On April 7, 2015 Merck KGaA and Pfizer reported the finalization of the co-promotion agreement allowing the companies to co-promote Pfizer’s anaplastic lymphoma kinase (ALK) inhibitor XALKORI (crizotinib) (Press release, Pfizer, APR 7, 2015, View Source [SID:1234502955]). This agreement showcases the alliance’s commitment to establishing a combined oncology sales organization in key markets in advance of the potential launch of avelumab*-based treatment regimens in the future.

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XALKORI is the first ALK inhibitor approved in the United States, Japan and the European Union (EU) and is supported by two positive global randomized trials in the first- and second-line ALK-positive advanced non-small cell lung cancer (NSCLC) treatment settings. To date, globally more than 8,000 patients have been treated with XALKORI, including those who received XALKORI in clinical trials.

Under the agreement, XALKORI will be co-promoted in two waves, the first of which will begin in the second and third quarters of 2015 in the United States, Canada, Japan and five European Union countries (France, Germany, Italy, Spain and the United Kingdom). In the United States and Canada, XALKORI will be co-promoted by EMD Serono, the US and Canadian biopharmaceutical businesses of Merck KGaA, Darmstadt, Germany. The second wave will begin in 2016 and includes China and Turkey.

In 2015, Merck KGaA, Darmstadt, Germany, will receive a reimbursement associated with its promotion of XALKORI, followed by an 80 percent (Pfizer), 20 percent (Merck KGaA, Darmstadt, Germany) profit sharing on the product starting in 2016. The co-promotion term will last through December 31, 2020 for the United States, Canada, Japan, France, Germany, Italy, Spain and the United Kingdom, and from January 1, 2016 through December 31, 2021 in China and Turkey. Pfizer will report the sales of XALKORI in countries where it is co-promoted with Merck KGaA, Darmstadt, Germany.

"We are proud and excited to share the legacy of XALKORI, a medicine that changed the treatment paradigm for patients with ALK-positive metastatic NSCLC, with Merck KGaA, Darmstadt, Germany," said Liz Barrett, president and general manager, Pfizer Oncology. "Through our co-promotion of XALKORI, we will establish a best-in-class global sales organization that will be exceptionally prepared for the potential launches of our future oncology medicines."

"As we progress our robust program to co-develop and co-commercialize avelumab, the co-promotion agreement is an exciting milestone for the alliance between Merck KGaA, Darmstadt, Germany, and Pfizer, allowing us to establish our combined oncology sales organization in key markets for the program," said Dr. Andrew Schiermeier, head of Global Oncology and general manager for the Alliance for Merck KGaA, Darmstadt, Germany, adding: "For Merck KGaA, Darmstadt, Germany, this agreement is particularly important as it accelerates the establishment of our United States and Canada oncology sales organization ahead of our potential avelumab launches and positions us for future success in this market."

This co-promotion relationship is related to the announcement in November 2014 of a global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer to jointly develop and commercialize avelumab, an investigational anti-PD-L1 monoclonal antibody, to accelerate the development of immuno-oncology medicines for patients with cancer. The immuno-oncology alliance will also advance Pfizer’s PD-1 antibody.

About Non-small Cell Lung Cancer

Globally, lung cancer is the most common cause of cancer-related deaths in men and the second most common in women, responsible for almost twice as many deaths as both breast and prostate cancer combined1. Non-small cell lung cancer is the most common type of lung cancer, accounting for 85 to 90 percent of all lung cancers2. Locally advanced and metastatic disease account for approximately 35 to 40 percent3 and 70 percent4 of patients, respectively with NSCLC.

About XALKORI (crizotinib)

XALKORI is a kinase inhibitor indicated in the US for the treatment of patients with metastatic non-small cell lung cancer whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. The US indication is not limited to any specific line of therapy. In the EU, XALKORI is indicated for the treatment of adults with previously treated ALK-positive advanced NSCLC. XALKORI has received approval in more than 80 countries.

XALKORI Important Safety Information

Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.2% of patients treated with XALKORI across clinical trials (n=1225). Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated. Permanently discontinue for ALT or AST elevation greater than 3 times ULN with concurrent total bilirubin elevation greater than 1.5 times ULN (in the absence of cholestasis or hemolysis), otherwise temporarily suspend and dose reduce XALKORI as indicated.

Pneumonitis: Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials (n=1225), 2.5% of XALKORI-treated patients had any grade ILD, 0.9% of patients had Grade 3 or 4, and 0.5% had fatal cases. These cases generally occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes and permanently discontinue XALKORI in patients with drug related pneumonitis.

QT Interval Prolongation: QTc prolongation can occur in patients treated with XALKORI. Across clinical trials (n=1225), QTc prolongation (all grades) was observed in 2.7% of patients and QTc greater than 500 ms on at least 2 separate ECGs occurred in 1.4% of patients. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia, otherwise temporarily suspend and dose reduce XALKORI as indicated.

