On January 26, 2016 Medivation, Inc. (NASDAQ: MDVN) and Astellas Pharma US, LLC, a United States (U.S.) subsidiary of Tokyo-based Astellas Pharma Inc. (TSE: 4503), reported that results from the STRIVE trial (NCT01664923) of enzalutamide compared to bicalutamide in men with castration-resistant prostate cancer (CRPC) were published in the Journal of Clinical Oncology (Press release, Medivation, JAN 26, 2016, View Source [SID:1234508864]). The article, titled, "Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial," appears in the January 25, 2016 online issue and will be published in a future print issue of the journal. Schedule your 30 min Free 1stOncology Demo! The study achieved its primary endpoint demonstrating a statistically significant increase in progression-free survival (PFS) for enzalutamide compared with bicalutamide (Hazard Ratio = 0.24; 95% Confidence Interval, 0.18-0.32; p < 0.0001). Median PFS was 19.4 months in the enzalutamide group compared with 5.7 months in the bicalutamide group.
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The median time on treatment in the STRIVE trial was 14.7 months in the enzalutamide group versus 8.4 months in the bicalutamide group. Serious adverse events were reported in 29.4% of enzalutamide-treated patients and 28.3% of bicalutamide-treated patients. Grade 3 or higher cardiac adverse events were reported in 5.1% of enzalutamide-treated patients versus 4.0% of bicalutamide-treated patients. One seizure was reported in the trial in the enzalutamide-treated group and none in the bicalutamide-treated group. The most common side effects noted more frequently in the enzalutamide-treated versus bicalutamide-treated patients included fatigue, back pain, hot flush, fall, hypertension, dizziness, and decreased appetite, consistent with the known safety profile of enzalutamide.
The STRIVE study is the second of two head-to-head studies of enzalutamide versus bicalutamide, the first of which was TERRAIN, which was published in the January 13, 2016 online issue of Lancet Oncology.
About the STRIVE Trial
The Phase 2 STRIVE trial enrolled 396 castration-resistant prostate cancer patients in the U.S. The trial randomized 257 patients with metastatic prostate cancer and 139 patients with non-metastatic prostate cancer whose disease progressed despite treatment with a luteinizing hormone-releasing hormone (LHRH) analogue therapy or following surgical castration. The primary endpoint of the trial was PFS, defined as time from randomization to radiographic (bone or soft tissue) progression, prostate-specific antigen (PSA) progression (defined by Prostate Cancer Working Group 2 criteria), or death due to any cause, whichever occurs first. The trial was designed to evaluate enzalutamide at a dose of 160 mg taken once daily (n=198) versus bicalutamide at a dose of 50 mg taken once daily (n=198), the approved dose in combination with a LHRH analogue.
About XTANDI (enzalutamide) capsules
XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).
Enzalutamide Mechanism of Action
Enzalutamide is an androgen receptor inhibitor that blocks multiple steps in the androgen receptor signaling pathway within the tumor cell. In preclinical studies, enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors, and inhibit androgen receptor nuclear translocation and interaction with DNA.
Important Safety Information
Contraindications XTANDI is not indicated for women and is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman.
Warnings and Precautions
Seizure In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience re- administering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.
Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.
Adverse Reactions
The most common adverse reactions (≥ 10%) reported from two combined clinical studies that occurred more commonly (≥ 2% over placebo) in XTANDI patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.
In Study 1, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups.
Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).
Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.
Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.
Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.
Drug Interactions
Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.
Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.
For Full Prescribing Information for XTANDI (enzalutamide) capsules, please visit View Source
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1‐800‐FDA‐1088.
Year: 2016
ImmunoGen Earns Milestone with Bayer’s Initiation of a Phase 2 Clinical Study Designed to Support Anetumab Ravtansine Registration
On January 26, 2016 ImmunoGen, Inc. (Nasdaq: IMGN), a biotechnology company that develops targeted anticancer therapeutics using its antibody-drug conjugate (ADC) technology, reported the Company earned a milestone payment with Bayer’s initiation of a global Phase 2 clinical study designed to support registration of anetumab ravtansine (BAY 94-9343) (Press release, ImmunoGen, JAN 26, 2016, View Source [SID:1234508863]). Anetumab ravtansine, a mesothelin-targeting ADC, is a potential new treatment for mesothelioma developed by Bayer using ImmunoGen’s ADC technology. Schedule your 30 min Free 1stOncology Demo! "We are excited that Bayer has advanced anetumab ravtansine into a clinical study designed to support its registration," commented Daniel Junius, President and CEO. "There is a significant need for new therapies for mesothelioma, and ImmunoGen is committed to transforming the treatment of difficult cancers – both through our own product programs and through partnerships with other companies."
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Bayer is developing anetumab ravtansine under a 2008 license agreement with ImmunoGen that granted the company exclusive rights to use ImmunoGen’s maytansinoid ADC technology to develop anticancer therapies targeting mesothelin. Bayer is responsible for the development, registration, and commercialization of anetumab ravtansine. ImmunoGen is entitled to receive milestone payments potentially totaling up to $170 million and royalties on commercial sales, if any.
