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Constellation Pharmaceuticals Initiates Phase 2 Portion of ProSTAR Clinical Trial in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC)

On December 10, 2018 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported an update of the ProSTAR study, its ongoing Phase 1b/2 clinical trial of CPI-1205 in patients with metastatic castration-resistant prostate cancer (mCRPC) (Press release, Constellation Pharmaceuticals, DEC 10, 2018, View Source [SID1234532000]).

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The ProSTAR study is evaluating CPI-1205, Constellation’s potent and highly selective small-molecule EZH2 inhibitor, in combination with either enzalutamide or abiraterone / prednisone ("abiraterone"), in mCRPC patients who experienced disease progression while receiving the other ARS inhibitor. Based on encouraging results from the Phase 1b portion of ProSTAR, the Company has initiated dosing in the randomized Phase 2 portion studying CPI-1205 in combination with enzalutamide versus enzalutamide alone. Constellation has also decided to expand the Phase 2 portion of the study by adding an arm evaluating CPI-1205 in combination with abiraterone in the second-line setting.

"We are pleased that CPI-1205 achieved its Phase 1b endpoints in ProSTAR, demonstrating an encouraging safety profile and evidence of clinical activity in both arms," said Adrian Senderowicz, Chief Medical Officer of Constellation

Pharmaceuticals. "As we advance into the Phase 2 portion of the study, we believe combination therapy with CPI-1205 may provide a meaningful second-line treatment option to patients with metastatic castration-resistant prostate cancer, an area of significant unmet medical need. We are excited about expanding our opportunity to include an arm evaluating CPI-1205 in combination with abiraterone in the second-line setting, given that very few patients experience a 50% reduction in PSAs on second-line treatment with abiraterone and that time to progression in this setting is typically short."

Initiation and Expansion of Phase 2 Portion of ProSTAR

As planned, Constellation has already begun dosing patients in the Phase 2 portion of the study, evaluating CPI-1205 in combination with enzalutamide versus enzalutamide alone. The Company continues to expect enrollment of up to 35 patients in both the treatment and the control arms.

Additionally, Constellation is expanding the trial to include a separate Phase 2 arm evaluating CPI-1205 in combination with abiraterone in up to 30 mCRPC patients who progressed on prior enzalutamide therapy. This arm, which will soon begin dosing patients, will not be randomized against a control arm due to the low response rate and lack of durability seen with abiraterone in the second-line setting.

In a recent randomized cross-over trial, only 4% of patients taking abiraterone after disease progression on enzalutamide, and only 31% of patients taking enzalutamide after disease progression on abiraterone, achieved a 50% reduction in PSA levels. Time to PSA progression was only 1.3 months and 2.7 months, respectively. Time to disease progression was only 1.6 months and 2.7 months, respectively.1

Constellation continues to expect to determine proof of concept for CPI-1205 in mid-2019.

1 D. Khalaf et al, Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mCRPC): results for 2nd-line therapy, poster presented at 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting.

About mCRPC

mCRPC is an advanced form of prostate cancer and is defined by disease progression despite treatment with androgen depletion therapy (ADT). mCRPC may present as one or any combination of the following: a continuous rise in serum levels of PSA, progression of known metastases, or appearance of new metastases. Prognosis is associated with several factors, including the

ability to perform certain daily activities and the presence of bone pain. Additional symptoms commonly include anemia (low healthy red blood cell levels), weight loss, fatigue, hypercoagulability (abnormal blood coagulation), and increased susceptibility to infection. mCRPC presents as a spectrum of disease ranging from patients without symptoms but rising PSA levels despite ADT, to patients with metastases and significant debilitation.

Immix Observes Clinical Benefit at Dose-Level 2 in Phase 1b Clinical Trial in Refractory Cancer

On December 10, 2018 Immix Biopharma, Inc reported positive interim results from its ongoing phase 1b/2a study testing IMX-110 in advanced solid tumors (Press release, Immix Biopharma, DEC 10, 2018, View Source [SID1234531999]). Immix observed Stable Disease at cohort (dose-level) 2 in a middle-aged male with stage IV colorectal cancer that was refractory to radiation therapy, chemotherapy and immunotherapy. The team observed no adverse events at this dose level.

The study is a multiple-ascending dose, Phase 1b clinical trial of IMX-110 to evaluate the compound’s safety, pharmacokinetics, pharmacodynamics and preliminary efficacy in patients with advanced solid tumors and is led by Principal Investigator Prof. Paul de Souza of Western Sydney University, Sydney. Currently, the team is awaiting additional preliminary efficacy readouts from patients in cohorts (dose-levels) 3 and 4, with cohort 5 enrollees set to be recruited imminently. For information about participating in this study, please visit clinicaltrials.gov: View Source

The company is also announcing its plans to investigate IMX-109, a nanoformulation of curcumin, in neurodegenerative and age-related diseases, with preliminary human data scheduled to be shared publicly in early 2019.

