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Pfizer Phase 3 Study Of Inotuzumab Ozogamicin Meets Primary Endpoint In Adult Patients With Relapsed Or Refractory Acute Lymphoblastic Leukemia

On April 21, 2015 Pfizer reported that the Phase 3 study investigating the treatment of inotuzumab ozogamicin met its first primary endpoint of demonstrating a higher complete hematologic remission rate in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) compared to that achieved with standard of care chemotherapy(Press release, Pfizer, APR 21, 2015, View Source [SID:1234503105]).

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The Phase 3 study has two primary endpoints, complete hematologic remission rate and overall survival. Pfizer is continuing the study to allow for the data on overall survival to mature.

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"We are excited about the results of the INO-VATE ALL study especially since relapsed and refractory acute lymphoblastic leukemia is a particularly difficult disease to treat in adults. The top-line results show that inotuzumab ozogamicin has the potential to be an important new treatment option for patients with relapsed or refractory disease," said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. "We look forward to discussing these data with the FDA and other regulatory authorities."

No new or unexpected safety issues were identified. Efficacy and safety data from this study will be submitted for presentation at an upcoming medical meeting.

About the INO-VATE ALL Study

The INO-VATE ALL Study, also known as Study 1022, is an open-label, randomized, Phase 3 study evaluating the safety and efficacy of the investigational compound inotuzumab ozogamicin as compared with a defined set of chemotherapy choices in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL).

The two primary endpoints are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Secondary endpoints include progression-free survival, volume of distribution and systemic clearance for inotuzumab ozogamicin in serum, duration of response, rate of stem-cell transplantation, minimal residual disease, cytogenetics, safety and quality of life (European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Core-30 and EuroQual-5D Health Questionnaire).1

Inotuzumab ozogamicin was administered intravenously once weekly for three weeks for a three to four week cycle up to six cycles. Chemotherapy options included fludarabine, cytarabine and G-CSF (FLAG); high dose cytarabine (HIDAC); or cytarabine and mitoxantrone.2

There were 326 patients enrolled in the trial. Enrollment is now complete.

About Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia with a poor prognosis in adults.3 The current foundational treatment is intensive, long-term chemotherapy.4 Approximately 20 to 40 percent of newly diagnosed adults with ALL are cured with current treatment regimens.5 For patients with relapsed or refractory adult ALL, the five-year overall survival rate is less than 10 percent.6

About Inotuzumab Ozogamicin

Inotuzumab ozogamicin is an investigational antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22,7 a cell surface antigen expressed on approximately 90 percent of B-cell malignancies,8 linked to a cytotoxic agent. When inotuzumab ozogamicin binds to the CD22 antigen on malignant B-cells, it is internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell.9

Inotuzumab ozogamicin originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing and clinical development activities for this molecule.

Pfizer Receives U.S. FDA Breakthrough Therapy Designation For XALKORI® (crizotinib) For The Treatment Of Patients With ROS1-Positive Non-Small Cell Lung Cancer

On April 21, 2015 Pfizer reported that XALKORI (crizotinib) received Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the potential treatment of patients with ROS1-positive non-small cell lung cancer (NSCLC) (Press release, Pfizer, APR 21, 2015, View Source [SID:1234503104]). Occurring in approximately one percent of NSCLC cases1, ROS1-positive NSCLC represents a particular molecular subgroup of NSCLC.2 XALKORI currently is approved in the U.S. for the treatment of patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Enacted as part of the 2012 FDA Safety and Innovation Act (FDASIA), Breakthrough Therapy designation is intended to expedite the development and review of a potential new medicine if it is "intended to treat a serious or life-threatening disease and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies."3The Breakthrough Therapy designation is distinct from the FDA’s other mechanisms to expedite drug development and review.4

"We are excited that the FDA has granted Breakthrough Therapy designation for XALKORI as a potential treatment for patients with ROS1-positive NSCLC," said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. "XALKORI pioneered precision medicine for ALK-positive metastatic NSCLC, and ROS1 represents a second molecular subgroup of NSCLC in which XALKORI has demonstrated a level of anti-tumor activity that can potentially make a real difference for patients."

Pfizer will work closely with the FDA on the development of XALKORI for ROS1-positive NSCLC and provide the information needed to support a potential regulatory submission.

The Breakthrough Therapy designation was based on a data analysis from an expansion cohort of a global Phase 1 study (Study 1001), which evaluated XALKORI in 50 patients with ROS1-positive advanced NSCLC. These data published in the November 20, 2014 issue of the New England Journal of Medicine demonstrated that XALKORI exhibited marked anti-tumor activity in patients with ROS1-positive advanced NSCLC.5 The safety profile of XALKORI in ROS1-rearranged advanced NSCLC was similar to that observed in patients with ALK-positive advanced NSCLC.5

About Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death worldwide.6 NSCLC accounts for about 85 percent of lung cancer cases and remains difficult to treat, particularly in the metastatic setting.7 Approximately 75 percent of NSCLC patients are diagnosed late with metastatic, or advanced, disease where the five-year survival rate is only 5 percent.7,8,9

About XALKORI (crizotinib)

XALKORI is a kinase inhibitor indicated in the U.S. for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. XALKORI has received approval in more than 80 countries10 including Australia, Canada, China, Japan, South Korea and the European Union.