Heat Biologics CSO to Present Interim Results From the Monotherapy Arm in Its Ongoing HS-410 Phase 2 Bladder Cancer Trial at the Phacilitate Immunotherapy World Conference
On January 26, 2016 Heat Biologics, Inc. ("Heat") (Nasdaq:HTBX), an immuno-oncology company developing novel therapies that activate a patient’s immune system against cancer, reported that Taylor Schreiber, M.D. Ph.D., Heat’s Chief Scientific Officer, will discuss three-month interim data from the unblinded, monotherapy cohort of the company’s ongoing Phase 2 trial of HS-410 (vesigenurtacel-L) for the treatment of high risk, non-muscle invasive bladder cancer (NMIBC) at the Phacilitate Immunotherapy World Conference in Washington, D.C. on January 25-27, 2016 (Press release, Heat Biologics, JAN 26, 2016, View Source [SID:1234508862]). In the monotherapy arm of Heat’s Phase 2 trial, a series of weekly intradermal injections of HS-410 is being dosed as an alternative to intravesical standard of care, Bacillus Calmette-Guérin (BCG). Schedule your 30 min Free 1stOncology Demo! Dr. Schreiber will report that to-date HS-410 has been well-tolerated, with no serious adverse events. Six out of seven patients in the 25-patient arm, who have reached the 3-month timepoint after treatment with HS-410 alone, remain recurrence free. One of those patients had carcinoma in situ (CIS) – the patient population believed to be least responsive to BCG – and that patient experienced complete response. Images of the bladder taken from treated patients showed changes that resemble lymphoid (T cell rich) structures that we have observed in biopsy samples, indicating that HS-410 is generating an immune response as expected.
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"These interim data are consistent with previous results from our Phase 1 trial, demonstrating that intradermal injections of HS-410 lead to a localized immune response within the urinary bladder," said Dr. Schreiber. "The fact that these localized immune responses are now being seen in the absence of standard of care, BCG, indicates that the response is due to HS-410. If the monotherapy arm of the trial demonstrates a trend toward low recurrence rates in the absence of BCG, that may extend options for subsequent pivotal study designs, and may potentially provide bladder cancer patients with an alternative to repeated BCG catheterization procedures. We look forward to presenting additional data from this trial in the future."
Heat continues to enroll the anticipated 25 patients who will receive HS-410 monotherapy and expects to complete enrollment in the first half of 2016. The three other blinded, randomized, placebo-controlled arms in the Phase 2 trial evaluating HS-410 in combination with BCG are fully enrolled with a total of 75 patients. Heat anticipates reporting topline efficacy, immune-response and safety data from those arms in the fourth quarter of 2016.
About HS-410 (vesigenurtacel-L)
HS-410 is an investigational product candidate for NMIBC based on Heat’s proprietary ImPACT immunotherapy platform, designed to generate CD8+ "killer" T cells that attack cancer cells. HS-410 is currently being evaluated in an ongoing Phase 2, placebo-controlled, 100-patient NMIBC trial at multiple centers and has been granted U.S. FDA Fast Track Designation for the treatment of NMIBC.
About Bladder Cancer
According to the American Cancer Society, bladder cancer is the fifth most common cancer in the U.S., with approximately 75,000 new cases and 16,000 deaths in 2015. About 75% of the newly diagnosed patients have NMIBC. A key issue for bladder cancer is the high rate of recurrence, for which limited treatment options are available beyond complete bladder removal.
Athenex Announces US FDA Allowance of the Investigational New Drug Application of Oradoxel, the Proprietary Oral Form of Docetaxel
On January 25, 2016 Athenex reported that it has received United States Food and Drug Administration (US FDA) allowance to proceed in the clinic with its proprietary oral form of Docetaxel (Press release, Athenex, JAN 25, 2016, View Source [SID1234517498]). This allowance to proceed represents Athenex’s sixth successful oncology investigational new drug (IND) application by the US FDA (5 oral anticancer drugs, one ointment) and the third such clinical drug candidate in Athenex’s oral absorption platform. Docetaxel is an established and effective high potency anti-cancer drug. Athenex has developed an oral form, called Oradoxel. The Athenex oncology oral absorption technology is based on a proprietary P-glycoprotein (Pgp) pump inhibitor ("Orascovery" platform) licensed exclusively from our business partner, Hanmi Pharmaceuticals, in 2011 for all major worldwide territories except Korea and Japan that were retained by Hanmi Pharmaceuticals. Athenex currently has the oral forms of paclitaxel and irinotecan in later stage clinical studies, which showed promising profiles in earlier clinical evaluations.
