1stOncology™: Cancer Intelligence Service – Page 16181 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Tokai Pharmaceuticals Announces Clinical Update

On July 26, 2016 Tokai Pharmaceuticals Inc. (NASDAQ:TKAI), a biopharmaceutical company focused on developing and commercializing innovative therapies for prostate cancer and other hormonally driven diseases, reported that it plans to discontinue the ARMOR3-SV clinical trial, the company’s pivotal Phase 3 study comparing galeterone to enzalutamide in treatment-naïve metastatic castration-resistant prostate cancer (mCRPC) patients whose prostate tumors express AR-V7, following the recommendation made yesterday by the trial’s independent Data Monitoring Committee (DMC) (Press release, Tokai Pharmaceuticals, JUL 26, 2016, View Source [SID:1234514045]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

Schedule Your 30 min Free Demo!

Based on a review of all safety and efficacy data, the DMC determined that the ARMOR3-SV trial will likely not succeed in meeting its primary endpoint of demonstrating an improvement in radiographic progression-free survival (rPFS) for galeterone versus enzalutamide in AR-V7 positive mCRPC. In making its recommendation, the DMC did not cite any safety concerns with galeterone in the trial. ARMOR3-SV is the first pivotal clinical trial in mCRPC to prospectively select AR-V7 positive patients, a population with an unmet medical need and aggressive disease course. The company plans to present data from the trial in a scientific forum once fully available and analyzed.

"We are very disappointed by this outcome. An immediate priority is to analyze the unblinded study data in detail as we evaluate potential paths forward for galeterone and our pipeline," said Jodie Morrison, President and Chief Executive Officer of Tokai. "We are deeply grateful for the support and commitment from the patients participating in the study, their caregivers, and the study investigators and their staff."

The company intends to evaluate its ongoing ARMOR2 expansion in mCRPC patients with acquired resistance to enzalutamide, and the planned study in patients who rapidly progress on either enzalutamide or abiraterone acetate. Tokai plans to allow all patients currently enrolled in the ARMOR2 and ARMOR3-SV trials to continue on therapy following consultation with their physicians and study investigators. The appropriate health authorities and clinical study investigators are being notified that ARMOR3-SV is being discontinued.

As of June 30, 2016, Tokai had approximately $43.9M in cash and cash equivalents.

About ARMOR3-SV
ARMOR3-SV was a pivotal Phase 3 trial comparing galeterone to Xtandi (enzalutamide) in mCRPC treatment-naïve patients whose prostate tumors express the AR-V7 splice variant. These truncated ARs are missing the C-terminal end of the AR that contains the ligand-binding domain, which is known as C-terminal loss. AR-V7 is the most common form of C-terminal loss. The trial employed a precision medicine approach for selection of patients with the AR-V7 splice variant by using an AR-V7 clinical trial assay successfully optimized for global use by Qiagen. The primary endpoint of ARMOR3-SV was radiographic progression-free survival assessed by blinded independent central review.

About Galeterone
Galeterone is an oral small molecule that utilizes the mechanistic pathways of current second-generation hormonal therapies, including abiraterone and enzalutamide, while also introducing a unique third mechanism – androgen receptor degradation – that impairs the function of androgen receptors, decreasing their sensitivity to androgen activity and reducing tumor growth. Tokai is developing galeterone for the treatment of patients with metastatic castration-resistant prostate cancer. Tokai has worldwide development and commercialization rights to galeterone.

Eisai And Halozyme Initiate Phase 1b/2 Clinical Trial With First Patient Dosing Of Eribulin In Combination With PEGPH20

On July 26, 2016 Halozyme Therapeutics, Inc. (NASDAQ: HALO) reported that Eisai Inc. has dosed the first patient in a collaborative phase 1b/2 clinical trial to assess whether Eisai’s eribulin mesylate (HALAVEN) in combination with Halozyme’s investigational drug PEGPH20 (PEGylated recombinant human hyaluronidase) can improve overall response rate (ORR) – the proportion of women that have a predefined reduction in tumor burden – as compared with eribulin alone as a therapy in women with advanced or metastatic, High-Hyaluronan (HA) HER2-negative breast cancer (Press release, Halozyme, JUL 26, 2016, View Source [SID:1234514042]).

"Initiation of this study is not only a major milestone in our collaboration with Eisai, it underscores our combined focus on advancing the treatment of metastatic breast cancer—one of the most common cancers in women worldwide," said Dr. Helen Torley, president and chief executive officer.

PEGPH20 is an investigational drug administered intravenously that targets the degradation of HA, a glycosaminoglycan – or chain of natural sugars throughout the body – that can accumulate around cancer cells to inhibit other therapies. Eribulin, a synthetic analog of halichondrin B, a natural product that was isolated from the marine sponge Halichondria okadai, is a microtubule dynamics inhibitor with a distinct binding profile that has been shown in in vitro studies to lead to apoptotic cell death after prolonged and irreversible mitotic blockage. In HA-high triple-negative breast preclinical animal models, the addition of PEGPH20 to eribulin showed a significant increase in tumor growth inhibition and overall tumor regression when compared to eribulin alone.

