On July 6, 2015 Janssen Biotech reported the opening of a daratumumab expanded access program (EAP) for eligible U.S. patients (Press release, Johnson & Johnson, JUL 6, 2015, View Source [SID:1234506170]).

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Daratumumab is an investigational human anti-CD38 monoclonal antibody being evaluated in clinical trials as a treatment for people with multiple myeloma. The multicenter, open-label EAP is available to multiple myeloma patients who are refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) or who have received three or more prior lines of therapy, including a PI and an IMiD. This is referred to as "double refractory" multiple myeloma, which occurs when a patient’s disease has become resistant to at least two of the most commonly utilized and active classes of anti-myeloma agents.

"We understand that heavily pre-treated or double refractory patients are in immediate need of new treatment options," said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Oncology, Janssen. "Through a research collaboration with the Multiple Myeloma Research Foundation, or MMRF, we have broadened our network of sites and sped site activation. Our goal is to provide timely access to daratumumab for multiple myeloma patients who may benefit while its application is under review with the U.S. Food and Drug Administration. MMRF’s significant experience in multiple myeloma research and innovation has helped to accelerate our efforts to meet this urgent patient need."

In the U.S., EAPs are conducted as clinical trials and designed to make investigational medicines available for patients with serious or life-threatening illnesses who are ineligible for ongoing interventional trials and have exhausted currently available treatment options.

Up to 40 medical centers in the U.S. will enroll patients in the daratumumab EAP. The MMRF played a key role in identifying sites geographically distributed across the U.S. and opening sites for enrollment.

"While we work urgently each day to find solutions for all who are fighting multiple myeloma, our most critical focus is for those individuals whose multiple myeloma has relapsed and often have few or no active treatment options," said Walter M. Capone, Chief Executive Officer and President of the MMRF. "In collaboration with pharmaceutical and biotech companies, the FDA, leading research institutions both within our wholly-owned subsidiary, the Multiple Myeloma Research Consortium and beyond, the MMRF is relentless in advancing the most promising science and accelerating the development of new, innovative multiple myeloma therapies. Our work together with Janssen on this important EAP is a perfect example of our mission in action, helping patients in every way possible, particularly at times of intense need."

On May 1, 2013, daratumumab received Breakthrough Therapy Designation from the FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an IMiD, the current standards of care, or who are double refractory to a PI and an IMiD. On June 5, 2015, Janssen announced it had initiated the rolling submission of its Biologics License Application (BLA) for daratumumab to the FDA for the treatment of this set of multiple myeloma patients. A rolling submission allows the company to submit portions of the regulatory application to the FDA as they are completed.[i] The regulatory submission for daratumumab will be primarily supported by data from the Phase 2 MMY2002 (SIRIUS) monotherapy study announced in May 2015 at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), along with additional data from four other studies, including the Phase 1/2 GEN501 monotherapy study.

About the daratumumab Expanded Access Program Protocol
The daratumumab expanded access program (EAP) is for U.S. patients 18 years of age or older who are double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) or who have received three or more prior lines of therapy, including a PI and an IMiD, who may benefit from treatment with daratumumab prior to its potential U.S. Food and Drug Administration (FDA) approval. The EAP has specific inclusion and exclusion criteria for patients to be considered for enrollment in the program, and patients must not be eligible for another daratumumab study. Interested patients should contact their physician to discuss whether they may be a candidate for daratumumab through the EAP. Additional information about the expanded access protocol can be found on clinicaltrials.gov (NCT02477891).

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.[ii] Multiple myeloma is the third most common blood cancer in the U.S., following only leukemia and lymphoma.[iii] Approximately 26,850 new patients will be diagnosed with multiple myeloma, and approximately 11,240 people will die from the disease in the U.S. in 2015.[iv] Globally, it is estimated that 114,251 people will be diagnosed and 80,019 will die from the disease.[v] While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.[vi]

About daratumumab
Daratumumab is an investigational human IgG1k monoclonal antibody (mAb) that binds with high affinity to the transmembrane ectoenzyme, CD38, on the surface of multiple myeloma cells. It induces rapid tumor cell death through diverse mechanisms of action. Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. 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 and non-Hodgkin’s lymphoma. In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab. With the exception of one study sponsored globally by the French multiple myeloma cooperative group, Intergroupe Francophone du Myelome (IFM), Janssen is the global sponsor of all current and future clinical studies for daratumumab.

