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Onconova Enrolls First Patient in Phase 3 INSPIRE Trial of Rigosertib

On December 07, 2015 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported the enrollment of the first patient in the INSPIRE trial for IV rigosertib as a treatment for higher-risk myelodysplastic syndromes (HR-MDS) after failure of hypomethylating agent (HMA) therapy (Press release, Onconova, DEC 7, 2015, View Source [SID:1234508457]).

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"There is a significant unmet medical need in patients who have failed treatment with an HMA, the only available therapy for HR-MDS," said Dr. Guillermo Garcia-Manero, lead investigator for the INSPIRE trial and Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center. "In previous clinical studies, rigosertib demonstrated positive results in HR-MDS patients with very poor prognosis. The INSPIRE trial is designed to assess the effects of IV rigosertib in these HR-MDS patients who have a short life-span and no effective therapies currently available."

The INSPIRE trial is a global, multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, or failed to respond to, or relapse after previous treatment with HMAs. The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care. The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated.

Clinical Trial Applications (CTAs) and/or site initiation activities for INSPIRE have begun in several European countries, Australia and Israel. Onconova’s collaboration partner in Japan and Korea, SymBio Pharmaceuticals, Ltd., will enroll patients in Japan. In addition, Baxalta Incorporated (BXLT), Onconova’s commercialization partner in Europe, is providing financial support for the trial, up to a specified cap.

About Rigosertib

Rigosertib is a small molecule that inhibits cellular signaling by acting as a Ras mimetic. This is believed to be mediated by direct binding of rigosertib to the Ras-binding domain (RBD) found in many Ras effector proteins, including the Raf kinases and PI3K. The initial therapeutic focus for rigosertib is myelodysplastic syndromes (MDS), a group of bone marrow disorders characterized by ineffective formation of blood cells that often converts into acute myeloid leukemia (AML). Clinical trials for rigosertib are being conducted at leading institutions in the United States, Europe, and the Asia-Pacific region. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.

About INSPIRE

The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the U.S. Food and Drug Administration and European Medicines Agency and derives from the findings of the ONTIME Phase 3 trial. INSPIRE is a multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, or failed to respond to, or relapse after previous treatment with HMAs within the first nine months of initiation of HMA treatment. The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care. The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials.gov (NCT02562443).

MEI Pharma Announces Positive Results from Phase II Study of Pracinostat in Acute Myeloid Leukemia, Plans to Initiate Phase III Registration Study

On December 7, 2015 MEI Pharma, Inc. (Nasdaq: MEIP), an oncology company focused on the clinical development of novel therapies for cancer, reported positive results from a Phase II study of its investigational drug candidate Pracinostat in combination with azacitidine (marketed as Vidaza) in elderly patients with newly diagnosed acute myeloid leukemia (AML) (Press release, MEI Pharma, DEC 7, 2015, View Source [SID:1234508456]). The results were presented earlier today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando. A copy of the presentation is now available at www.meipharma.com.

According to the oral presentation by principal investigator Dr. Guillermo Garcia-Manero, MD Anderson Cancer Center, 28 of the 50 patients in the study (56%) achieved the primary endpoint of complete response (CR) plus complete response with incomplete blood count recovery (CRi) plus morphologic leukemia-free state (MLFS), including 21 patients (42%) who achieved a CR. Notably, 19 of the 21 patients who achieved a CR are still alive with a 100% one-year survival rate among all CR patients, indicating a correlation between CR and survival with this low intensity therapy.

Median overall survival for all 50 patients in the study has not been reached, with 28 patients still living and a median observation time of 14.3 months. These data compare favorably to a recent international Phase III study of azacitidine (AZA-001)1, which showed a median overall survival of 10.4 months with azacitidine alone and a CR rate of 19.5% in a similar patient population. Median survival among patients with high-risk cytogenetics in this study (n=21) was 13.3 months, more than double the median survival of the high-risk population in the AZA-001 study (6.4 months).

"These are impressive results by virtually any measure for a group of patients in dire need of effective new treatment options," said Dr. Garcia-Manero. "Not only did we observe a high rate of responses, but many occurred rapidly and continued to improve with ongoing therapy. Most importantly, we are seeing an encouraging trend in overall survival, particularly among patients who achieved a complete response. These data clearly support further development of Pracinostat in combination with azacitidine for the treatment of elderly patients with AML."