XALKORI Important Safety Information

Hepatotoxicity: Across three main clinical trials fatal hepatotoxicity occurred in 0.2% of patients. Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI.

Pneumonitis: Across three main clinical trials interstitial lung disease (ILD)/pneumonitis occurred in 2% of patients. Permanently discontinue in patients with ILD/pneumonitis.

QT Interval Prolongation: Across three main clinical trials QT interval prolongation occurred in 2.7% of patients. Monitor with electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT. Temporarily suspend, dose reduce, or permanently discontinue XALKORI.

Bradycardia: XALKORI can cause bradycardia. Across three main clinical trials 11% of patients experienced a heart rate of less than 50 beats per minute. Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI.

Embryofetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI.

Adverse Reactions: Across three main clinical trials the most common adverse reactions (≥25%) were vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.

In a phase 3 study in patients with previously treated ALK-positive metastatic NSCLC randomized to XALKORI (n=172) or chemotherapy (n=171), serious adverse reactions were reported in 37.2% of patients treated with XALKORI. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients occurred in 9 (5%) patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, ILD, pneumonia, pneumonitis, pulmonary embolism, respiratory failure, and sepsis. Grade 3 or 4 events occurring at a higher incidence with XALKORI than with chemotherapy and at greater than 2%, were syncope (3%), QT prolongation (3%), and pulmonary embolism (5%). Elevation of ALT of any grade occurred in 76% of patients and grade 3 or 4 in 17% of patients. Neutropenia of any grade occurred in 49% of patients and grade 3 or 4 in 12% of patients. Lymphopenia of any grade occurred in 51% of patients and grade 3 or 4 in 9% of patients. Renal cysts occurred in 4% and neuropathy occurred in 19% of patients treated with XALKORI.

Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Dose reduction may be needed for co-administered drugs that are predominantly metabolized by CYP3A.

Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, consider whether to discontinue nursing or discontinue XALKORI.

Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment.

Renal Impairment: Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr<30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment.

For more information and full prescribing information, please visit www.XALKORI.comExternal Links icon.

Juno Therapeutics’ CAR T Cell Product Candidate JCAR017 Continues to Demonstrate Encouraging Outcomes in Pediatric Patients With Relapsed/Refractory CD19 Positive Acute Lymphoblastic Leukemia

On April 21, 2015 Juno Therapeutics reported encouraging clinical responses in a Phase 1 study evaluating JCAR017 in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL) (Press release, Juno, APR 21, 2015, View Source [SID:1234503099]). The results of this trial to date demonstrated that 91% of patients achieved a complete remission as documented by flow cytometry. Adverse events were consistent with what has been previously reported. JCAR017 is a chimeric antigen receptor (CAR) T cell product candidate subject to a licensing arrangement with Seattle Children’s Research Institute. The results were presented in an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2015 in Philadelphia, Pennsylvania.

"The 91% remission rate in this Phase 1 study of JCAR017 is highly encouraging, particularly when considering these pediatric patients failed to respond to standard treatments," said Michael Jensen, M.D., Scientific Co-Founder, Juno Therapeutics, and Director of the Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute. "Based on these results we are eager to advance this study, and to continue advancing the use of cell therapies to change how we treat cancer and provide patients the opportunity for better treatment options."

Data from the ongoing, open-label, Phase 1 dose escalation study were presented by Dr. Jensen at AACR (Free AACR Whitepaper) today. The study is evaluating escalating doses of JCAR017 in pediatric patients with relapsed/refractory CD19 positive ALL. JCAR017, a defined cell product candidate, was successfully manufactured for all enrolled patients. The study was designed and conducted by Seattle Children’s Research Institute with patients from Seattle Children’s Research Institute.

In an intent-to-treat analysis, a complete remission documented by flow cytometry in 20 of 22 patients (91%) was measured. The complete remissions were observed at all doses evaluated in patients with prior CD19-directed therapy as well as in patients with infantile ALL. Severe cytokine release syndrome and/or severe neurotoxicity was observed in 8 patients. Four relapses have been observed to date, only one of which had CD19 positive disease.

Clinical data of Medigene’s dendritic cell (DC) vaccines presented at AACR conference

On April 20, 2015 Medigene AG (MDG1, Frankfurt, Prime Standard) reported that early clinical data of its dendritic cell (DC) vaccines were presented today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Philadelphia, USA (Press release, MediGene, APR 20, 2015, View Source [SID:1234506589]). The clinical data were collected in an ongoing compassionate use program[1] conducted at the Department of Cellular Therapy at the Oslo University Hospital, Norway, under the responsibility of Prof. Gunnar Kvalheim. The poster presentation titled "A new generation of dendritic cells to improve cancer therapy shows prolonged progression free survival in patients with solid tumors" provides data from patients with various types of tumour which were included in this program.

