On April 18, 2017 Argos Therapeutics Inc. (Nasdaq:ARGS), an immuno-oncology company focused on the development and commercialization of individualized immunotherapies based on the Arcelis precision immunotherapy technology platform, reported interim results from its randomized, active controlled, open-label, multi-center Phase 3 ADAPT trial of Rocapuldencel-T in combination with sunitinib/standard-of-care for the treatment of newly diagnosed metastatic renal cell carcinoma (mRCC) (Press release, Argos Therapeutics, APR 18, 2017, View Source [SID1234518608]). The Company also provided perspective on its decision to continue the trial.

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A total of 462 patients were enrolled in the ADAPT study and randomized 2:1 between combination treatment with Rocapuldencel-T and sunitinib (combination arm) vs. sunitinib monotherapy (control arm). For both arms, the protocol permits switching to other standard-of-care treatments for mRCC for reasons such as intolerance to therapy or disease progression. The primary efficacy endpoint for the study is a statistically significant improvement in overall survival, with secondary efficacy endpoints evaluated to date of progression-free survival, objective response rate and disease control rate, and an exploratory efficacy endpoint of immune response. The trial was opened in January 2013 and completed enrollment in July 2015 at 107 sites across North America, Europe and Israel.

The most recent interim analysis was conducted by the Independent Data Monitoring Committee (IDMC) in February 2017 (data cut-off as of February 3, 2017) after 75% of the targeted number of 290 events (deaths) for the analysis of the primary endpoint of overall survival had occurred. In accordance with the statistical analysis plan, median overall survival was estimated using the Kaplan-Meier method. At the time of the interim analysis, the estimated median overall survival for the combination arm was 27.7 months (95% Confidence Interval (CI): 23.0, 35.9) compared to 32.4 months (95% CI: 22.5, -) for the control arm. The hazard ratio was 1.10 (95% CI: 0.83, 1.46), which was greater than the pre-defined futility boundary for the final interim analysis of 0.98. As a result, the IDMC recommended that the study be discontinued for futility. The IDMC concluded that the study was unlikely to demonstrate a statistically significant improvement in overall survival in the combination arm, utilizing the intent-to-treat population, the primary endpoint of the study. The IDMC also noted that Rocapuldencel-T was generally well-tolerated in the trial.

As previously reported, notwithstanding the IDMC recommendation, the Company determined to continue to conduct the trial pending further review and analysis of the data and discussions with the FDA. This determination was made after discussion of the results of the interim analysis with the ADAPT trial principal investigators, Robert Figlin, MD (Cedars Sinai) and Christopher Wood, MD (MD Anderson Cancer Center). In making this determination, Argos considered, among other factors, the degree of maturity of the data set, the mechanism of action of Rocapuldencel-T, which involves the induction of long-term memory immune responses, and the IDMC’s assessment of the safety profile of Rocapuldencel-T. Of note, at the time of the IDMC’s February interim analysis, the median duration of follow-up was 20.0 months and more than half the patients in both treatment groups were still alive.

Subsequent to the IDMC meeting, to explore the hypothesis that longer follow-up time may provide useful information to identify a potential beneficial effect of Rocapuldencel-T, the Company conducted a post-hoc subgroup analysis of overall survival in the first third of patients enrolled in the study (n=154). In these patients, for whom generally the longest follow-up data was available, the estimated median overall survival for the combination arm was 30.1 months (95% CI: 23.3, -) compared to 22.2 months (95% CI: 17.2, -) for the control arm. The hazard ratio in this post-hoc subgroup analysis was 0.88 (95% CI: 0.56, 1.36).