The open-label study enrolled a total of 50 patients at 15 centers across the U.S. Median age in the study was 76 years. Patients received 60 mg of Pracinostat orally three times a week for three weeks followed by one week of rest and 75 mg m2 of azacitidine via subcutaneous injection or intravenous infusion for the first seven days of each 28-day cycle. The combination of Pracinostat and azacitidine was generally well tolerated in the study, with no unexpected toxicities. The most common grade 3/4 treatment-emergent adverse events reported in >10% of all patients included febrile neutropenia, thrombocytopenia, anemia and fatigue.

"We are very excited about our growing body of AML data, which continues to exceed expectations and guide us forward with the development of this program," said Daniel P. Gold, Ph.D., President and Chief Executive Officer of MEI Pharma. "Over the past several months we have learned that our randomized study of Pracinostat and azacitidine in myelodysplastic syndrome (MDS) was hindered by a high rate of discontinuations due to adverse events, but appeared to show a benefit for patients who were able to tolerate treatment for at least four cycles compared to azacitidine alone. The results from our AML study demonstrate that many patients are achieving responses within the first two cycles, with fewer discontinuations overall due to adverse events compared to our MDS study, suggesting a prudent development path forward for the combination.

"Based on these findings," continued Dr. Gold, "we will now begin to prepare for a Phase III registration study of Pracinostat and azacitidine in elderly patients with newly diagnosed AML, which we plan to initiate in the second half of 2016. We look forward to sharing more information regarding the design of this study in the months ahead."

About Pracinostat

Pracinostat is a potent oral inhibitor of a group of enzymes called histone deacetylases, or HDACs. HDACs belong to a larger set of proteins collectively known as epigenetic regulators that can alter gene expression by chemically modifying DNA or its associated chromosomal proteins. Abnormal activity of these regulators is believed to play an important role in cancer and other diseases. Pracinostat has been tested in multiple Phase I and Phase II clinical studies in advanced hematologic diseases and solid tumor indications. The results of these studies suggest that Pracinostat has potential best-in-class pharmacokinetic properties when compared to other oral HDAC inhibitors, with side effects often associated with drugs of this class, including fatigue and myelofibrosis. Pracinostat has not been approved for commercial distribution in the U.S.

MEI Pharma owns exclusive worldwide rights to Pracinostat.

About AML

Acute myeloid leukemia (also known as acute myelogenous leukemia) is the most common acute leukemia affecting adults, and its incidence is expected to continue to increase as the population ages. The American Cancer Society estimates about 20,830 new cases of AML per year in the U.S., with an average age of about 67 years. Treatment options for AML remain virtually unchanged over the past 30 years. Front line treatment consists primarily of chemotherapy, while the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend azacitidine or decitabine (marketed as Dacogen) as low intensity treatment options for AML patients over the age of 60 who are unsuitable for induction chemotherapy.

ImmunoCellular Therapeutics Establishes Agreement with Alliance Foundation Trials, LLC for ICT-107 Phase 3 Registrational Trial in Glioblastoma

On December 7, 2015 ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT: IMUC) reported the establishment of an agreement with a major cancer research group, Alliance Foundation Trials, LLC (AFT), for the phase 3 registrational trial of its cancer immunotherapy ICT-107 in patients with newly diagnosed glioblastoma (Press release, ImmunoCellular Therapeutics, DEC 7, 2015, View Source [SID:1234508455]). AFT in conjunction with the Alliance for Clinical Trials in Oncology comprises nearly 10,000 cancer specialists at hospitals, medical centers, and community clinics across the United States. AFT will support the phase 3 trial by providing access to its large network of clinical sites and patients, with the goal of accelerating patient enrollment in the trial. Multiple phase 3 clinical trial sites have been opened for patient enrollment in the US, with additional sites anticipated to open in Canada and Europe in the coming weeks and months.

Andrew Gengos, ImmunoCellular Chief Executive Officer, commented: "Working in collaboration with AFT has the potential to significantly accelerate enrollment in the ICT-107 phase 3 trial, and to engage the participation of important clinical sites throughout in the US. AFT is one of the most highly respected cancer organizations in America, and we are appreciative of their endorsement and support for our registrational trial."

ImmunoCellular has reached agreement with the FDA on a Special Protocol Assessment (SPA) with respect to the primary and secondary endpoints as well as the statistical plan for the phase 3 trial. ImmunoCellular has also been awarded a $19.9 million grant from the governing Board of the California Institute for Regenerative Medicine (CIRM), California’s stem cell agency, to implement the phase 3 registration trial.

