On January 5, 2017 CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA: CTIC) reported that the full clinical hold (February 2016) implemented by the U.S. Food and Drug Administration (FDA) on all clinical trials conducted under the Investigational New Drug (IND) application for pacritinib has now been removed (Press release, CTI BioPharma, JAN 5, 2017, View Source [SID1234517273]). Schedule your 30 min Free 1stOncology Demo! The Company’s complete response submission included, among other items, final Clinical Study Reports for both PERSIST-1 and 2 trials and a dose-exploration clinical trial protocol that the FDA requested. The new trial, PAC203 plans to enroll up to approximately 105 patients with primary myelofibrosis who have failed prior ruxolitinib therapy to evaluate the safety and the dose response relationship for efficacy (spleen volume reduction at 24 weeks) of three dose regimens: 100 mg once-daily, 100 mg twice-daily (BID) and 200 mg BID. The 200 mg BID dose regimen was used in PERSIST-2. The Company expects to start the trial in the second quarter of 2017.
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"We are pleased to resolve the full clinical hold through working diligently with the FDA to provide a comprehensive response to their requests," said Richard Love, Interim President and CEO of CTI BioPharma. "We look forward to discussing with the FDA the future development of pacritinib. We believe pacritinib can ultimately address the unmet need of patients with myelofibrosis who are ineligible to receive or are not benefitting from the approved JAK1/JAK2 inhibitor, ruxolitinib, as these patients have limited treatment options."
About the Phase 3 Development Program of Pacritinib
Pacritinib was evaluated in two Phase 3 clinical trials, known as the PERSIST program, for patients with myelofibrosis, with one trial in a broad set of patients without limitations on platelet counts, the PERSIST-1 trial; and the other in patients with low platelet counts, the PERSIST-2 trial. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high risk myelofibrosis including, but not limited to, patients with disease-related thrombocytopenia (low platelet counts); patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy; or patients who are intolerant of, or whose symptoms are not well controlled (sub-optimally managed) on other JAK2 therapy.
Clinical studies under the investigational new drug (IND) for pacritinib were subject to a full clinical hold issued by the FDA in February 2016. The FDA noted interim overall survival results from the PERSIST-2 showing a detrimental effect on survival were consistent with the results from PERSIST-1 and that deaths in PERSIST-2 in pacritinib-treated patients include intracranial hemorrhage, cardiac failure and cardiac arrest.
PERSIST-1 was a randomized (2:1), controlled, open-label, multinational Phase 3 trial evaluating the efficacy and safety of pacritinib compared to BAT, excluding JAK2 inhibitors, which included a broad range of currently utilized treatments – in 327 patients with myelofibrosis, regardless of the patients’ platelet counts. The study included patients with severe or life-threatening thrombocytopenia. Patients were randomized to receive 400 mg pacritinib once daily or BAT, excluding JAK2 inhibitors. The trial met its primary endpoint of spleen volume reduction (35 percent or greater from baseline to Week 24 by MRI/CT scan).
PERSIST-2 was a randomized (1:1:1), controlled, open-label, multinational Phase 3 clinical trial evaluating pacritinib compared to best available therapy (BAT), including the approved JAK1/JAK2 inhibitor ruxolitinib, for patients with myelofibrosis whose platelet counts were less than or equal to 100,000 per microliter (≤100,000/μL). Patients were randomized to receive 200 mg pacritinib twice daily (BID), 400 mg pacritinib once daily (QD) or BAT. Results of the trial were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual meeting in Dececember 2016. The trial met one of its co-primary endpoints, that of spleen volume reduction (35 percent or greater from baseline to Week 24 by MRI/CT scan). The co-primary endpoint of reduction of Total Symptom Score (TSS) was not achieved but trended toward improvement in TSS. Irrespective of prior ruxolitinib treatment, pacritinib therapy resulted in a statistically significant higher proportion of patients with SVR than patients on BAT. Although secondary objectives could not be evaluated formally due to the study not achieving one of the primary objectives, when the two pacritinib dosing arms were evaluated separately versus BAT, pacritinib BID showed a higher percent of SVR and TSS responses compared to BAT; whereas, pacritinib given QD showed only a higher percent SVR responses compared to BAT. There was no significant difference in overall survival (OS) across treatment arms, censored at the time of clinical hold. The most common treatment-emergent adverse events (AEs), occurring in 20 percent or more of patients treated with pacritinib within 24 weeks, of any grade, were gastrointestinal (generally manageable diarrhea, nausea and vomiting) and hematologic (anemia and thrombocytopenia) and were generally less frequent for BID versus QD administration. The most common serious treatment-emergent AEs (incidence of ≥5 percent reported in any treatment arm irrespective of grade) were anemia, thrombocytopenia, pneumonia and acute renal failure none of which exceeded 8 percent individually in any arm.
