On October 3, 2016 Amgen (NASDAQ:AMGN) reported that the Journal of Clinical Oncology (JCO) published results from the Phase 1/2 ‘205 single-arm trial evaluating BLINCYTO (blinatumomab) in pediatric patients with Philadelphia chromosome‑negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) (Press release, Amgen, OCT 3, 2016, View Source [SID:SID1234515549]). Based on data from an exploratory pooled analysis of 70 patients who received the recommended dose of BLINCYTO in the Phase 1 or Phase 2 portions of the study, 27 patients (39 percent, 95 percent confidence interval [CI], 27–51 percent) achieved complete remission within the first two cycles.

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The most frequent grade ≥3 adverse events (AEs) among the patients who received the recommended dose were anemia (36 percent), thrombocytopenia (21 percent), febrile neutropenia (17 percent), hypokalemia (17 percent) and neutropenia (17 percent). The most common AEs overall were pyrexia (80 percent), anemia (41 percent), nausea (33 percent) and headache (30 percent).

"This study showed that BLINCYTO can induce deep molecular remissions in children with highly refractory, multiply relapsed ALL," said senior author Lia Gore, M.D., professor of Pediatrics, Medical Oncology and Hematology, University of Colorado Anschutz Medical Campus.

"Pediatric patients with relapsed or refractory Ph- B-cell precursor ALL are in critical need of new treatment options," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "The publication of this data in the Journal of Clinical Oncology provides clinical evidence of the potential of BLINCYTO in this patient population and underscores the significance of the recent regulatory approval for use of BLINCYTO in these patients."

Among patients who achieved complete remission within the first two cycles of treatment, 52 percent had a complete minimal residual disease (MRD) response, a measure of eradication of residual disease at the molecular level. Complete MRD response was an exploratory endpoint in both phases of the study.

Data from the ‘205 study were the basis of a supplemental Biologics License Application (sBLA) for BLINCYTO to include new data supporting the treatment of pediatric patients with Ph- relapsed or refractory B-cell precursor ALL. On Aug. 30, 2016, the U.S. Food and Drug Administration (FDA) approved the sBLA for BLINCYTO to include this new data supporting the treatment of pediatric patients with Ph- relapsed or refractory B-cell precursor ALL. This indication is approved under accelerated approval, and continued approval may be contingent upon verification of clinical benefit in subsequent trials.

ALL is a rapidly progressing cancer of the blood and bone marrow. Although very rare in adults, it is the most common type of cancer in children.1,2 Of the children diagnosed with ALL in the U.S. each year, approximately 15-20 percent (375-500) will experience relapse.3-5 Prognosis for children with ALL who are refractory or experience a relapse is extremely poor, and post-relapse survival is only achieved in 40-50 percent of patients.6-8

About Study ‘205
Study ‘205 evaluated the safety and efficacy of BLINCYTO in a Phase 1/2 open-label, multicenter, single-arm study in 93 pediatric patients with Ph- relapsed or refractory B-cell precursor ALL (second or later bone marrow relapse, any marrow relapse after allogeneic hematopoietic stem cell transplantation [alloHSCT], or refractory to other treatments and had >25 percent blasts in bone marrow). Treatment in this study has been completed and subjects are being monitored for long-term efficacy.

BLINCYTO was administered as a continuous intravenous infusion. The recommended dose for this study was determined to be 5 μg/m2/day on Days 1-7 and 15 μg/m2/day on Days 8-28 for cycle 1, and 15 μg/m2/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. Patients who responded to BLINCYTO, but later relapsed, had the option to be retreated with BLINCYTO.

The treated population included 70 patients who received at least one infusion of BLINCYTO at the recommended dose; the median number of treatment cycles was one (range: 1 to 5). Among treated patients, the median age was eight years (range: seven months to 17 years), 40 out of 70 (57.1 percent) had undergone alloHSCT prior to receiving BLINCYTO, and 39 out of 70 (55.7 percent) had refractory disease. Four patients had less than the 25 percent bone marrow blasts required for protocol entry, but had more than five percent.

About BLINCYTO (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

BLINCYTO was granted breakthrough therapy, priority review and orphan drug designations by FDA, and is now approved in the U.S. for the treatment of Ph- relapsed or refractory B-cell precursor ALL.

In November 2015, BLINCYTO was granted conditional marketing authorization in the European Union for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.

BLINCYTO U.S. Product Safety Information

Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications
BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Interrupt or discontinue BLINCYTO as outlined in the Prescribing Information (PI).
Neurological Toxicities: Approximately 64% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to onset of any neurological toxicity was 4 days. The most common (≥ 10%) manifestations of neurological toxicity were headache, tremor, dizziness, and altered state of consciousness. Severe, life-threatening, or fatal neurological toxicities occurred in approximately 17% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The neurological toxicity profile varied by age group. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.

