On March 29, 2016 TESARO, Inc. (Nasdaq:TSRO), an oncology-focused biopharmaceutical company, reported it has dosed the first patient in a Phase 1, dose-escalation study of its lead anti-PD-1 monoclonal antibody candidate, TSR-042 (Press release, TESARO, MAR 29, 2016, View Source [SID:1234510113]). Following identification of a dose and schedule for TSR-042, the trial is planned to expand into tumor specific cohorts. Schedule your 30 min Free 1stOncology Demo! "TSR-042 is the first antibody candidate from our immuno-oncology portfolio to enter clinical trials, and our goal is to identify a dose and schedule for TSR-042 by the end of 2016," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "We continue to believe that immuno-oncology has the potential to transform our approach to cancer therapy and we look forward to continuing to advance our immuno-oncology portfolio. We expect to submit an investigational new drug application for a second antibody candidate from our immuno-oncology portfolio, TSR-022, our anti-TIM-3 antibody candidate, during the second quarter of this year."
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About TSR-042
TSR-042 is a monoclonal antibody candidate targeting PD-1 and was developed as part of a collaboration between TESARO and AnaptysBio, Inc. This collaboration was initiated in March of 2014, and is focused on the development of monospecific antibody drug candidates targeting TIM-3 (TSR-022), LAG-3 and PD-1 and bi-specific antibody drug candidates targeting PD-1/TIM-3 and PD-1/LAG-3, in addition to a novel bispecific antibody candidate designed to target undisclosed targets.
TESARO and MD Anderson Cancer Center Announce Immuno-Oncology Collaboration and Exclusive License Agreement
On March 29, 2016 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, and the Institute for Applied Cancer Science at The University of Texas MD Anderson Cancer Center reported an exclusive collaboration to discover and develop small molecule product candidates against undisclosed immuno-oncology targets (Press release, TESARO, MAR 29, 2016, View Source [SID:1234510112]). This collaboration leverages MD Anderson’s expertise in drug discovery and translational medicine and TESARO’s oncology drug development and commercialization capabilities.
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MD Anderson’s Institute for Applied Cancer Science (IACS) is a fully integrated drug discovery and development group that aims to transform cancer care through the discovery and deployment of impactful new drugs to eliminate cancer. The TESARO collaboration is IACS’s first to specifically focus on small molecule drug discovery.
"We are excited to be partnering with the exceptional group of drug hunters at MD Anderson’s IACS to identify drug candidates against targets we collectively believe will build upon the recognized promise of immuno-oncology for patients living with cancer," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "We intend for this partnership to expand and complement TESARO’s existing portfolio of immuno-oncology programs and we continue to believe that immuno-oncology will transform our approach to cancer therapy."
Under terms of the agreement, TESARO will receive exclusive worldwide rights to develop and commercialize any small molecule product candidates that result from this collaboration. MD Anderson will be responsible for conducting research activities aimed at identifying clinical candidates with defined characteristics targeting certain immuno-oncology targets. TESARO will fund research, development, and commercialization expenses for this collaboration. Additional terms of this agreement were not disclosed.
"This synergistic partnership provides an opportunity to fast-track novel immune-modulating therapies towards our cancer patients," said Phil Jones, Ph.D., Executive Director and Head of the IACS platform. "This alliance is optimally aligned with IACS’ mission to rapidly advance impactful therapies into clinical practice."
About MD Anderson
The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. The institution’s sole mission is to end cancer for patients and their families around the world. MD Anderson is one of only 45 comprehensive cancer centers designated by the National Cancer Institute (NCI). MD Anderson is ranked No. 1 for cancer care in U.S. News & World Report’s "Best Hospitals" survey. It has ranked as one of the nation’s top two hospitals since the survey began in 1990, and has ranked first for 11 of the past 14 years. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).