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Douglas Kramer, MD, Athenex Vice President of Clinical Development and Regulatory Affairs stated "Our team submitted to the FDA a comprehensive IND package for Oradoxel of over 35,000 pages, including information on our oral absorption platform. Our Pgp pump inhibitor has been demonstrated to enhance the oral absorption of well-known oncology drugs that today are only available to patients as intravenous medicines. We are excited for the possibilities to make a difference in helping more cancer patients."
Gerald Fetterly, PhD, Athenex Vice President of Clinical Pharmacology added "We have learned in the clinic that converting existing intravenous high potency oncology drugs into oral forms opens the door to optimizing a wide array of patient dosing regimens which cannot be achieved with IV. Oral forms of dosing allow the patients to be exposed over a longer period of time to the potent active pharmaceutical ingredients and clinical studies have shown expected pharmacokinetic blood levels of exposure; leading to good clinical efficacy with less adverse side effects compared with the intravenous counterparts."
Athenex Chairman and CEO Johnson YN Lau, MBBS, MD, FRCP, commented, "I want to congratulate both our Athenex Hong Kong team and the Athenex US team, and thank our collaborators on this project on achieving this important successful regulatory milestone. The Oradoxel project was initially developed by the Athenex Hong Kong team in the Henry Cheng Research Laboratory for Drug Development, Department of Applied Biology and Chemical Technology (ABCT), The Hong Kong Polytechnic University and this project was also partially supported by a SERAP matching grant from the Hong Kong Innovation and Technology Commission. Hong Kong should be congratulated as an innovator of important drug development science for cancer patients globally. This accomplishment also reinforces the successful execution of our business strategy creating a medical technology bridge between China and the United States."
In addition to its primary territories, Athenex is also developing Oraxol and Oratecan with Hanmi Pharmaceuticals, the originator of the Orascovery platform, in Korea and Japan, with PharmaEssentia in Taiwan and Singapore, and with ZenRx in New Zealand and Australia.
Affimed Enters into Collaboration with Merck to Evaluate AFM13 in Combination with KEYTRUDA® (pembrolizumab) for Patients with Hodgkin Lymphoma
On January 25, 2016 Affimed N.V. (Nasdaq: AFMD), a clinical stage biopharmaceutical company focused on discovering and developing highly targeted cancer immunotherapies, reported that it has entered into a clinical research collaboration in immunooncology with Merck (NYSE: M RK), known as MSD outside the United States and Canada (Press release, Affimed Therapeutics, JAN 25, 2016, View Source [SID:SID1234515606]). Under the terms of the agreement, Affimed will fund and conduct a Phase 1b clinical trial to investigate the combination of Merck’s anti - PD - 1 therapy, KEYTRUDA (pembrolizumab), with Affimed’s proprietary drug candidate AFM13 for the treatment of patients with Hodgkin lymphoma whose disease has relapsed or is refractory to chemotherapy, including treatment with the marketed antibody - drug - conjugate Adcetris TM (brentuximab vedotin). Merck will supply Affimed with KEYTRUDA for the clinical trial. The purpose of the study is to establish a dosing regimen for this combination therapy and assess its safety and efficacy. Affimed is on track to initiate the study in the first half of 2016.
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AFM13 is a bispecific antibody targeting CD30, an antigen specifically expressed in a variety of T - and B - cell lymphomas and targeting CD16A, an antigen expressed on natural killer (NK - ) cells, which are important for the activation of the innate immune system and the subsequent killing of tumor cells. KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD - 1 and its ligands, PD - L1 a nd PD - L2, thereby activating T lymphocytes, which may affect both tumor cells and healthy cells.
In patient - derived xenograft models, AFM13, in combination with an antiPD1 antibody, demonstrated impressive synergy, with up to 90 percent of the tumor eradicated. In this preclinical work, conducted at Stanford University, it was also shown that both NK and Tcells infiltrated the tumors and that cytokine levels, including notably interferongamma, were elevated.
"Our development strategy is to combine our NKcell engagers with other immunotherapies that could enhance their efficacy through the uptake of both NK - cells and Tcells, and the collaboration with Merck is an important step in executing this strategy," said Dr. Adi Hoess, CEO of Affimed.
"AFM13, a firstinclass NKcell engager, has shown an acceptable safety profile and preliminary antitumor activity in the firstinhuman Phase 1 study . Additionally, preclinical studies indicate that a combination with an anti PD1 therapy could act synergistically and rep resent an additional future treatment option for patients." "Evaluating the potential for innovative combination therapies through strategic collaborations in difficulttotreat tumor types continues to be an important part of our clinical development program for KEYTRUDA," said Dr. Eric Rubin, vice president and therapeutic area head, oncology early - stage development, Merck Research Laboratories . "In partnering with companies such as Affimed, we continue our efforts to bring forward new scientific breakthroughs for patients with Hodgkin lymphoma and the field of immuno-oncology overall."
The agreement is between Affimed and Merck, through a subsidiary. The collaboration agreement includes a provision for the potential expansion of the collaboration to include a subsequent Phase 3 clinical trial. Additional details were not disclosed.