On July 6, 2015 Oncolytics Biotech reported that Dr. Devalingam Mahalingam of the Cancer Therapy and Research Centre, University of Texas Health Science Centre San Antonio, made a poster presentation at the ESMO (Free ESMO Whitepaper) World Congress on Gastrointestinal Cancer (Press release, Oncolytics Biotech, JUL 6, 2015, View Source [SID:1234506168]).

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The poster, titled "Oncolytic Virus Therapy in Pancreatic Cancer: Clinical Efficacy and Pharmacodynamic Analysis of REOLYSIN in Combination with Gemcitabine in Patients with Advanced Pancreatic Adenocarcinoma," covers final results from the Company’s REO 017 Phase 2 study.

"These data suggest that this drug combination can increase median overall survival, as well as generate an approximate two-fold increase in one-year survival rates, and a five-fold increase in two-year survival rates when compared to gemcitabine therapy alone as seen in historical data," said Dr. Matt Coffey, COO of Oncolytics. "The observation of clear overall survival (OS) benefit combined with apparent limited impact on progression free survival (PFS) is increasingly becoming characteristic of immune-based therapeutic treatments. We are incorporating this finding into both our new and existing studies to ensure we follow OS where possible."

Highlights of the data presented include:

A survival analysis for 33 patients showing a median progression free survival (PFS) of four months and median overall survival (OS) of 10.2 months;
Data showing one- and two-year survival rates of 45% and 24%, respectively; and
An analysis demonstrating upregulation of immune checkpoint marker PD-L1 in post treatment tumours suggesting the potential to combine oncolytic viral therapy with anti-PD-L1 inhibitors in future trials.

Of the 29 patients evaluable for clinical response, one patient had a partial response (PR), 23 had stable disease (SD) and five had progressive disease as their best response. This translated into a clinical benefit rate (CBR) (complete response (CR) + PR + SD) of 83%.

"This is the second cancer where we have confirmed that PD-L1 is upregulated in target tumors following our collaborators initial observations of PD-L1 upregulation in glioblastoma," said Dr. Brad Thompson, President and CEO of Oncolytics. "We are currently analyzing archived samples from other completed studies and current samples from ongoing studies to determine if this is a common effect to most cancers. A systemic viral therapy that generally led to upregulation of PD-L1 would allow increased use of anti PD-L1 drugs in cancers where there is insufficient PD-L1 to make therapy possible."

REO 017 is a U.S. Phase 2, single-arm clinical trial using intravenous administration of REOLYSIN in combination with gemcitabine (Gemzar) in chemotherapy-naïve patients with advanced or metastatic pancreatic cancer. Eligible patients were treated with gemcitabine at 800 mg/m2 on days 1 and 8, and REOLYSIN at 1×1010 TCID50 administered IV on days 1, 2, 8 and 9 every 3 weeks. Tumor assessment was performed every two cycles. The trial enrolled 33 evaluable patients (34 total) using a one sample, two-stage design. In the first stage, 17 patients were to be enrolled, and best response noted. If three or more responses were observed (defined as CR, PR, or SD for 12 weeks or more) among the 17 patients, the study would enroll an additional 16 patients for a total of at least 33 evaluable patients. As previously disclosed, this initial endpoint was met after six evaluable patients were enrolled. The primary objective of the trial was to determine the CBR of intravenous multiple doses of REOLYSIN in combination with gemcitabine in patients with advanced or metastatic pancreatic cancer. The secondary objectives were to determine PFS, and to determine the safety and tolerability of REOLYSIN when administered in combination with gemcitabine.

A copy of the poster presentation will be available on the Oncolytics website at: View Source

On July 6, 2015 ImmunoCellular Therapeutics reported the establishment of an agreement with Novella Clinical (Novella), to conduct the phase 3 registration trial of ICT-107 in patients with newly diagnosed glioblastoma (Press release, ImmunoCellular Therapeutics, JUL 6, 2015, View Source [SID:1234506167]).

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Novella is a full-service, global clinical research organization (CRO) providing clinical trial services to small to mid-sized oncology companies. The ICT-107 phase 3 trial will include approximately 120 clinical sites in the US, Europe and Canada, and will recruit about 400 patients with newly diagnosed glioblastoma. ImmunoCellular anticipates initiating the phase 3 trial in the fourth quarter of 2015.

