On June 24, 2015 Spectrum Pharmaceuticals reported the publication of results from the pivotal BELIEF (CLN-19) Study, which was selected as a Rapid Communication in the Journal of Clinical Oncology (JCO), the journal of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (Press release, Spectrum Pharmaceuticals, JUN 24, 2015, View Source [SID:1234505796]).

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The study, led by Dr. Owen O’Connor from the Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, NY, showed that monotherapy with Beleodaq produced complete and durable responses with manageable toxicity in patients with R/R PTCL across the major subtypes, irrespective of the number or type of prior therapies.

Beleodaq, previously known as belinostat, is a histone deacetylase (HDAC) inhibitor indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on tumor Response Rate and Duration of Response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

Peripheral T-cell lymphomas are a diverse group of non-Hodgkin lymphomas with a poor prognosis and no accepted standard of care for relapsed or refractory patients. Unfortunately, current treatment options for most of these patients induce responses in only a minority of cases ( < 30%), and thus long-term survival is relatively poor. The BELIEF study evaluated the efficacy and tolerability of Beleodaq as a single agent in R/R PTCL. This study was an open-label, single-arm, non-randomized, international trial conducted at 62 centers that enrolled 129 patients with R/R PTCL, who had progressed following ≥1 prior therapy with a median number of prior therapies of two (1-8). These patients received Beleodaq (1,000 mg/m2) as daily 30-minute infusions on Days 1-5 every 21 days until disease progression or unacceptable toxicity.

The primary endpoint of the BELIEF study was ORR as assessed centrally by an Independent Review Committee using the International Working Group (IWG) criteria. The ORR in the 120 evaluable patients was 25.8% (31 patients) (95% CI 18.3 – 34.6), including 13 Complete Responses (10.8%) (95% CI 5.9 – 17.8) and 18 Partial Responses (15%) (95% CI 9.1 – 22.7). Secondary endpoints included a median DoR of 13.6 months by IWG criteria and 8.4 months to disease progression or death, with the longest ongoing patient at ≥36 months. The most common Grade 3/4 adverse events were anemia (10.8%), thrombocytopenia (7%), dyspnea (6.2%), and neutropenia. No clinically relevant ECG changes were identified, and cardiovascular monitoring of ECGs is not required at baseline or during treatment. In this pivotal study, monotherapy with Beleodaq produced complete and durable responses with manageable toxicity in patients with R/R PTCL across the major disease subtypes, irrespective of the number or type of prior therapies and with a low incidence of Grade 3/4 thrombocytopenia.

"We are pleased to have the results of the pivotal Beleodaq study selected for publication as a Rapid Communication in such a prominent journal," said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. "This is a highly distinguished category that JCO reserves for papers judged to have special impact to their broad clinical readership. Spectrum has a unique PTCL franchise, marketing two FDA approved drugs for this indication, Folotyn (pralatrexate injection) and Beleodaq. We are very proud to be able to offer patients and clinicians more treatment options with two approved treatments for R/R PTCL."

"This is a very exciting time in the treatment of patients with PTCL," said Dr. Owen A. O’Connor, MD, PhD, Director of the Center for Lymphoid Malignancies, Professor of Medicine and Experimental Therapeutics at Columbia Medical Center, New York Presbyterian Medical Center, one of the lead investigators in the BELIEF study. "At long last we finally have tools in the therapeutic armamentarium to help our patients. Belinostat represents the latest drug approved for patients with R/R PTCL that has relatively few side effects and produces long durations of benefit, even in patients who have received multiple conventional treatments in the past. Now that we have several new options to treat the disease when it comes back, we need to use these drugs to make better up-front treatment platforms; Belinostat will be an important part of that future."

On June 23, 2015 Synta Pharmaceuticals reported the publication in this month’s issue of Cancer Immunology Research of an in-depth review describing the rationale for pursuing the combination of Hsp90 and immune checkpoint inhibition for cancer therapy (Press release, Synta Pharmaceuticals, JUN 23, 2015, View Source [SID:1234505793]).

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The review article, titled "Targeting Heat-Shock Protein 90 (Hsp90) as a Complementary Strategy to Immune Checkpoint Blockade for Cancer Therapy," is available online at View Source Synta is currently studying the Hsp90 inhibitor ganetespib in several randomized studies, including the GALAXY-2 trial, a global, randomized, multi-center Phase 3 study of ganetespib and docetaxel for the second-line treatment of advanced non-small cell lung adenocarcinoma.