Epizyme Presents Updated Data from Ongoing Phase 1 Study of Tazemetostat Showing Objective, Durable Responses in Relapsed or Refractory Non-Hodgkin Lymphoma

On December 7, 2015 Epizyme, Inc. (NASDAQ:EPZM), a clinical stage biopharmaceutical company creating novel epigenetic therapeutics for cancer patients, reported updated results from the ongoing phase 1 trial of tazemetostat (EPZ-6438), a first-in-class oral EZH2 inhibitor (Press release, Epizyme, DEC 7, 2015, View Source [SID:1234508454]). Data from this trial continue to show meaningful clinical activity with tazemetostat when used as an oral monotherapy in patients with either relapsed or refractory Non-Hodgkin Lymphoma (NHL). Nine of 16 response-evaluable patients with NHL have achieved an objective response, with the duration of responses lasting up to 19 months as of the data cutoff. The data were presented today by Vincent Ribrag, M.D., Institut Gustave Roussy, at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (ASH) (Free ASH Whitepaper).

"In this ongoing phase 1 study, we continue to observe meaningful and durable clinical activity with tazemetostat in NHL patients," said Dr. Ribrag. "The phase 2 five-arm study, which is currently underway, will advance our understanding of the clinical utility of this agent in the different subsets of NHL. I believe tazemetostat has the potential to become an important new addition to the available treatment options for our patients."

Summary Results

As of the November 7, 2015 cutoff, the following clinical data were reported:

Twenty-one patients with relapsed or refractory NHL were enrolled into the phase 1 study; 16 of the 21 patients were response-evaluable as defined by the study protocol.
Nine of 16 (56 percent) response-evaluable NHL patients achieved an objective response.
On an intent-to-treat basis, seven of 12 (58 percent) response-evaluable NHL patients treated at or above the recommended phase 2 dose of 800 mg twice daily (BID) achieved an objective response.

Four patients remained on study at data cutoff with ongoing objective responses, including three patients who had been on drug for at least 18 months.

800 mg BID showed superior tolerability, equivalent anti-tumor activity and equivalent pharmacodynamic activity as compared to the 1600 mg BID dose.

The majority of adverse events were grade 1 or grade 2 within the 55 patients with NHL and solid tumors who were evaluable for safety. The most common adverse events, regardless of attribution, were asthenia, anorexia, thrombocytopenia, nausea, constipation, diarrhea, and vomiting. Four grade 3 or greater treatment-related adverse events have been observed including one each of: grade 3 hypertension, grade 3 liver function test elevation, grade 4 thrombocytopenia, and grade 4 neutropenia.

Study Design

This open-label, multi-center, phase 1 study is investigating tazemetostat as monotherapy in patients with relapsed or refractory B-cell Non-Hodgkin Lymphoma or advanced solid tumors. The study objectives include identification of the recommended phase 2 dose or maximum tolerated dose, safety, tolerability, pharmacokinetics and preliminary evaluation of anti-tumor activity. Five cohorts were studied in the dose escalation phase: 100 mg, 200 mg, 400 mg, 800 mg and 1600 mg; and two cohorts, 800 mg and 1600 mg, were evaluated in the dose expansion phase. All doses were given twice daily. In addition, the study included two clinical pharmacology sub-studies: one for food effect and the other for drug-drug interaction. In the food effect sub-study, patients received a single 200 mg dose of tazemetostat either fasted or immediately after a high-fat breakfast in a randomized crossover fashion with seven days between doses. Patients received 400 mg BID after completing the seven-day crossover component of the study. Five of the 21 NHL patients were in the food effect sub-study.

Expanded Tazemetostat Registration-Supporting Phase 2 Program in NHL

Epizyme is conducting an international, multi-center, phase 2 study comprised of five independent arms. This study, which began enrolling patients in the second half of 2015, will assess the safety and efficacy of 800 mg BID of tazemetostat in patients with relapsed or refractory NHL, stratified by cell of origin and EZH2 mutation status. Epizyme plans to present interim results from the phase 2 study at a medical conference in mid-2016.

About EZH2 in Cancer

EZH2 is a histone methyltransferase (HMT) that is increasingly understood to play a potentially oncogenic role in a number of cancers. These include Non-Hodgkin Lymphoma, INI1-deficient cancers such as malignant rhabdoid tumors, epithelioid sarcomas and synovial sarcoma; and a range of other solid tumors.

About Tazemetostat

Epizyme is developing tazemetostat for the treatment of non-Hodgkin lymphoma patients and patients with INI1-deficient solid tumors. Tazemetostat is a first-in-class small molecule inhibitor of EZH2 created by Epizyme using its proprietary product platform. In many human cancers, aberrant EZH2 enzyme activity results in misregulation of genes that control cell proliferation resulting in the rapid and unconstrained growth of tumor cells. Tazemetostat is the WHO International Non-Proprietary Name (INN) for EPZ-6438.