In 2012, MD Anderson announced its Moon Shots Program, an ambitious and comprehensive action plan to make a giant leap forward in cancer patient care, which was inspired by America’s drive a generation ago to put a man on the moon. IACS is one of 10 platforms supporting the Moon Shots Program. Like a biotech company embedded in a comprehensive cancer center, the drug discovery experts at IACS connect with basic scientists, clinical researchers, and strategic partners to develop novel drugs for cancer patients, employing a Bench at BedsideTM approach to shorten the drug development timeline.
BioLineRx Reports Successful Top-Line Results in Phase 2 Trial for AML
On March 29, 2016 BioLineRx (NASDAQ/TASE: BLRX) reported positive top-line results from BL-8040’s Phase 2 clinical trial in relapsed or refractory acute myeloid leukemia (r/r AML) (Press release, BioLineRx, MAR 29, 2016, View Source [SID:1234510106]). Detailed results are planned to be presented at an upcoming scientific conference. Schedule your 30 min Free 1stOncology Demo! The BL-8040 oncology platform is a short cyclic peptide that functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. Results of the Phase 2 clinical trial showed that BL-8040, as a single agent and in combination with Cytarabine (Ara-C), was safe and well tolerated at all doses tested up to and including the highest dose level of 2.0 mg/kg, with no major adverse events (n=45). The composite complete remission rate, including both complete remission (CR) and complete remission with incomplete blood count recovery (CRi), was 38% in subjects receiving up to two cycles of BL-8040 treatment at doses of 1 mg/kg and higher (n=39). Patients included in the study were patients that had undergone a significant number of prior treatments or that were refractory to induction treatment. The data include three compassionate-use patients treated at the study sites under the identical treatment protocol.
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Importantly, the data suggest, for the first time, a correlation between improved clinical response and patients with a high disease burden in the bone marrow, along with a lower peripheral circulation of AML blasts at baseline (indicative of potential CXCR4 disease dependency). This finding may serve as a biomarker for patient selection in future BL-8040 AML studies.
In addition, treatment with BL-8040 continues to show a triple effect on the leukemic cells. First, BL-8040 monotherapy triggered robust mobilization of AML cells from the bone marrow to the peripheral blood, thereby sensitizing these cells to the Ara-C chemotherapy and improving its efficacy. Second, BL-8040 monotherapy showed a direct apoptotic effect on the leukemia cells in the bone marrow. Last, BL-8040 induced leukemia progenitor cells towards differentiation, as evidenced by a decrease in the number of leukemia progenitor cells, along with a three-fold increase in differentiated granulocytes, in the bone marrow biopsy conducted on day 3 of the treatment cycle prior to the Ara-C treatment, as compared to the biopsy performed at baseline.
Dr. Jorge Cortes, Chief of the AML and CML Sections at the MD Anderson Cancer Center in Houston, stated, "The outlook for relapsed or refractory AML patients remains poor. I am therefore very encouraged by the response rate demonstrated using the combination of BL-8040 with Cytarabine in such patients, which is backed by a sound scientific rationale. The response rate is especially compelling for the identified sub-population. These impressive clinical results from the Phase 2 study support further development of the compound in the AML space."
Dr. Kinneret Savitsky, CEO of BioLineRx, commented, "We are very enthusiastic about the positive results from the Phase 2 trial with BL-8040 for the treatment of relapsed or refractory AML. We are especially excited that for the first time, we see a direct correlation between clinical response and a specific subset of the study patient population. Given that AML is a heterogeneous disease, the ability to pre-define the population that may benefit from CXCR4 inhibition is very important for future development."