In addition, also subsequent to the IDMC meeting, the Company began conducting a pre-defined analysis of immune responses, an exploratory efficacy endpoint, using multi-parametric flow cytometry. Data available as of March 31, 2017 included 109 of the 190 samples from patients in the combination arm, with analysis of the remaining samples ongoing. Samples were collected from patients in the combination arm enrolled at US sites who provided consent for immune monitoring. Of the 109 subjects for whom this analysis was completed, 96 (88%) met the criterion for inclusion in the pre-defined subgroup of immune responders, suggesting that Rocapuldencel-T is having its intended effect of stimulating an immune response in the majority of patients. Immune responders are defined as patients who have an increase of more than two standard deviations from the patient-specific baseline in the number of memory T cells (CD8+/CD28+/CD45RA-) at one or more time points. Of note, median overall survival at the time of the February interim analysis had not yet been reached in the subgroup of immune responders (95% CI: 30.1, -). Additionally, consistent with the mechanism of action of Rocapuldencel-T, a statistically significant correlation was observed between the increase from baseline in the number of Rocapuldencel-T-induced memory T cells (CD8+/CD28+/CD45RA-) and overall survival in patients for whom immune response data has been analyzed and who received at least seven doses of Rocapuldencel-T (including both immune responders and non-responders, n=72).

The Company continues to analyze the data from the trial and plans to meet with the FDA in May 2017, but currently believes based on the data it has reviewed that the trial should be continued until completion. Based on these analyses and discussions, the Company will make a determination as to the next steps for the Rocapuldencel-T clinical program.

About the Arcelis Technology Platform

Arcelis is a precision immunotherapy technology that captures both mutated and variant antigens that are specific to each patient’s individual disease. It is designed to overcome immunosuppression by producing a specifically targeted, durable memory T cell response without adjuvants that may be associated with toxicity. The technology is potentially applicable to the treatment of a wide range of different cancers and infectious diseases, and is designed to overcome many of the manufacturing and commercialization challenges that have impeded other personalized immunotherapies. The Arcelis process uses only a small disease sample or biopsy as the source of disease-specific antigens, and the patient’s own dendritic cells, which are optimized from cells collected by a single leukapheresis procedure. The proprietary process uses RNA isolated from the patient’s disease sample to program dendritic cells to target disease-specific antigens. These activated, antigen-loaded dendritic cells are then formulated with the patient’s plasma, and administered via intradermal injection as an individualized immunotherapy.

On April 18, 2017 Mateon Therapeutics, Inc. (OTCQX:MATN), a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of orphan oncology indications, reported interim data from its first scheduled analysis of the ongoing Phase 2/3 study (FOCUS) in patients with platinum resistant ovarian cancer (prOC) (Press release, Mateon Therapeutics, APR 18, 2017, View Source [SID1234518606]).

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The interim analysis was conducted after the first 20 patients enrolled into the trial had been treated for at least two months or had discontinued from the trial. The analysis was conducted primarily to evaluate the safety of the triplet drug combination as well as to evaluate early signs of efficacy.

"I am encouraged that the safety data is better than we expected and that the efficacy data is in line with our expectations," stated William D. Schwieterman, M.D., President and Chief Executive Officer. "After executing on the strategy we developed in late 2015, it is gratifying to be able to report new data for CA4P supporting its use in combination with bevacizumab and chemotherapy as a new treatment for platinum-resistant ovarian cancer. I am eager to see results from the additional interim analyses planned for later this year."

Safety Results

No significant safety issues were identified in the interim analysis, and the overall safety profile of CA4P was similar to or better than results seen in previous randomized trials of CA4P. Most adverse events that occurred more frequently in the CA4P-treated arm were mild to moderate in severity.

As expected, the most common adverse event observed was an acute increase in blood pressure, which peaked within an hour of infusion and then dissipated over the next two to three hours. Nearly all patients (89%) receiving CA4P experienced some blood pressure increase, compared to 20% of patients in the control arm. Rates of grade 3 hypertension were similar between the treatment and control groups, and there were no cases of grade 4 hypertension. Other adverse events that occurred more frequently in the treatment arm included anemia, abdominal pain, constipation, nausea, vomiting, fatigue, cough, mucosal inflammation and dyspnoea (breathing difficulty).

There was a lower than expected rate of hematological adverse events, and no patients receiving CA4P experienced neutropenia or leukopenia (low blood counts of neutrophils or white blood cells).