Infections: Approximately 25% of patients receiving BLINCYTO experienced serious infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.

Tumor Lysis Syndrome (TLS): TLS, which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.

Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.

Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.

Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment. The median time to onset of elevated liver enzymes was 3 days. In patients receiving BLINCYTO, the majority of these events were observed in the setting of CRS. The median time to onset for these events was 15 days. Grade 3 or greater elevations in liver enzymes occurred in 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.

Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.

Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Adverse Reactions

The most common adverse reactions (≥ 20%) in the safety population studied in clinical trials were pyrexia (66%), headache (34%), nausea (27%), edema (26%), hypokalemia (26%), anemia (25%), febrile neutropenia (24%), neutropenia (22%), thrombocytopenia (20%), and abdominal pain (20%). The safety population included 225 patients weighing 45 kg or more and 57 patients weighing less than 45 kg. For some adverse reactions, there were differences in the incidence rates by age subgroup.
In patients weighing greater than or equal to 45 kg, serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia (9%), pyrexia (6%), sepsis (5%), pneumonia (5%), device-related infection (4%), neutropenia (3%), tremor (3%), overdose (3%), encephalopathy (3%), infection (2%), confusion (3%) and headache (2%).
In patients weighing less than 45 kg, serious adverse reactions were reported in 51% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia (12%), febrile neutropenia (9%), cytokine release syndrome (4%), convulsion (4%), device-related infection (4%), hypoxia (4%), sepsis (4%), and overdose (4%).
U.S. Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).
Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide, for BLINCYTO at www.BLINCYTO.com.

On October 3, 2016 Jazz Pharmaceuticals plc (Nasdaq; JAZZ) reported the initiation of a rolling submission of a New Drug Application (NDA) to the United States (U.S.) Food and Drug Administration (FDA) on September 30, 2016, seeking marketing approval of Vyxeos (cytarabine and daunorubicin liposome injection), an investigational agent for the treatment of acute myeloid leukemia (AML) (Press release, Jazz Pharmaceuticals, OCT 3, 2016, View Source [SID:SID1234515536]). The company expects to complete the submission of the NDA by early 2017, and will request a priority review.

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"Our initiation of the rolling NDA submission for Vyxeos brings us closer to an important goal of providing a new treatment option for patients with acute myeloid leukemia, a devastating and life-threatening disease," said Karen Smith M.D., Ph.D., global head of research and development and chief medical officer at Jazz Pharmaceuticals. "AML represents a disease area within the hematological cancers, where there remains a significant unmet medical need. Vyxeos, if approved, would be the first new treatment demonstrating a significant advancement in treating AML in over 20 years."

Vyxeos was granted Breakthrough Therapy Designation in May 2016 for the treatment of adults with therapy-related AML or AML with myelodysplasia-related changes. The FDA grants Breakthrough Therapy designation to expedite the development and review of new medicines that are intended to treat serious or life-threatening diseases when the clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on at least one clinically significant endpoint. The Breakthrough Therapy designation allows a company to submit individual sections of its NDA for review by the FDA as they are completed rather than waiting until the entire application is complete before it can be submitted and reviewed.

Celator Pharmaceuticals, Inc. completed and announced the results of its Phase 3 trial evaluating Vyxeos in patients with high-risk AML in March 2016. Jazz Pharmaceuticals completed the acquisition of Celator Pharmaceuticals in July 2016.

About Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is a rapidly progressing and life-threatening blood cancer that rises in frequency with age.1 The American Cancer Society estimates that there will be 19,950 new cases of AML and 10,430 deaths from AML in the U.S. in 2016.2 In the European Union, the number of new cases is estimated to be 20,100 in 2016.3

The median age at diagnosis is 67 and with rising age there is progressive worsening of prognosis.1,4 Advancing age is associated with increasing risk of specific chromosomal/mutational changes and risk of pre-malignant marrow disorders which give rise to more aggressive and less responsive forms of AML.5,6 As patients age there is also reduced tolerance for intensive chemotherapy.7 As a consequence, advances in supportive care, intensive chemotherapy, and bone marrow transplantation have primarily benefitted younger patients with approximately one third of patients 18-60 years of age achieving cure.5,7 Older patients have not achieved higher rates of cure or improved upon a 5-year survival rate of 10-20% in spite of 40 years of research. 7, 8

About Vyxeos

Vyxeos (cytarabine and daunorubicin liposome injection), or CPX-351, is a combination of cytarabine and daunorubicin encapsulated within a nano-scale liposome at a 5:1 molar ratio. Vyxeos was granted orphan drug status by the FDA and the European Commission for the treatment of acute myeloid leukemia. Vyxeos was granted Breakthrough Therapy Designation for the treatment of adults with therapy-related AML or AML with myelodysplasia-related changes and was also granted Fast Track designation by the FDA for the treatment of older patients with secondary AML.