About Pacritinib
Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia and lymphoma. In addition to myelofibrosis, the kinase profile of pacritinib suggests its potential therapeutic utility in conditions such as acute myeloid leukemia, or AML, myelodysplastic syndrome, or MDS, chronic myelomonocytic leukemia, or CMML, and chronic lymphocytic leukemia, or CLL, due to its inhibition of c-fms, IRAK1, JAK2 and FLT3.
About Myelofibrosis and Myeloproliferative Neoplasms
Myelofibrosis is one of three main types of myeloproliferative neoplasms (MPN), which are a closely related group of progressive blood cancers. The three main types of MPNs are primary myelofibrosis (PMF), polycethemia vera (PV) and essential thrombocythemia (ET).1
Myelofibrosis is a serious and life-threatening bone marrow disorder caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response and scars the bone marrow. The replacement of bone marrow with scar tissue limits its ability to produce red blood cells, prompting the spleen and liver to take over this function. Symptoms that arise from this disease include enlargement of the spleen, anemia, extreme fatigue and pain.
The estimated prevalence of MPNs suggest there are approximately 300,000 people living with the disease in the U.S., of which myelofibrosis accounts for approximately 18,000 patients.2 In Europe, there is a wide variation of prevalence observed across data sources. Myelofibrosis has a median age of 64 at the time of diagnosis3 and is a progressive disease with approximately 20 percent of patients eventually developing acute myeloid leukemia (AML).4 The median survival for high-risk myelofibrosis patients is less than 1.5 years, while the median survival for patients with myelofibrosis overall is approximately 6 years.4
Year: 2017
Tarveda Therapeutics Announces Phase 1/2a Clinical Trial of PEN-221 Underway in Patients with Neuroendocrine Tumors and Small Cell Lung Cancer
On January 4, 2017 Tarveda Therapeutics a biopharmaceutical company discovering and developing Pentarins as a new class of potent and selective anti-cancer medicines, reported that a Phase 1/2a clinical trial evaluating PEN-221 in patients with advanced neuroendocrine tumors and small cell lung cancer expressing the somatostatin receptor 2 (SSTR2) is underway, with patients enrolled and treated (Press release, Tarveda Therapeutics, JAN 4, 2017, View Source [SID1234517269]). The somatostatin receptor is highly expressed in neuroendocrine cancers. PEN-221 is a novel, miniaturized drug conjugate designed to selectively target SSTR2 and then internalize and release its potent DM1 payload in the tumor cell.
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"Pentarins are engineered to rapidly penetrate and kill solid tumors that have proven challenging for treatment modalities such as antibody drug conjugates and chemotherapeutics," said Gordon B. Mills, M.D., Ph.D., Professor and Chair, Department of Systems Biology, at The University of Texas MD Anderson Cancer Center, Houston, TX. "The miniaturized size, unique design and potent payloads of Pentarins allow for sustained payload release in solid tumors to drive potential efficacy while sparing normal tissue.
"PEN-221 has high affinity for the SSTR2 on the surface of neuroendocrine and small cell lung cancer cells, which facilitates internalization followed by release of its potent cell-killing payload, DM1. Pentarins offer a new treatment approach to address the deficits of current treatments, and PEN-221 has the potential to address the urgent and significant medical need of patients with neuroendocrine and small cell lung cancers. Having an imaging approach to identify neuroendocrine and small cell lung cancers expressing the somatostatin receptor 2 makes the PEN-221 trial an exciting proof-of-concept as well as an opportunity for patients with these challenging tumors," concluded Mills.
The Phase 1/2a first-in-human study is an open-label, multicenter trial to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of PEN-221 in patients with SSTR2-expressing advanced neuroendocrine cancers, including a range of neuroendocrine tumors and small cell lung cancer. Utilizing FDA-approved imaging diagnostics, the study employs a seamless, Phase 1/2a design that identifies and selects advanced cancer patients with SSTR2 expressing tumors. These patients are believed to be the most likely to benefit from treatment with PEN-221. For additional information on this clinical trial, please visit clinicaltrials.gov, identifier number NCT02936323.
"The initiation of this Phase 1/2a clinical trial of PEN-221 in patients with neuroendocrine tumors and small cell lung cancer marks an important milestone in the development of this product candidate and our Pentarin drug conjugates," said Leila Alland, M.D., Chief Medical Officer of Tarveda. "PEN-221 consistently demonstrated complete and durable regressions in hard-to-treat xenograft cancer models. We and our industry leading clinical investigators are excited to advance this therapy into the clinic."