There were no cardiovascular adverse events reported.

Efficacy Results

Progression free survival, the primary endpoint of the study, currently favors the CA4P arm of the study, although Mateon believes that it is too early in the clinical trial to draw any conclusions.

Two of nine (22%) patients treated with CA4P had partial responses (PR) compared to one of eleven (9%) in the control arm. The magnitude of the responses was larger in the active treatment arm, with reductions in lesion size of approximately 76% and 64% for the patients receiving CA4P compared to a reduction of 46% for the patient receiving control.

About FOCUS
The FOCUS Study is a randomized, double-blind, 2-arm, parallel-group, phase 2/3 study to evaluate the efficacy and safety of physician’s choice chemotherapy (PCC) plus bevacizumab and CA4P versus PCC plus bevacizumab in patients with platinum-resistant ovarian cancer. The primary endpoint of the FOCUS Study is progression free survival (PFS). The Study will also evaluate CA4P’s effect on objective response rate (ORR), overall survival (OS) and other parameters. For additional information on the FOCUS Study, please visit www.clinicaltrials.gov, study identifier NCT02641639.

On April 18, 2017 Novartis reported that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to CTL019, an investigational chimeric antigen receptor T cell (CAR-T) therapy, for the treatment of adult patients with relapsed and refractory (r/r) diffuse large B-cell lymphoma (DLBCL), who have failed two or more prior therapies (Press release, Novartis, APR 18, 2017, View Source [SID1234518601]). This is the second indication for which CTL019 has received this designation; the first being for the treatment of r/r B-cell acute lymphoblastic leukemia (ALL) in pediatric and young adult patients.

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"At Novartis, we are eager to unlock the full potential of CTL019, including the potential to help patients with r/r DLBCL," said Vas Narasimhan, Global Head of Drug Development and Chief Medical Officer, Novartis. "We look forward to working closely with the FDA to help bring this potential new treatment option to patients as soon as possible."

CAR-T cell therapy is different from typical small molecule or biologic therapies currently on the market because it is manufactured for each individual patient. During the treatment process, T cells are drawn from a patient’s blood and reprogrammed in the laboratory to create T cells that are genetically coded to hunt the patient’s cancer cells and other B-cells expressing a particular antigen.

CTL019 was first developed by the University of Pennsylvania (Penn). In 2012, Novartis and Penn entered into a global collaboration to further research, develop and then commercialize CAR-T cell therapies, including CTL019, for the investigational treatment of cancers. Through the collaboration, Novartis holds the worldwide rights to CARs developed with Penn for all cancer indications. In March 2017, Novartis announced that the FDA accepted the company’s Biologics License Application filing and granted priority review for CTL019 in the treatment of r/r pediatric and young adult patients with B-cell ALL.

The Breakthrough Therapy designation is based on data from the multi-center Phase II JULIET study (NCT02445248), which is evaluating the efficacy and safety of CTL019 in adult patients with r/r DLBCL. JULIET is the second global CAR-T trial, following the Novartis ELIANA study (NCT02435849) investigating CTL019 in r/r B-cell ALL. Findings from JULIET are expected to be presented at an upcoming medical congress.

"We are encouraged by the FDA’s recognition in the potential of CTL019 for this indication, which follows our promising studies of this therapy for ALL and the FDA filing by Novartis in pediatric and young adult ALL that received priority review," said the Penn team’s leader, Carl June, MD, director of the Center for Cellular Immunotherapies in the Perelman School of Medicine at the University of Pennsylvania. "Work with our collaborators at trial sites across the world is paving a path to bring personalized cell therapies to more patients with these devastating blood cancers."

According to FDA guidelines, treatments that receive Breakthrough Therapy designation are those that treat a serious or life threatening disease or condition and demonstrate a substantial improvement over existing therapies on one or more clinically significant endpoints based on preliminary clinical evidence. The designation also indicates that the agency will expedite the development and review of CTL019 in adults with r/r DLBCL. This marks the 14th Breakthrough Therapy designation for Novartis since the FDA initiated the program in 2013, underscoring an emphasis to develop innovative treatments in disease areas with significant unmet need.