In summary, one lung cancer patient, one prostate cancer patient, four glioblastoma patients and three acute myeloid leukaemia (AML) patients have started treatment with dendritic cells so far. The new generation of dendritic cells characterized by superior in-vitro functionality when compared to commonly used dendritic cells could be produced from cells of all patients, regardless of the type of malignancy. The included patients suffering from solid tumours clearly showed a longer progression free survival than could be expected according to the stage of their disease, except for the patient with prostate cancer, who due to personal reasons prematurely dropped out of the program. The three AML patients which were included in this dendritic cell compassionate use program have been showing a promising course of disease, however these cases are still too early for evaluation.

Conclusion of this evaluation by Prof. Gunnar Kvalheim, Head of Department of Cellular Therapy, Oslo University Hospital: "Solid tumour patients suffering from advanced disease treated with these DC vaccines have a prolonged progression free survival, showing that this immunotherapeutic approach will be a promising alternative to current standard therapies."

More detailed information can be found in the abstract under the following link: View Source;sKey=eae2d342-dd5a-41ba-9eb4-63990d3122b8&cKey=1ff23671-9f76-44fd-891b-50b8fbfdd1b6&mKey=19573a54-ae8f-4e00-9c23-bd6d62268424

The Oslo University Hospital has an agreement with Medigene for use of Medigene`s new generation DC vaccines for their ongoing academic clinical studies.

Prof. Dolores J. Schendel, Chief Scientific Officer of Medigene AG: "These positive results encourage us in pursuing our DC vaccine development program for which we have recently started our own clinical AML trial, complementing the ongoing academic clinical studies."

About Medigene’s DC vaccines: The platform for the development of new generation antigen-tailored DC vaccines is the most advanced platform of the three highly innovative and complementary immunotherapy platforms of Medigene Immunotherapies. The DC vaccines are currently being evaluated in a company-sponsored clinical trial in acute myeloid leukaemia (AML) as well as in two ongoing clinical investigator-initiated trials: a clinical phase I/II trial in AML at the Ludwig-Maximilian University Hospital Großhadern, Munich, and a clinical phase II trial in prostate cancer at the Oslo University Hospital. Moreover, a compassionate use program is being conducted at the Department of Cellular Therapy at the Oslo University Hospital.

Medigene’s dendritic cell product platform allows the design of new generation dendritic cell vaccines. Dendritic cells can take up antigens efficiently, process them and present them on their surface in a form that can induce antigen-specific T cells to proliferate and mature. This way T cells can recognize and eliminate antigen-bearing tumour cells. Dendritic cells can also induce natural killer cells (NK cells) to become active and attack tumour cells. Scientists of Medigene Immunotherapies have developed new, fast and efficient methods for preparing autologous (patient-specific) mature dendritic cells which have relevant characteristics to activate both T cells and NK cells. The dendritic cells can be loaded with various tumour antigens to treat different types of cancer and are designed for treatment of minimal residual disease or use in combination therapies.

Curadev Announces Research Collaboration and Licensing Agreement to Develop Cancer Immunotherapeutic

On April 20, 2015 Curadev Pharma reported that it has entered into a research collaboration and exclusive license agreement with Roche for the development and commercialization of IDO1 and TDO inhibitors (Press release, Curadev, APR 20, 2015, View Source [SID:1234503106]). The agreement covers the development of the lead preclinical immune tolerance inhibitor and a research collaboration with Roche’s research and early development organization to further explore the IDO and TDO pathways.

IDO1 (indoleamine-2, 3-dioxygenase-1) and TDO (tryptophan-2, 3-dioxygenase) are enzymes that mediate cancer-induced immune suppression. This mechanism is exploited by tumor cells as well as certain type of immune cells, limiting the anti-tumor immune response.

Dual inhibition of the IDO1 and TDO pathways promises to maintain the immune response, prevent local tumor immune escape and potentially avoid resistance to other immunotherapies when used in combination, and could lead to new treatment options for cancer patients. Curadev’s preclinical lead-compound, a small-molecule that shows potent inhibition of the two rate-limiting enzymes in the tryptophan – to kynurenine metabolic pathways, has the potential for mono therapy as well as combination with Roche’s broad oncology pipeline and portfolio.

"We are very excited to be working with the global leader in oncology with their unrivalled expertise in clinical development," said Arjun Surya, PhD, Chief Scientific Officer, Curadev. "The collaboration acknowledges our focused research efforts on patient-critical drug targets that have yielded a drug candidate that could make a significant difference in the development of novel treatments for patients suffering from cancer."

Under the terms of agreement, which includes a research collaboration with Roche’s research and early development organization to further extend Curadev’s findings, Curadev will receive an upfront payment of $25 million and will be eligible to receive up to $530 million in milestone payments based on achievement of certain predetermined events and sales levels as well as escalating royalties potentially reaching double digits for the first product from the collaboration developed and commercialized by Roche. Curadev would also be eligible for milestones and royalties on any additional products resulting from the research collaboration. Roche will fund future research, development, manufacturing and commercialization costs and will also provide additional research funding to Curadev for support of the research collaboration.