"The results continue to demonstrate that BL-8040 not only significantly induces mobilization of leukemic cells from the protective microenvironment of the bone marrow into the peripheral blood, but also directly leads to apoptosis of leukemic progenitor cells and triggers terminal differentiation of the cells into granulocytes. Combined with the impressive remission rate reported from subjects receiving BL-8040 doses of 1 mg/kg or higher, the results strongly suggest that BL-8040 has potent anti-leukemic activity and, in combination with Cytarabine, may improve the response typically achieved in this advanced AML population. These successful results also reinforce our excitement about BL-8040’s overall potential in the AML space, including as an AML consolidation treatment that is currently being investigated in a large Phase 2b study at approximately 25 sites in Germany. Given these positive results, we now plan to meet with the regulatory authorities to discuss the next steps in the development of this promising program."
"In order to further expand and enhance the potential of this unique oncology platform, we are continuing to perform and plan multiple additional clinical studies for BL-8040, including our recently announced immuno-oncology collaboration with Merck on a Phase 2 study to investigate BL-8040 in combination with KEYTRUDA for the treatment of pancreatic cancer," concluded Dr. Savitsky.
About the r/r AML Phase 2 study
The Phase 2 trial was a multicenter, open-label study under an IND, conducted at ten clinical sites in the U.S. and Israel, and was designed to assess the safety, efficacy pharmacodynamics and pharmacokinetic parameters of BL-8040 in combination with Cytarabine (Ara-C) for the treatment of adult relapsed or refractory AML patients. Forty-two patients with r/r AML were enrolled in the study (36 of which received a dose of 1 mg/kg and higher). The study included a dose escalation stage followed by an expansion stage. Each patient received a once daily dose of BL-8040 monotherapy (from 0.5 to 2.0 mg/kg) on days 1-2, followed by the same dose of BL-8040 plus Ara-C on days 3-7. Extensive pharmacodynamic parameters, such as mobilization of leukemic cells and induction of apoptosis, were assessed after monotherapy with BL-8040 using peripheral blood sampling and bone marrow aspirates at baseline and on Day 3 prior to Ara-C administration. Clinical response to treatment was evaluated by bone marrow biopsy on Day 30.
About BL-8040
BL-8040 is a clinical-stage drug candidate for the treatment of acute myeloid leukemia, as well as other hematological indications. It is a short cyclic peptide that functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis (growth of new blood vessels in the tumor), metastasis (spread of the disease to other organs or organ parts) and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a Phase 1/2, open-label, dose escalation, safety and efficacy clinical trial in 18 multiple myeloma patients, BL-8040, when combined with G-CSF, demonstrated an excellent safety profile at all doses tested and was highly effective in the mobilization of hematopoietic stem cells and white blood cells from the bone marrow to the peripheral blood. Additionally, in a Phase 1 stem-cell mobilization study in healthy volunteers, BL-8040 as a single agent was safe and well tolerated at all doses tested and resulted in efficient stem-cell mobilization and collection in all study participants. Importantly, the results of this study support the use of BL-8040 as one-day, single-dose collection regimen, which is a significant improvement upon the current standard of care.
BL-8040 also mobilizes cancer cells from the bone marrow and may therefore sensitize these cells to chemo- and bio-based anti-cancer therapy. Importantly, BL-8040 has also demonstrated a direct anti-cancer effect by inducing apoptosis. Pre-clinical studies show that BL-8040 inhibits the growth of various tumor types including multiple myeloma, non-Hodgkin’s lymphoma, leukemia, non-small cell lung carcinoma, neuroblastoma and melanoma. BL-8040 also significantly and preferentially stimulated apoptotic cell death of malignant cells (multiple myeloma, non-Hodgkin’s lymphoma and leukemia). Significant synergistic and/or additive tumor cell killing activity has been observed in-vitro and in-vivo when tumor cells were treated with BL-8040 together with Rituximab, Bortezomib, Imatinib, Cytarabine and the FLT-3 inhibitor AC-220 (in NHL, MM, CML, AML, and AML-FLT3-ITD models, respectively). In addition, the recently completed Phase 2 clinical trial in AML patients has demonstrated robust mobilization and apoptosis of cancer cells, along with a clinically meaningful response rate. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.