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"Establishing this agreement with Novella Clinical moves us one more critical step forward in the implementation of our phase 3 ICT-107 registrational trial," said Andrew Gengos, ImmunoCellular Chief Executive Officer. "Novella’s special expertise in oncology clinical trials, combined with their strong international network, experience working with oncology cooperative groups, and reputation for high quality, efficiency and cost-effectiveness, make them an excellent partner for our ICT-107 program. We are rapidly building the infrastructure for our phase 3 program and remain on track to initiate the trial later this year."

Novella’s President Richard Staub added, "We are proud and very pleased to be selected to support this proprietary oncology immunotherapy platform for glioblastoma. We look forward to working alongside ImmunoCellular to navigate the development and successful execution of this pivotal program to ultimately benefit patients."

On July 6, 2015 ArQule reported interim data from an ongoing investigator-initiated Phase 2 clinical trial with tivantinib in combination with cetuximab in patients with MET-High, KRAS wild-type metastatic colorectal cancer (CRC) NCT01892527 who recently progressed on anti-EGFR antibodies (Press release, ArQule, JUL 6, 2015, View Source [SID:1234506164]). These data were presented on Friday, July 3rd at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) World GI 2015 (abstract number O-008) by Dr. Lorenza Rimassa, MD, Deputy Director, Medical Oncology Unit at Humanitas Cancer Center, in Rozzano (Milan, Italy).

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"Considering that in CRC objective response rate (ORR) often correlates with overall survival (OS) benefit, the preliminary results obtained combining tivantinib with cetuximab are encouraging," said Dr. Rimassa. "Since all patients enrolled in this trial were MET-High and had recently progressed on a combination regimen including cetuximab or panitumumab, the data may support the hypothesis that MET inhibition can reverse resistance to EGFR inhibitors as well as the need for rigorous tissue collection procedures at enrollment to allow for a more robust correlative outcome assessment related to the MET pathway."

The primary endpoint of the trial is ORR in the biomarker defined population. Secondary study endpoints are progression-free survival (PFS), overall survival (OS) and safety. The ESMO (Free ESMO Whitepaper) World GI presentation included data from 21 patients enrolled in Stage 1 of this trial. One patient, still on therapy, experienced a complete response (CR) and 2 patients experienced durable confirmed partial responses (PRs). Stable disease was observed in 8 patients, including 2 short duration PRs, for an overall Disease Control Rate (CR + PR + SD) of 52.4%. Having met the Stage 1 endpoint (≥2 confirmed responses), the trial continued to Stage 2 and has recently completed enrollment.

Adverse events were in line with those historically reported, including skin toxicity attributed to cetuximab, and neutropenia attributed to tivantinib. Neutropenia was addressed timely with growth factors and dose adjustments.

The trial is a 2-stage, investigator-initiated study testing tivantinib plus cetuximab after recent progression on anti-EGFR antibodies. The trial is coordinated by the Humanitas Cancer Center in Milan, Italy. Stage 1 enrolled 21 patients, and Stage 2 recently completed enrollment of 20 additional patients. Final results from the 41 patients enrolled are expected by the end of 2015.

About Colorectal Cancer (CRC)

Colorectal cancer is the second leading cause of cancer-related deaths in the U.S. and is the third most common cancer in men and women. According to the National Cancer Institute, it is estimated that more than 132,000 new cases of colorectal cancer will be diagnosed in 2015, and an estimated 49,700 deaths from the disease will occur this year. The estimated incidence rate was 42.4 per 100,000 people during the period 2008-2012.

About MET and tivantinib (ARQ 197)

Tivantinib is an orally administered, selective inhibitor of MET, a receptor tyrosine kinase, which is currently in Phase 2 and Phase 3 clinical trials. In healthy adult cells, MET can be present in normal levels to support natural cellular function, but in cancer cells, MET can be inappropriately and continuously activated. When abnormally activated, MET plays multiple roles in aspects of human cancer, including cancer cell growth, survival, angiogenesis, invasion and metastasis. The activation of certain cell signaling pathways, including MET, has also been associated with the development of resistance to anti-EGFR (epidermal growth factor receptor) antibodies such as cetuximab and panitumumab.

Pre-clinical data have demonstrated that tivantinib inhibits MET activation in a range of human tumor cell lines and shows anti-tumor activity against several human tumor xenografts. In clinical trials to date, treatment with tivantinib has been generally well tolerated and has shown clinical activity in the tumors studied. Tivantinib has not yet been approved for any indication in any country.

In December 2008, ArQule and Daiichi Sankyo signed a license, co-development and co-commercialization agreement for tivantinib in the U.S., Europe, South America and the rest of the world, excluding Japan, China (including Hong Kong), South Korea and Taiwan.