About IMX-110
IMX-110 is a first-in-class combination therapy designed to inhibit cancer resistance and evolvability while inducing apoptosis. IMX-110 contains NF-kB/Stat3/pan-tyrosine kinase inhibitor curcumin combined with a small amount of doxorubicin encased in a nano-sized delivery system for optimal tumor penetration. The nanoparticle is tunable in that it can be bound to various targeting moieties, allowing it to deliver even more payload to tumors or other cell populations of interest, if needed. IMX-110 showed preclinical efficacy in glioblastoma, multiple myeloma, triple-negative breast, colorectal, ovarian, and pancreatic tumor models — with the mechanism of action being a 5x increase in cancer cell apoptosis compared to doxorubicin or curcumin alone, and a wholesale shift in the tumor-immune system microenvironment post administration.

About IMX-109
IMX-109 is a nanoformulation of curcumin, a substance with significant preclinical evidence of activity in inflammation-driven and age-related diseases, whose clinical use to-date has been hampered by the poor bioavailability of natural curcumin.

Daiichi Sankyo and Sarah Cannon Research Institute Launch Strategic Collaboration to Develop Novel Cancer Therapies

On December 10, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and Sarah Cannon Research Institute reported a strategic oncology development collaboration (Press release, Daiichi Sankyo, DEC 10, 2018, View Source [SID1234531997]). This partnership brings together Daiichi Sankyo’s expertise in developing novel cancer agents with Sarah Cannon’s leadership in designing and optimizing clinical trials to expand treatment options for patients.

"We look forward to partnering with Sarah Cannon to accelerate drug development globally for patients with cancer who need more innovative therapies," said Tom Held, Vice President, Head, Antibody Drug Conjugate Task Force, Oncology Research and Development, Daiichi Sankyo. "We believe that this collaboration will help to make an impact in the field of cancer research, as we combine our operational and scientific expertise to focus on the development of targeted therapies, such as antibody drug conjugates. We look forward to initiating with Sarah Cannon joint clinical activities in the U.S. and Japan as quickly as possible."

"Sarah Cannon’s expertise and focus on oncology drug development provides a solid platform to enable us to partner with Daiichi Sankyo on exploring these promising new agents," said Johanna Bendell, MD, Chief Development Officer, Sarah Cannon. "We greatly value the trust that Daiichi Sankyo has placed in our team and are excited to offer novel therapies for our cancer patients."

Through Sarah Cannon Development Innovations, its full-service, oncology-focused contract research organization (CRO), Sarah Cannon will provide comprehensive clinical development services and operational delivery to several of Daiichi Sankyo’s translational development programs. The collaboration will enable rapid patient enrollment to clinical trials through Sarah Cannon’s extensive research network across the U.S. and UK, which serves thousands of patients annually in clinical trials, as well as through Daiichi Sankyo’s clinical network in Japan.

Varian Announces First Quarter Fiscal Year 2019 Earnings Release Date

On December 10, 2018 Varian (NYSE: VAR) reported that it will report results for the first quarter of fiscal year 2019 after market close on Wednesday, January 23, 2019 (Press release, Varian Medical Systems, DEC 10, 2018, View Source [SID1234531996]). The news release will be followed by a teleconference available to all interested at 1:30 p.m. Pacific Time. To access the teleconference call and replay:

Teleconference: Access from within the U.S. by dialing 1-877-869-3847, and from outside the U.S. by dialing 1-201-689-8261.

Replay: Access from within the U.S. by dialing 1-877-660-6853 and from outside the U.S. by dialing 1-201-612-7415, and enter conference ID 13685671. The teleconference replay will be available until 5:00 p.m. Pacific Time, Friday, January 25, 2019.

Webcast: To access the live webcast and replay, visit the company website at: www.varian.com/investors and click on the link for First Quarter Earnings Results.

For automatic e-mail alerts regarding Varian news and events, investors can subscribe on the company website: View Source

Astellas Launches XOSPATA® (gilteritinib) in the U.S. for the Treatment of Adult Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) with a FLT3 Mutation

On December 10, 2018 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D. "Astellas") reported that XOSPATA (generic name: gilteritinib) is now available for prescription in the United States for the treatment of adult patients who have relapsed or refractory (resistant to treatment) Acute Myeloid Leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test (Press release, Astellas, DEC 10, 2018, View Source [SID1234531995]).1 An oral monotherapy, XOSPATA is the first and only FLT3-targeting agent approved by the FDA for the treatment of relapsed or refractory FLT3 mutation-positive (FLT3mut+) AML.

XOSPATA was approved by the U.S. Food and Drug Administration (FDA) on November 28, 2018. Health professionals, patients and their caregivers can learn more about XOSPATA and support services provided through Astellas at View Source

"Astellas aims to pursue cutting-edge science that provides value to patients," said Mark Reisenauer, senior vice president, oncology business unit, Astellas. "XOSPATA is an excellent example of how we are continuing to advance on this promise to patients."