About Acute Myeloid Leukemia (AML)
Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow and is the most common type of acute leukemia in adults. According to the American Cancer Society, approximately 19,000 new cases of AML were diagnosed in the United States in 2014, and the median age of AML patients was 67 years old. The first treatment line for patients with AML includes a combination of chemotherapy drugs and is called induction treatment. The median survival for AML patients receiving induction chemotherapy is less than two years, with shorter survival for patients over the age of 60 or for those with certain gene or chromosome aberrations. Due to relapsed or refractory disease (where the disease is not responsive to standard treatments), the overall five-year survival rate for AML is between 10 and 40 percent.
Advaxis Combination Trial with MedImmune Completes First Dose-Escalation Cohort
On March 29, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical stage biotechnology company developing cancer immunotherapies, reported their combination study with MedImmune, the global biologics research and development arm of AstraZeneca, has completed the first dose-escalation cohort in a study evaluating axalimogene filolisbac (AXAL) in combination with durvalumab and has commenced the second dose-escalation cohort (Press release, Advaxis, MAR 29, 2016, View Source [SID:1234510102]). Schedule your 30 min Free 1stOncology Demo! The study is evaluating the safety and efficacy of AXAL, Advaxis’ lead immunotherapy candidate, in combination with MedImmune’s investigational anti-PD-L1 immune checkpoint inhibitor, durvalumab, for the treatment of patients with advanced, recurrent or refractory human papillomavirus (HPV)-associated cervical cancer and HPV-associated head and neck cancer.
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"I am proud that we have reached this stage because combination therapies hold great potential for cancer patients," said Daniel J. O’Connor, President and Chief Executive Officer at Advaxis. "This trial is exploring how we can harness the power of immuno-oncology to block anti-tumor T-cell immunity and simultaneously target HPV-associated cancers. It is these kinds of combination therapies that may dramatically change the course of how we treat cancer."
The first dose-escalation cohort evaluated AXAL at 1×109 cfu with 3mg/kg durvalumab and the second dose-escalation cohort will now examine AXAL at 1×109 cfu in combination with 10mg/kg durvalumab. Upon completion of dose escalation, the Phase II study will randomize 90 patients to receive AXAL in combination with durvalumab vs. durvalumab alone. The primary efficacy endpoints include objective response rate and progression-free survival.
The companies plan to submit an abstract to a major medical meeting on the dose-escalation portion of the study in the second half of the year. Further information about the Phase I/II 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 an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). PD-L1 can be expressed by tumors to evade detection by the immune system through binding to PD-1 on cytotoxic T lymphocytes. Durvalumab blocks the PD-L1 interaction with PD-1, countering the tumor’s immune-evading tactics. Durvalumab is being developed, alongside other immunotherapies, to empower the patient’s immune system and attack the cancer. Durvalumab is being investigated in an extensive clinical trial program, as monotherapy or in combination with tremelimumab, in NSCLC, head and neck, bladder, gastric, pancreatic, HCC and blood cancers.
Bayer Receives Approval for Xofigo® in Japan (for specialized target groups only)
On March 29, 2016 Bayer reported that the Ministry of Health, Labour and Welfare (MHLW) in Japan has granted marketing authorization for Xofigo (radium-223 dichloride, radium-223) for the treatment of patients with castration-resistant prostate cancer and bone metastases (Press release, Bayer, MAR 29, 2016, View Source [SID:1234510092]). The product is already approved in more than 40 countries worldwide, including the U.S. and the countries of the European Union (EU). Schedule your 30 min Free 1stOncology Demo! "A majority of men living with advanced prostate cancer develop bone metastases, resulting in symptoms that can interfere with daily life, such as tiredness, weakness or difficulty doing normal activities, and decreased overall survival," explained Dr. Hiroji Uemura, associate professor and department director of Urology and Renal Transplantation, Yokohama City University Medical Center. "Xofigo has an anti-tumor effect that enables us to directly target bone metastases and potentially prolong survival, a critical treatment goal for patients with advancing disease. In addition, it is expected to delay the time to the first symptomatic skeletal event."