DLBCL is the most common form of lymphoma and accounts for approximately 30 percent of all non-Hodgkin lymphoma cases[1]. Ten to 15 percent of DLBCL patients fail to respond to initial therapy or relapse within three months of treatment, and an additional 20 to 25 percent relapse after initial response to therapy[2].

Because CTL019 is an investigational therapy, the safety and efficacy profile has not yet been established. Access to investigational therapies is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the therapy. Because of the uncertainty of clinical trials, there is no guarantee that CTL019 will ever be commercially available anywhere in the world.

On April 18, 2017 Cellectar Biosciences, Inc. (Nasdaq: CLRB) (the "company"), an oncology-focused, clinical stage biotechnology company, reported the Japanese Patent Office has granted a method of use patent for two of the company’s phospholipid drug conjugates (PDCs), CLR 131, the company’s lead compound, and CLR 125, each in combination with radiation and/or other therapies to treat cancer stem cells. CLR 125 is a radiotherapeutic isotope conjugated to the company’s proprietary PDC delivery platform, which may be uniquely suited to treat select cancer and micro-metastatic disease (Press release, Cellectar Biosciences, APR 18, 2017, View Source [SID1234518603]).

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The recently issued method of use patent, JP 6092624 includes seven claims for CLR 131 and CLR 125 in treating cancer stem cells in a variety of cancers, including brain (glioma), kidney, colorectal, ovarian, prostate, breast, pancreatic and skin cancers, as well as squamous cell carcinoma. The claims further specify the combination of either CLR 131 or CLR 125 with external beam radiation as part of combination therapy with chemotherapy, tumor resection, ablative therapy, or local physical treatment on the basis of cold (cryo), heat (thermal), radiofrequency, and microwave treatments. The patent allows intellectual property protection in Japan through June 11, 2030.

"This method of use patent strengthens our intellectual property portfolio in a strategic market and further validates the clinical utility of our PDC compounds on both cancer cells and cancer stem cells," said Jim Caruso, president and CEO of Cellectar. "We continue to be encouraged by the progress in the clinical development of our lead compound CLR 131, and this expanded patent protection further supports our belief in its utility in blood cancers, for which we are currently conducting both a Phase I and II trial, as well as its potential in other cancer types."

About CLR 131
CLR 131 is an investigational compound under development for a range of hematologic malignancies. It is currently being evaluated as a single-dose treatment in a Phase I clinical trial in patients with relapsed or refractory (R/R) multiple myeloma as well as in a Phase II clinical trial for R/R MM and select R/R lymphomas with either a one- or two-dose treatment. Based upon preclinical and interim Phase I study data, treatment with CLR 131 provides a novel approach to treating hematological diseases and may provide patients with therapeutic benefits, including overall survival, an improvement in progression-free survival, surrogate efficacy marker response rate, and overall quality of life. CLR 131 utilizes the company’s patented PDC tumor targeting delivery platform to deliver a cytotoxic radioisotope, iodine-131, directly to tumor cells. The FDA has granted Cellectar an orphan drug designation for CLR 131 in the treatment of multiple myeloma.

About Phospholipid Drug Conjugates (PDCs)
Cellectar’s product candidates are built upon its patented cancer cell-targeting delivery and retention platform of optimized phospholipid ether-drug conjugates (PDCs). The company deliberately designed its phospholipid ether (PLE) carrier platform to be coupled with a variety of payloads to facilitate both therapeutic and diagnostic applications. The basis for selective tumor targeting of our PDC compounds lies in the differences between the plasma membranes of cancer cells compared to those of normal cells. Cancer cell membranes are highly enriched in lipid rafts, which are glycolipoprotein microdomains of the plasma membrane of cells that contain high concentrations of cholesterol and sphingolipids, and serve to organize cell surface and intracellular signaling molecules. PDCs have been tested in more than 80 different xenograft models of cancer.