to inform future rucaparib study designs in patients with advanced BRCAmut pancreatic cancer.

About Rucaparib Clinical Development
The ARIEL (Assessment of Rucaparib in Ovarian Cancer Trial) program is a novel, integrated translational-clinical program designed to accurately and prospectively identify ovarian cancer patients with tumor genotypes associated with benefit from rucaparib therapy.

ARIEL2 is a two-part single-arm open label study. Part 1 is in platinum-sensitive patients designed to identify pre-specified tumor characteristics that predict sensitivity to rucaparib using DNA sequencing to evaluate each patient’s tumor and updated results are described above. Part 2, also referred to as the ARIEL2 Extension, is enrolling up to 300 patients with advanced ovarian cancer who have received at least three prior chemotherapy regimens and includes platinum-sensitive, -resistant and -refractory patients. It will evaluate clinical response in patients classified into molecularly-defined subgroups, including gBRCA-mutant, sBRCA-mutant and the BRCA-like signature by a prospectively defined genomic signature.
The phase 2 portion of Study 10, the initial dose finding study, enrolled patients with relapsed, high-grade ovarian cancer associated with a deleterious germline BRCA mutation who have received 2-4 prior lines of chemotherapy.
The ARIEL3 pivotal study is a randomized, double-blind study comparing the effects of rucaparib against placebo to evaluate whether rucaparib given as a maintenance therapy to platinum-sensitive patients can extend the period of time for which the disease is controlled after a positive outcome with platinum-based chemotherapy. Patients are randomized to receive either placebo or rucaparib and the primary endpoint of the study is PFS. The primary efficacy analysis will evaluate, in a step-down process, BRCA-mutant patients, all patients with a BRCA-like signature (including BRCA and non-BRCA), and then all patients.
The ARIEL4 confirmatory study is expected to begin during the second half of 2016, and will compare treatment with rucaparib vs chemotherapy in relapsed ovarian cancer patients with BRCA mutations. The primary endpoint of the study is PFS.
In addition to the ARIEL program in ovarian cancer, the Company is exploring rucaparib in other solid tumor types with significant BRCA and BRCA-like populations, including a pivotal prostate cancer study expected to initiate during the second half of 2016.
Multiple combination studies are planned to initiate in the second half of 2016, including with inhibitors of PD-L1.
For more information, please visit www.arielstudy.com.
Subgroup analysis of later-line BRCA-mutant patients from ARIEL2 Parts 1 and 2 and Study 10 will form the basis of rucaparib’s rolling New Drug Application (NDA) to the U.S. FDA. The NDA submission will include platinum-sensitive, -resistant and -refractory patients from ARIEL2 Part 2, in addition to the platinum-sensitive patients from ARIEL2 Part 1 and Study 10.

The NDA submission is expected to complete by the end of Q2 2016, and a European Marketing Authorization Application (MAA) to the European Medicines Agency is planned for Q4 2016. Rucaparib was granted Breakthrough Therapy designation from the U.S. Food and Drug Administration in April 2015.

Presentation Details
The poster presentation, titled "RUCAPANC: An open-label, phase 2 trial of the PARP inhibitor rucaparib in patients (pts) with pancreatic cancer (PC) and a known deleterious germline or somatic BRCA mutation" was presented Saturday by Robert Vonderheide, MD, D. Phil., University of Pennsylvania, Philadelphia, PA during the Poster Session titled "Gastrointestinal (Noncolorectal) Cancer", from 8:00am-11:30am CDT (Abstract 4110; Poster Board #102).

The poster presentation, titled "Refinement of prespecified cutoff for genomic loss of heterozygosity (LOH) in ARIEL2 part 1: A phase II study of rucaparib in patients (pts) with high grade ovarian carcinoma (HGOC)" is being presented today by Robert L. Coleman, MD, The University of Texas MD Anderson Cancer Center, Houston, TX during the Poster Session titled "Gynecologic Cancers" from 1:00pm-4:30pm CDT (Abstract 5540 Poster Board #363).

The poster presentation, titled "Feasibility of monitoring response to the PARP inhibitor rucaparib with targeted deep sequencing of circulating tumor DNA (ctDNA) in women with high grade serous carcinoma on the ARIEL2 trial" is being presented today by Mitch Raponi, D. Phil, Biochemistry and Molecular Genetics, Clovis Oncology on behalf of the author, Anna Piskorz, PhD, Cancer Research UK Cambridge Institute, University of Cambridge during the Poster Session titled "Gynecologic Cancers" from 1:00pm-4:30pm CDT (Abstract 5549 Poster Board #372).

The poster presentations will be available online at View Source as of the time of their scheduled presentation at the meeting.

About Rucaparib
Rucaparib is an oral, potent small molecule inhibitor of PARP1, PARP2 and PARP3 being developed for the treatment of ovarian cancer, specifically in patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA, including those with high genomic loss of heterozygosity (LOH) commonly referred to as "BRCA-like." Clovis is also exploring rucaparib in other solid tumor types with significant BRCA and BRCA-like populations, including prostate, breast and gastroesophageal cancers. Rucaparib was granted Breakthrough Therapy designation by the U.S. FDA in April 2015. Clovis holds worldwide rights for rucaparib.