About Pentarins
Tarveda is developing Pentarins, potent and selective miniaturized drug conjugates with high affinity for specific cell surface and intracellular targets. Pentarins are engineered to bind to their tumor cell targets and provide sustained release of their potent therapeutic payloads deep into solid tumor tissue. Comprised of a targeting ligand conjugated to a potent cell-killing agent through a chemical linker, Pentarins are designed to overcome the deficits of both larger antibody drug conjugates and small molecules that limit their therapeutic effectiveness against solid tumors. Together, the components of Tarveda’s Pentarins have distinct, yet synergistic, anticancer attributes: the small size of Pentarins allows for effective penetration and distribution into the tumor tissue, the ligand’s targeting ability allows for specific binding and retention in tumor cells, and the chemical linker is tuned to optimize the release of the potent, cell-killing payload inside the cancer cells for efficacy.
BAVARIAN NORDIC PROVIDES UPDATE ON ANTICIPATED TIMING OF PROSPECT STUDY
On January 4, 2017 Bavarian Nordic A/S (OMX: BAVA, OTC: BVNRY) reported guidance for the current estimated timing of interim and final overall survival analysis from the PROSPECT study – a placebo controlled Phase 3 study designed to investigate the efficacy of PROSTVAC to prolong the survival of men with metastatic castration-resistant prostate cancer (mCRPC) (Press release, Bavarian Nordic, JAN 4, 2017, View Source [SID1234517268]).
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The company maintains its previous guidance that full data is expected within this year, albeit in the second half of 2017, with the third interim analysis likely to occur around mid-2017. This estimate is based on a decline in the number of average monthly events currently seen in the PROSPECT study.
"As there has been speculation that the third interim could occur during first quarter of 2017, we believe it is important to update the market on the current estimated timelines for readout of the Phase 3 study" said Paul Chaplin, President and CEO of Bavarian Nordic.
While the company remains blinded to all patient specific data, the latest estimates have been provided by the independent Data Monitoring Committee (DMC) following a routine analysis of the current survival data.
"While we will have to await the final read out of the PROSPECT study to establish the efficacy of PROSTVAC, we are encouraged that the current monthly event rate has declined. This is great news for the patients. Not only is this consistent with an improvement in the standard of care for patients with mCRPC, which has been observed in recent years, but could also be indicative of a therapeutic effect of PROSTVAC as well" said Paul Chaplin.
About the PROSPECT study
PROSPECT is a global, randomized, double-blind, placebo-controlled phase 3 study being conducted under a Special Protocol Assessment (SPA) from the FDA. The objective of the study is to determine whether PROSTVAC alone or in combination with GM-CSF is effective in prolonging overall survival. The study has been fully enrolled with 1,297 asymptomatic or minimally symptomatic mCRPC patients as of January 2015. Patients were enrolled at more than 200 sites in 15 countries. Both the first and second interim analyses confirmed that the study would continue as planned. Final study data requires 534 events in both comparisons of treatment arms versus placebo, and the third interim analysis will occur at 427 events.
About PROSTVAC
PROSTVAC (rilimogene galvacirepvec/rilimogene glafolivec, or "rilimogene") is a prostate specific antigen (PSA)-targeted immunotherapy candidate designed to enhance or stimulate the body’s immune response, specifically T cells that will home to and kill prostate cancer cells, altering the course of the disease and improving overall survival (OS) of patients with prostate cancer. A robust data package has been established that includes 18 ongoing or completed clinical studies, comprising more than 2,000 patients of which more than 1,100 patients have been actively treated with PROSTVAC, which has been generally well-tolerated. A randomized, placebo-controlled Phase 2 trial demonstrated the potential of PROSTVAC to extend the median overall survival by 8.5 months in patients with advanced prostate cancer. These results led to the initiation of the PROSPECT pivotal Phase 3 study.
PROSTVAC is being developed in collaboration with the National Cancer Institute under a Cooperative Research and Development Agreement.
Five Prime Therapeutics and Bristol-Myers Squibb Extend Research Term in Collaboration to Discover Novel Immuno-Oncology Therapies for Three Immune Checkpoint Pathways
On January 4, 2017 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that Bristol-Myers Squibb Company (NYSE:BMY) has exercised its option to extend the research term of its discovery collaboration agreement with Five Prime for the discovery, development and commercialization of immuno-oncology therapies directed toward targets in three undisclosed immune checkpoint pathways (Press release, Five Prime Therapeutics, JAN 4, 2017, View Source [SID1234517266]). Schedule your 30 min Free 1stOncology Demo! The original collaboration agreement was established in March 2014 and focused on two undisclosed immune checkpoint pathways. In January 2016, the companies added a third immune checkpoint pathway to the collaboration. Bristol-Myers Squibb has now elected to extend the research term from its original ending date of March 2017 to March 2018, and will provide additional research funding for the 12-month extension of the research term.