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Prostate cancer is the second most commonly diagnosed malignancy in men worldwide, and its incidence is rising in Japan. Prostate cancer is the fifth leading cause of death from cancer in men worldwide and the sixth leading cause of death from cancer in Japanese men.
"We are pleased that Xofigo is now available in Japan, providing a new and innovative therapy with a proven clinical benefit to patients with advanced disease," said Dr. Joerg Moeller, member of the Executive Committee of Bayer AG’s Pharmaceutical Division and Head of Development. "Prostate cancer has a significant impact on men in Japan, and this is an important step in our ongoing commitment to deliver therapies to patient’s need."
The approval is based on data from the pivotal Phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial, as well as data from additional trials to evaluate the safety and efficacy of radium-223 in Japanese patients. At the interim analysis of the ALSYMPCA trial, radium-223 significantly improved overall survival (OS) [HR=0.681 (95% CI 0.542-0.857), p=0.00096]. The second analysis conducted after the study was unblinded showed a further improvement in OS for patients treated with radium-223 vs. placebo, with a median OS of 14.9 months vs. 11.3 months [HR=0.695 (95% CI 0.581-0.832)]. Median time to first symptomatic skeletal event, a secondary endpoint in ALSYMPCA, was 15.6 months for radium-223 versus 9.8 months for placebo [HR= 0.658 (95% CI 0.522-0.830)].
The most common adverse events (occurring at a rate of 25% or greater, all grades) in patients receiving radium-223 in the ALSYMPCA trial were bone pain (patients treated with radium-223: 51.7%, patients in the placebo group: 63.5%), nausea (35.5%, 33.9%), anemia (31.2%, 30.6%), fatigue (26.5%, 25.9%), diarrhea (25.7%, 15.0%). The most common hematologic laboratory abnormalities were anemia (31.2%, 30.6%), neutropenia (5.0%, 1.0%), pancytopenia (2.0%, 0%), thrombocytopenia (4.2%, 0.3%) and lymphocytopenia (0.8%, 0.3%).
ALSYMPCA Trial Design
The ALSYMPCA trial was a Phase III, randomized, double-blind, placebo-controlled international study of Xofigo with best standard of care vs. placebo with best standard of care in symptomatic castration-resistant prostate cancer (CRPC) patients with bone metastases. Interim and updated analyses of the trial showed Xofigo significantly improved overall survival.
About Castration-Resistant Prostate Cancer (CRPC) and Bone Metastases
The stage of prostate cancer is one of the most important factors in determining treatment options and the outlook for recovery. If prostate cancer spreads, or metastasizes, beyond the prostate gland, it often first grows into nearby tissues or lymph nodes before spreading to the bones.
CRPC is an advanced form of prostate cancer. Approximately nine in 10 patients with advanced prostate cancer (90 percent) develop bone metastases, impacting survival and quality of life. In fact, bone metastases lead to an increased risk of morbidity and death in patients with CRPC. Therefore, diagnosing and treating bone metastases at the earliest onset is critical for patients.
About Xofigo (radium-223 dichloride)
Xofigo is an alpha particle-emitting therapeutic anti-tumor pharmaceutical. The active ingredient in Xofigo is the alpha particle-emitting isotope radium-223, which mimics calcium and selectively targets bone, specifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite. The high linear energy transfer of alpha emitters leads to a high frequency of double-strand DNA breaks in adjacent tumor cells, resulting in a potent cytotoxic effect. The alpha particle range from radium-223 is less than 100 micrometers, which minimizes damage to the surrounding normal tissue.
In countries of the EU, Xofigo is indicated for the treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. Radium-223 is also being studied in additional trials for men with prostate cancer as well as in Phase II studies for women with breast cancer.