On October 3, 2016 Roche reported that new results from studies with its approved or investigational medicines across more than 20 cancer types will be presented during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress from 7 – 11 October 2016 in Copenhagen, Denmark (Press release, Hoffmann-La Roche , OCT 3, 2016, View Source [SID:SID1234515529]). These include the first pivotal phase III results for Tecentriq, outcomes from early studies of cancer immunotherapy-based combinations, results from clinical studies with a broad range of Roche’s investigational medicines, and new insights from studies that continue to shape a better understanding of how different types of cancer develop and affect people around the world.

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"At Roche, our focus on understanding human immunology and cancer biology is helping us to develop new medicines that improve outcomes for people with cancer," said Sandra Horning, M.D., Roche’s Chief Medical Officer and Head of Global Product Development. "We look forward to the presentation of the pivotal OAK data for Tecentriq during ESMO (Free ESMO Whitepaper)’s Presidential Symposium, as well as other presentations such as new data from our collaboration with Foundation Medicine that showcase how we are expanding our understanding of each individual’s cancer."

At ESMO (Free ESMO Whitepaper), positive results from the Tecentriq phase III lung cancer study known as OAK will be presented as a "late-breaking" abstract in the ESMO (Free ESMO Whitepaper) Presidential Symposium 2 on Sunday, 9 October. Roche recently announced that the study met its co-primary endpoints and showed a statistically significant and clinically meaningful improvement in overall survival (OS) compared with docetaxel chemotherapy in people with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease progressed on or after treatment with platinum-based chemotherapy. In the United States, Roche’s Biologics License Application (BLA) for Tecentriq in NSCLC was granted Priority Review with an action date of 19 October 2016.

In addition to OAK, 19 Roche cancer immunotherapy abstracts featuring Tecentriq and other innovative molecules will be presented. This includes early data assessing Tecentriq in an investigational combination with the approved, targeted Roche medicines Zelboraf (vemurafenib) and Cotellic (cobimetinib) in melanoma, and as a novel investigational combination with Cotellic in colorectal cancer.

Overview of key presentations at ESMO (Free ESMO Whitepaper) 2016
Investigational medicine Abstract title Abstract number
Alecensa
(alectinib)

Updated efficacy and safety from the global phase II NP28673 study of alectinib in patients (pts) with previously treated ALK+ non-small-cell lung cancer (NSCLC)
1263P

Ipatasertib (RG7440) PTEN loss as a predictive biomarker for the Akt inhibitor ipatasertib combined with abiraterone acetate in patients with metastatic castration-resistant prostate cancer (mCRPC) 718O

Tecentriq (atezolizumab)

Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC LBA44

Atezolizumab (atezo) in platinum (plat)-treated locally advanced/metastatic urothelial carcinoma (mUC): Updated OS, safety and biomarkers from the Ph II IMvigor210 study
783P

IMvigor210: updated analyses of first-line (1L) atezolizumab (atezo) in cisplatin (cis)-ineligible locally advanced/metastatic urothelial carcinoma (mUC)​
782PD​

Safety, clinical activity and biomarkers of atezolizumab (atezo) in advanced ovarian cancer (OC)​
871P

Efficacy and safety of cobimetinib (cobi) and atezolizumab (atezo) in an expanded phase 1b study of microsatellite-stable (MSS) metastatic colorectal cancer (mCRC)​
470P​

Preliminary safety and clinical activity of atezolizumab combined with cobimetinib and vemurafenib in BRAF V600-mutant metastatic melanoma​
1109PD

Clinical activity, safety and predictive biomarker results from a phase Ia atezolizumab (atezo) trial in extensive-stage small cell lung cancer (ES-SCLC)​
1425PD​

Safety, clinical activity and biomarkers of atezolizumab (atezo) in advanced ovarian cancer (OC)​
871P​

The SP142 PD-L1 IHC assay for atezolizumab (atezo) reflects pre-existing immune status in NSCLC and correlates with PD-L1 mRNA
1171P

Tumor mutation load assessed by FoundationOne (FM1) is associated with improved efficacy of atezolizumab (atezo) in patients with advanced NSCLC 77P

Real-World Data Second-line metastatic urothelial carcinoma treatment and survival in real-world patients in the US 801P