The collaborative study will seek to determine whether or not the combination therapy of eribulin and PEGPH20 can improve the overall response rate in patients with metastatic breast cancer with high levels of HA. The study protocol includes metastatic HER2-negative patients with HA-high breast cancer that were previously untreated and those that received one prior line of therapy.

About Advanced Breast Cancer

Advanced or metastatic breast cancer is a very difficult condition to treat and only 26.3 percent of women will survive beyond five years. (SEER 2016)

About PEGPH20

PEGPH20 is an investigational PEGylated form of Halozyme’s proprietary recombinant human hyaluronidase under clinical development for the potential systemic treatment of tumors that accumulate hyaluronan.

FDA granted orphan drug designation to PEGPH20 for treatment of pancreatic cancer and fast track for PEGPH20 in combination with gemcitabine and nab-paclitaxel for the treatment of metastatic pancreatic cancer. Additionally, the European Commission, acting on the recommendation from the Committee for Orphan Medicinal Products of the European Medicines Agency, designated investigational drug PEGPH20 an orphan medicinal product for the treatment of pancreatic cancer.

About Eribulin Mesylate Injection (Available as HALAVEN)

Halaven (eribulin mesylate) is a microtubule dynamics inhibitor indicated for the treatment of patients with:

Metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.
Unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.
Discovered and developed by Eisai, eribulin is a synthetic analog of halichondrin B, a natural product that was isolated from the marine sponge Halichondria okadai. First and only in the halichondrin class, eribulin is a microtubule dynamics inhibitor with a distinct binding profile. Eribulin is believed to work primarily via a tubulin-based mechanism that causes prolonged and irreversible mitotic blockage, ultimately leading to apoptotic cell death. Additionally, in preclinical studies of human breast cancer, eribulin demonstrated complex effects on the tumor biology of surviving cancer cells, including increases in vascular perfusion resulting in reduced tumor hypoxia, and changes in the expression of genes in tumor specimens associated with a change in phenotype, promoting the epithelial phenotype, opposing the mesenchymal phenotype. Eribulin has also been shown to decrease the migration and invasiveness of human breast cancer cells.

Adaptimmune Receives Orphan Drug Designation in the European Union for its NY-ESO SPEAR® T-cell Therapy for Treatment of Soft Tissue Sarcoma

On July 26, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy for treatment of cancer, reported that the European Commission has designated the company’s NY-ESO SPEAR T-cell therapy as an orphan medicinal product for the treatment of soft tissue sarcoma, a solid tumor cancer (Press release, Adaptimmune, JUL 26, 2016, View Source [SID:1234514041]).

Adaptimmune previously received orphan drug destination from the U.S. Food and Drug Administration for its NY-ESO SPEAR T-cell therapy in this indication.

"We are delighted to have received the European Commission’s orphan medicinal product designation," said Dr. Rafael Amado, Adaptimmune’s Chief Medical Officer. "We look forward to progressing our NY-ESO SPEAR T-cell therapy through clinical trials with the goal of eventually making this product available in Europe to patients with advanced soft tissue sarcoma."

Orphan drug designation by the European Commission provides certain regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than five in 10,000 persons in the European Union (EU), and where no satisfactory treatment is available. The designation provides incentives for companies seeking protocol assistance and scientific advice from the European Medicines Agency (EMA) during the product development phase and a 10-year period of marketing exclusivity in the EU following product approval.

Data from recent published epidemiological studies estimate the prevalence of soft tissue sarcoma in the EU to be 2.86 per 10,000 which corresponds to approximately 146,918 people based on the total population of 513.7 million people in the EU, Norway, Iceland, and Liechtenstein as of January 1, 2015 [EUROSTAT 2015].

The European Commission’s decision follows the positive opinion adopted by the EMA’s Committee for Orphan Medicinal Products recommending Adaptimmune’s SPEAR T-cell therapy targeting NY-ESO for designation as an orphan medicinal product for the treatment of soft tissue sarcoma announced by Adaptimmune on June 20, 2016.

About Soft Tissue Sarcoma
Soft tissue sarcomas can develop from soft tissues including fat, muscle, nerves, fibrous tissues, blood vessels, or deep skin tissues. There are approximately 50 types of soft tissue sarcomas, including synovial sarcoma, a cancer of the connective tissue around the joints. Soft tissue sarcomas can develop at almost any anatomic site, such as the extremities, trunk or thorax, abdomen and retroperitoneum, pelvis and the head and neck region. The more common soft tissue sarcomas originate from muscle, nerve tissue, fat, or deep skin tissue. For a number of sarcomas, such as synovial sarcoma, the tissue origin is not well characterized. Surgical resection is the standard therapy for localized disease and radiation therapy (preoperative or postoperative) and/or chemotherapy is added in selected cases.