Astellas is providing a full range of patient support services for XOSPATA in the U.S. XOSPATA Support SolutionsSM offers access and reimbursement support to help patients access XOSPATA as prescribed by their healthcare providers . XOSPATA Support SolutionsSM also provides information regarding patient healthcare coverage options and financial assistance programs that may be available to help eligible patients with financial needs. Patients, caregivers and healthcare providers can visit www.xospatasupportsolutions.com or call 844-632-9272 to learn more.

Astellas reflected the impact from this launch in its financial forecasts of the current fiscal year ending March 31, 2019.

About Acute Myeloid Leukemia
Acute Myeloid Leukemia (AML) is a cancer that impacts the blood and bone marrow,2 and its incidence increases with age.3 The American Cancer Society estimates that in 2018, approximately 19,000 people will be diagnosed with AML in the U.S.3

About XOSPATA (gilteritinib)
XOSPATA is indicated for the treatment of adult patients who have relapsed or refractory Acute Myeloid Leukemia (AML) with a FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an FDA-approved test.1 XOSPATA is also approved by the Japan Ministry of Health, Labor and Welfare (MHLW) for relapsed or refractory AML with FLT3 mutations. It is launched as XOSPATA 40 mg Tablets in Japan.

Gilteritinib was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and commercialize gilteritinib.

Astellas is currently investigating gilteritinib in various FLT3 mutation-positive AML patient populations through several Phase 3 trials. Visit AstellasAMLTrials.com to learn more about ongoing gilteritinib clinical trials.

Important Safety Information

Contraindications
XOSPATA is contraindicated in patients with hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials.

Warnings and Precautions
Posterior Reversible Encephalopathy Syndrome (PRES) There have been rare reports of PRES with symptoms including seizure and altered mental status with XOSPATA. Symptoms have resolved after discontinuation of XOSPATA. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XOSPATA in patients who develop PRES.

Prolonged QT Interval XOSPATA has been associated with prolonged cardiac ventricular repolarization (QT interval). Of the 292 patients treated with XOSPATA in the clinical trial, 1.4% were found to have a QTc interval greater than 500 msec and 7% of patients had an increase from baseline QTc greater than 60 msec. Perform electrocardiogram (ECG) prior to initiation of treatment with XOSPATA, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt and reduce XOSPATA dosage in patients who have a QTcF >500 msec. Hypokalemia or hypomagnesemia may increase the QT prolongation risk. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration.

Pancreatitis There have been rare reports of pancreatitis in patients receiving XOSPATA in clinical studies. Evaluate patients who develop signs and symptoms of pancreatitis. Interrupt and reduce the dose of XOSPATA in patients who develop pancreatitis.

Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, XOSPATA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 6 months after the last dose of XOSPATA. Advise males with female partners of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 4 months after the last dose of XOSPATA. Pregnant women, patients becoming pregnant while receiving XOSPATA or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

Adverse Reactions
The most frequent non-hematological serious adverse reactions (≥5%) reported in patients were pneumonia (19%), sepsis (13%), fever (13%), dyspnea (7%) and renal impairment (5%).

Overall, 22 of 292 patients (8%) discontinued XOSPATA treatment permanently due to an adverse reaction. The most common adverse reactions (>1%) leading to discontinuation were pneumonia (2%), sepsis (2%) and dyspnea (1%). The most common adverse reactions (≥20%) were myalgia/arthralgia (42%), transaminase increased (41%), fatigue/malaise (40%), fever (35%), non-infectious diarrhea (34%), dyspnea (34%), edema (34%), rash (30%), pneumonia (30%), nausea (27%), stomatitis (26%), cough (25%), headache (21%), hypotension (21%), dizziness (20%) and vomiting (20%).

Other clinically significant adverse reactions occurring in ≤10% of patients included: electrocardiogram QT prolonged (7%), cardiac failure (grouped terms) (4%), pericardial effusion (3%), pericarditis (2%), differentiation syndrome (1%), anaphylactic reaction (1%) and posterior reversible encephalopathy syndrome (1%).

Lab Abnormalities: The most common lab abnormalities (>20%) that were Grade ≥3 that occurred ≥10% were: hypophosphatemia (12%), alanine aminotransferase increased (12%), hyponatremia (12%), aspartate aminotransferase increased (10%).

Drug Interactions
Combined P-gp and Strong CYP3A Inducers: Concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer decreases XOSPATA exposure which may decrease XOSPATA efficacy. Avoid concomitant use of XOSPATA with combined P-gp and strong CYP3A inducers.

Strong CYP3A inhibitors: Concomitant use of XOSPATA with a strong CYP3A inhibitor increases XOSPATA exposure. Consider alternative therapies that are not strong CYP3A inhibitors. If the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for XOSPATA adverse reactions. Interrupt and reduce XOSPATA dosage in patients with serious or life-threatening toxicity.

Drugs that Target 5HT2B Receptor or Sigma Nonspecific Receptor: Concomitant use of XOSPATA may reduce the effects of drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). Avoid concomitant use of these drugs with XOSPATA unless their use is considered essential for the care of the patient.

Specific Populations
Lactation: Advise women not to breastfeed during treatment with XOSPATA and for 2 months after the last dose.