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The review article describes preclinical findings that suggest that proteasomal degradation of cellular client proteins associated with Hsp90 inhibition may augment antitumor immune response through increased cellular antigen expression and subsequent enhanced T-cell recruitment and tumor-cell recognition. The review article also explains that client proteins affected by Hsp90 inhibition include oncogenes that may drive expression of Programmed Death-Ligand 1 (PD-L1), a key immune checkpoint. The resulting reduction of PD-L1 expression on tumor cells may increase T-cell mediated cytotoxic activity and complement the activity of selective anti-PD-1 or anti-PD-L1 antibody therapies. This is supported by in vivo study results, where ganetespib was found to potentiate the antitumor efficacy of anti-PD-L1 antibody treatment. In these studies, the combination of ganetespib and an anti-PD-L1 antibody displayed significantly greater antitumor activity than either individual agent, in mouse models of both colon carcinoma and melanoma.

"While there is still more to learn regarding the mechanistic basis for combining Hsp90 and immune checkpoint inhibitors, and the role of Hsp90 in antitumor immunity, the findings in this review suggest that this approach may be complementary and therapeutically advantageous. We look forward to exploring the combination of immune checkpoint inhibitors and ganetespib in future clinical studies," said Chen Schor, President and Chief Executive Officer of Synta. "Our team and collaborators are also conducting preclinical studies investigating potential combinations of ganetespib and other emerging forms of immunotherapy for cancer, including T-cell therapy. We are encouraged by our progress thus far and will look to present and publish results of these studies in the future."

On June 23, 2015 BIND Therapeutics reported that the U.S. Food and Drug Administration (FDA) has authorized the use of AstraZeneca’s Accurin AZD2811 in clinical trials under an investigational new drug (IND) application (Press release, BIND Therapeutics, JUN 23, 2015, View Source [SID:1234505791]).

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BIND is collaborating with AstraZeneca on the development of AZD2811, an Aurora B Kinase inhibitor that has been shown to be active in both solid and hematological tumors in preclinical models, and the companies anticipate enrolling patients in a phase 1 clinical trial with AZD2811 in the fourth quarter of this year. BIND will earn a $4 million milestone payment upon first dosing a patient in a phase 1 clinical trial with AZD2811.

Preclinical data on AZD2811 were presented at the 2015 American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual meeting in April 2015, including data demonstrating promising in vivo and in vitro tumor growth inhibition as monotherapy in models of diffuse large B-cell lymphomas (DLBCL) and small cell lung cancer (SCLC). Additional data showed that AZD2811 delivers prolonged exposure to active drug while having the potential to adapt the dosing regimen, potentially achieving an improved therapeutic index. In addition, using mass spectrometric imaging, AZD2811 was shown to accumulate in tumors and achieve prolonged tumor drug exposure. This represents the first time distribution of nanoparticles in tumors has been demonstrated. Previously, preclinical tumor model data were presented showing that AZD2811 minimizes the bone marrow toxicity seen with the parent compound, which has limited the clinical utility of Aurora B kinase inhibitors as a class.

"We have worked diligently with our collaborators at AstraZeneca to quickly advance the Aurora B kinase inhibitor program, AZD2811, through preclinical development," said Andrew Hirsch, president and chief executive officer of BIND Therapeutics. "The data recently presented at AACR (Free AACR Whitepaper) describing the optimized pharmacological properties of AZD2811 further demonstrate the unique attributes of Accurins as a new treatment modality with the potential to produce therapeutics with best-in-class profiles. With AZD2811 now cleared to begin a phase 1 study, we are positioned to have two Accurins in clinical development, with our lead Accurin BIND-014 currently in phase 2 studies."

BIND and AstraZeneca expect to enroll the first patient in a phase 1 clinical trial with AZD2811 in the fourth quarter of 2015. Under terms of the collaboration, AstraZeneca is responsible for clinical development and commercialization and BIND is responsible for conducting clinical manufacturing through at least the end of phase 2 clinical trials.

About Accurins
Accurins, a new class of targeted therapeutics developed using BIND’s Medicinal Nanoengineering platform, are nanoparticles engineered to have a profound impact on the treatment of disease. The elegant and novel design of Accurins allow for prolonged circulation, controlled and tunable release and selective targeting of a therapeutic payload to diseased tissue or cells while avoiding immune surveillance detection and systemic toxicities.

Accurins can be engineered for multiple therapeutic applications and have the potential to integrate numerous payloads, including highly potent drugs with mechanism-based toxicities that limit therapeutic benefit, DNA, RNA, proteins and immunotherapy agents. This attribute enables Accurins to target multiple diseases, including cancer, inflammatory, vascular, and infectious disease.