Phase 1/2 Combination Trial of AXAL and Durvalumab Completes Second Dose-Escalation Cohort

On July 26, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical stage biotechnology company developing cancer immunotherapies, reported its combination study of axalimogene filolisbac (AXAL) with AstraZeneca’s anti-PD-L1 durvalumab has completed the second dose-escalation cohort and has commenced enrollment for the Part A expansion and Part B phases of the study (Press release, Advaxis, JUL 26, 2016, View Source [SID:1234514033]).

The study is evaluating the safety and efficacy of combination treatment with AXAL and durvalumab in patients with advanced, recurrent or refractory human papillomavirus (HPV)-associated cervical cancer and HPV-associated head and neck cancer.

The goal of the Part A expansion is to enroll 20 patients with HPV-associated head and neck cancer to receive AXAL at 1×109 cfu plus 10 mg/kg of durvalumab. Part B of the trial will evaluate AXAL at 1×109 cfu with 10mg/kg of durvalumab in patients with cervical cancer, with the goal to randomize 45 patients to a durvalumab monotherapy and 45 patients for the combination therapy.

Data from the first dose-escalation cohort will be submitted as an abstract for an upcoming major medical meeting this fall. Further information about the Phase 1/2 study can be found on ClinicalTrials.gov, using Identifier NCT02291055.

About Cervical Cancer

Cervical cancer is the fourth most common cancer in women worldwide. In the United States, nearly 13,000 new cases are diagnosed annually and approximately 4,100 deaths are reported because of cervical cancer. According to the WHO/ICO Information Centre on HPV and Cervical Cancer, about 3.9 percent of women in the U.S. are estimated to harbor high-risk cervical HPV infection at a given time, and 71.7 percent of invasive cervical cancers are attributed to high-risk HPV strains.

About Axalimogene Filolisbac

Axalimogene filolisbac (AXAL) is Advaxis’ lead Lm Technology immunotherapy candidate for the treatment of HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer. In a completed randomized Phase 2 study in recurrent/refractory cervical cancer, AXAL showed apparent prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of the company’s Lm Technology. AXAL has Orphan Drug Designation in the U.S. for the treatment of invasive cervical cancer, head and neck, and anal cancer.

About Durvalumab

Durvalumab is a selective, high-affinity human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. The PD-1/PD-L1 pathway is an important checkpoint used by tumour cells to inhibit antitumour responses. PD-L1 upregulation is observed on tumour cells from a broad range of human cancers and may cause tumor immune evasion. Targeting and blocking the inhibitory effects of PD-L1 with durvalumab is an important immunotherapeutic approach designed to boost anti-tumor immune responses in patients with cancer. Durvalumab is being investigated in an extensive clinical trial program, as monotherapy or in combination with other immunotherapeutic and small molecules, in NSCLC, head and neck, bladder, gastric, pancreatic, HCC and blood cancers

Daratumumab Receives Breakthrough Therapy Designation from U.S. Food and Drug Administration in Combination with Standard of Care Regimens for Previously Treated Multiple Myeloma

On July 26, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for DARZALEX (daratumumab) injection in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy (Press release, Genmab, JUL 26, 2016, View Source [SID:1234514029]). Breakthrough Therapy Designation is a program intended to expedite the development and review of drugs to treat serious or life-threatening diseases in cases where preliminary clinical evidence shows that the drug may provide substantial improvements over available therapy. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop and commercialize daratumumab.

"This is the second time daratumumab has earned the distinction of a Breakthrough Therapy Designation. We are pleased that the FDA continues to recognize the potential of daratumumab to help patients with multiple myeloma. We continue to work with our strategic partner Janssen and the regulatory authorities to advance daratumumab to bring this treatment to more patients suffering from multiple myeloma as quickly as possible," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

The Breakthrough Therapy Designation for daratumumab was granted on the basis of data from two Phase III studies: CASTOR (MMY3004; NCT02136134) evaluating daratumumab in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in patients with relapsed or refractory multiple myeloma, and POLLUX (MMY3003; NCT02076009) evaluating daratumumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma.

About Breakthrough Therapy Designation
The Breakthrough Therapy Designation was enacted as part of the 2012 FDA Safety and Innovation Act (FDASIA) and is intended to expedite development of drugs to treat serious and life-threatening medical conditions when preliminary clinical evidence demonstrates that the drug may have substantial improvement on at least one clinically significant endpoint over available therapies. Breakthrough Therapy Designation includes all the features of the Fast Track Designation, as well as more intensive guidance from the FDA on a drug’s clinical development program.

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,1,2 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,1,2 antibody-dependent cellular phagocytosis3,4 and antibody-dependent cellular cytotoxicity.1,2 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were accompanied by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.1,5

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, non-Hodgkin’s lymphoma and a solid tumor indication.