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Bristol-Myers Squibb will utilize Five Prime’s discovery capabilities to advance these three immuno-oncology programs toward the identification of drug candidates for continued research and development. Drug candidates developed against targets in these pathways may be studied either as single agents or in combination with approved Bristol-Myers Squibb immuno-oncology therapies or others in development. Five Prime and Bristol-Myers Squibb continue work on antibody drug candidates targeting these pathways. Bristol-Myers Squibb has advanced the first antibody from this collaboration to IND-enabling activities.
"We are pleased that the demonstrated productivity of our unique research capabilities has prompted Bristol-Myers Squibb, a clear leader in immuno-oncology, to invest further in our efforts to find new drug candidates to modulate three checkpoint pathways," said Luis Borges, Ph.D., senior vice president of research, at Five Prime. "Together, we have made significant progress that includes an antibody candidate that could lead to an IND application for our collaborator."
Under the terms of the original agreement, Bristol-Myers Squibb will obtain exclusive, worldwide rights to develop and commercialize products directed toward certain protein targets in the three checkpoint pathways identified by Five Prime prior to and during the collaboration. Bristol-Myers Squibb paid an upfront fee of $20 million to Five Prime and will provide up to $11.6 million in research funding over the course of the entire research term. Five Prime will be eligible to receive up to $300 million in future development (including $5 million upon filing of the first IND application by Bristol-Myers Squibb), regulatory and sales-based milestone payments per collaboration product and tiered mid-single-digit rising to low-double-digit royalty payments on net sales of each product commercialized by Bristol-Myers Squibb.
Affimed and MD Anderson Announce Clinical Immuno-Oncology Development Collaboration
On January 4, 2017 Affimed N.V. (Nasdaq: AFMD), a clinical stage biopharmaceutical company focused on discovering and developing highly targeted cancer immunotherapies, and The University of Texas MD Anderson Cancer Center reported an exclusive strategic clinical development and commercialization collaboration to evaluate Affimed’s TandAb technology in combination with MD Anderson’s natural killer cell (NK) product (Filing, 6-K, Affimed, JAN 4, 2017, View Source [SID1234517262]). Schedule your 30 min Free 1stOncology Demo!
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NK-cells are white blood cells which monitor the body for infected and cancerous cells. The technology to grow NK-cells from umbilical cord blood was developed at MD Anderson.
This collaboration will leverage MD Anderson’s expertise in NK-cells and translational medicine, and Affimed’s capabilities to develop tumor-targeting bispecific TandAb immune cell engagers.
"In our effort to broaden the applications of our NK-cell engager products, we are excited to partner with the world-leading NK-cell experts at MD Anderson to investigate their unique product together with our first-in-class NK-cell engager AFM13 in Hodgkin lymphoma," said Adi Hoess, Ph.D., CEO of Affimed. "Harnessing the advantages of both antibody-based and cell therapy approaches has the potential to better exploit the therapeutic activity of NK-cells. We believe this partnership could benefit many hematological malignancies, including in multiple myeloma, where Affimed is developing AFM26, a BCMA/CD16A bispecific antibody. For us, this partnership is an important step in executing our strategy to develop transformative cancer therapies."
Collaborative studies will research, develop, and eventually commercialize novel oncology therapeutics resulting from this combination of products. MD Anderson will be responsible for conducting preclinical research activities aimed at investigating its NK-cells derived from umbilical cord blood in combination with Affimed’s lead NK-cell engager, the CD30- and CD16A-targeting TandAb AFM13. These are intended to be followed by a Phase 1 clinical trial. Affimed will fund research and development expenses for this collaboration and the agreement includes a provision for the potential expansion of the partnership. Affimed holds an option to exclusive worldwide rights to develop and commercialize any product developed under the collaboration.
"We look forward to joining the cord blood-derived NK-cells developed at MD Anderson with our collaborator’s technology which we believe will benefit our patients," said Katayoun Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation and Cellular Therapy at MD Anderson.
AFM13 is a bispecific NK-cell TandAb simultaneously targeting CD16A on NK-cells and CD30 on tumor cells. AFM13 is designed to treat CD30-positive malignancies including Hodgkin lymphoma (HL) and T-cell lymphoma (TCL) and is currently in Phase 2 development in HL patients. Based on its safety profile, AFM13 is being developed both as monotherapy and in combination with other therapeutics such as Merck’s checkpoint inhibitor KEYTRUDA.
Elizabeth Shpall, M.D., professor of Stem Cell Transplantation and Cellular Therapy at MD Anderson, and Rezvani’s co-leader on the project, believes the collaboration "holds true potential to produce a novel cellular therapeutic for the treatment of high-risk Hodgkin lymphoma."