Additional information about this program, including clinical trial information, may be found here: View Source

Sunesis Pharmaceuticals Announces Presentation of Positive Results From MD Anderson Sponsored Trial in AML at ASH Annual Meeting

On December 7, 2015 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported the presentation of updated results from an ongoing Phase 1b/2 University of Texas MD Anderson cancer Center-sponsored trial of vosaroxin in combination with decitabine in older patients with previously untreated acute myeloid leukemia (AML) and high-risk myelodyplastic syndrome (MDS) (Press release, Sunesis, DEC 7, 2015, View Source;p=RssLanding&cat=news&id=2120499 [SID:1234508453]). The results are being presented today at 8:00 AM in an oral session titled "Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: New Epigenetic Approaches" taking place from 7:00 AM to 8:30 AM ET at the 56th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida. The presentation (abstract 461, Orange County Convention Center, W109), titled "Phase I/II Study of Vosaroxin and Decitabine in Newly Diagnosed Older Patients (pts) with Acute Myeloid Leukemia (AML) and High Risk Myelodyplastic Syndrome (MDS)," is available at www.sunesis.com.

"Inability to tolerate frontline chemotherapy greatly limits treatment options and worsens prognoses among older patients with newly diagnosed AML and MDS," said Naval Daver, M.D., Assistant Professor, Department of Leukemia, University of Texas MD Anderson Cancer Center, and a study investigator. "This study demonstrates compelling outcomes both for the high rate of complete remission seen with vosaroxin and decitabine, historically the best predictor or overall survival, and the tolerability of the combination. Particularly noteworthy are outcomes in patients who received the 70 mg/m2 induction dose of vosaroxin, where early mortality is low and overall survival is very promising."

To date, 61 patients (54 AML, 7 high-risk MDS) with a median age of 69 years (range, 60-78) have been enrolled in the Phase 1b/2 trial. All 61 patients have completed at least 2 cycles of therapy and were evaluable for response: 32 patients (52%) achieved complete response (CR), 9 patients (15%) achieved CR with incomplete platelet recovery (CRp), and 4 patients (7%) achieved CR with incomplete peripheral blood count recovery (CRi) for an overall response rate of 74%. Minimal residual disease (MRD) by 19 color flow-cytometry was evaluable in 33 of the 45 responders. MRD was not detectable in 22 of 33 (67%) evaluable responders. The median number of cycles to response was 1; 15 patients have required >1 cycle to achieve response. Eleven (19%) patients have proceeded to allogeneic stem cell transplant. The median follow-up is 7.7 months (2.2 – 24.5). The regimen was well tolerated with the main therapy related grade 3 or higher non-infectious toxicities being mucositis in 11 (18%) patients and elevated bilirubin in 8 (13%) patients.

Median overall survival (OS) for all patients is 8.8 months. Four-week and 8-week mortality for all patients were 0 and 13%, respectively. The induction dose of vosaroxin was 90 mg/m2 in 22 patients and 70 mg/m2 in 39 patients.

"This trial continues to reinforce observations from VALOR and other studies of vosaroxin, in the front-line and relapsed refractory AML settings, demonstrating that vosaroxin can become a new backbone of treatment and in combination with other important therapeutic candidates can increase the rates of complete response, translating to promising overall survival," said Daniel Swisher, Chief Executive Officer of Sunesis. "We look forward to exploring vosaroxin’s treatment potential within other segments of the AML and MDS disease spectrum through a comprehensive program of investigator-led and Sunesis-led studies."

About QINPREZO (vosaroxin)
QINPREZO (vosaroxin) is an anti-cancer quinolone derivative (AQD), a class of compounds that has not been used previously for the treatment of cancer. Preclinical data demonstrate that vosaroxin both intercalates DNA and inhibits topoisomerase II, resulting in replication-dependent, site-selective DNA damage, G2 arrest and apoptosis. Both the U.S. Food and Drug Administration (FDA) and European Commission have granted orphan drug designation to vosaroxin for the treatment of AML. Additionally, vosaroxin has been granted fast track designation by the FDA for the potential treatment of relapsed or refractory AML in combination with cytarabine. Vosaroxin is an investigational drug that has not been approved for use in any jurisdiction.
The trademark name QINPREZO is conditionally accepted by the FDA and the EMA as the proprietary name for the vosaroxin drug product candidate.