Bradycardia: Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia with a heart rate less than 50 beats per minute occurred in 11% of patients treated with XALKORI (n=1174). Monitor heart rate and blood pressure regularly. Avoid using XALKORI in combination with other agents known to cause bradycardia to the extent possible. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring. Otherwise temporarily suspend and resume or dose reduce XALKORI as indicated.

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. If the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

Adverse Reactions: Safety was evaluated in a phase 3 study in patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=172) or chemotherapy (n=171). Serious adverse reactions were reported in 37.2% 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. Common adverse reactions occurring in ≥25% included vision disorder (diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters), diarrhea, nausea, vomiting, constipation, edema, decreased appetite, fatigue, upper respiratory infection, and dysgeusia. Grade 3 or 4 events occurring at a higher incidence with XALKORI than with chemotherapy and at greater than 2% incidence 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 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 coadministered 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.com.

On April 6, 2015 Clovis Oncology reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for the Company’s investigational agent rucaparib as monotherapy treatment of advanced ovarian cancer in patients who have received at least two lines of prior platinum-containing therapy, with BRCA-mutated tumors, inclusive of both germline BRCA (gBRCA) and somatic BRCA (sBRCA) mutations (Press release, Clovis Oncology, APR 6, 2015, View Source [SID:1234502943]).

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Rucaparib is an oral, potent inhibitor of PARP1 and PARP2 being developed for the treatment of platinum-sensitive ovarian cancer, specifically in patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA, commonly referred to as "BRCA-like" or "BRCAness." The Breakthrough Therapy designation was granted based on interim efficacy and safety results from two ongoing Phase 2 studies of rucaparib in ovarian cancer, including a Phase 2 study in women with gBRCA mutations, and the ARIEL2 treatment study.

A clinical data update from the ARIEL2 study presented last week at the 2015 Annual Meeting on Women’s Cancer demonstrated that seventy percent (16/23) of evaluable BRCA-mutant patients achieved a RECIST and/or CA-125 response, and 65% (15/23) achieved a RECIST response. Responses were observed in both germline and somatic BRCA-mutant tumors.

"It is a distinct achievement for a company our size to have been granted Breakthrough Therapy designation for two separate products under development, and especially in less than one year," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "In the case of rucaparib, we believe it is in recognition of the encouraging response rate observed in women with BRCA-mutated advanced ovarian cancer treated with rucaparib, and this designation reinforces the unique profile of rucaparib among PARP inhibitors, as well as our leadership in the differentiated clinical development of a PARP inhibitor. This includes prospectively demonstrating meaningful activity in an additional group of advanced ovarian cancer patients whose tumors are not mutant BRCA, but whose tumors possess similar DNA repair deficiencies that behave like BRCA mutations. Rucaparib is the only PARP inhibitor to have shown activity in this broader, but still selected, patient population."

"Women with ovarian cancer are in need of better therapeutic options, and there is great focus on the potential of PARP inhibitors; data presented to date in mutant BRCA patients treated with rucaparib are very encouraging, as is the Breakthrough Therapy designation conferred by the FDA," said Robert L. Coleman, MD, Professor & Deputy Chairman, Vice Chair, Clinical Research, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Cancer Center in Houston and one of the two principal investigators of the ARIEL3 study. "I am very enthusiastic about the substantive progress made by Clovis with both rucaparib and its patient selection tool that appears to be moving beyond BRCA to efficiently identify responder versus non-responder populations. Continuing successful development of this drug and its companion diagnostic will be a huge advance for women with this disease. Importantly, these data suggest that the majority of women tested might benefit from rucaparib treatment. We hope that the ARIEL2 extension study in around 300 women, and the randomized ARIEL3 trial in 540 women, will offer definitive support both for rucaparib and the companion diagnostic."

A clinical data update from the ARIEL2 study presented last week at the 2015 Annual Meeting on Women’s Cancer demonstrates encouraging activity and safety in women with advanced, platinum-sensitive ovarian cancer with gBRCA and sBRCA mutations. Seventy percent (16/23) of evaluable BRCA-mutant patients achieved a RECIST and/or CA-125 response, and 65% (15/23) achieved a RECIST response. Responses were observed in both germline and somatic BRCA-mutant tumors. In addition, data presented last week further demonstrate that Clovis’ proprietary BRCA-like DNA signature, run by its partner Foundation Medicine, successfully predicts which ovarian cancer patients respond to rucaparib therapy. In patients with normal BRCA genes, rucaparib activity was substantially higher for those with the prospectively-defined BRCA-like HRD signature versus biomarker negative patients. Forty-eight percent (12/25) of patients with the BRCA-like signature achieved a RECIST and/or CA-125 response, and 40% (10/25) achieved a RECIST response. In biomarker negative patients, few responses were observed: eight percent (1/13) of patients achieved a RECIST and/or CA-125 response.

These data also demonstrate that rucaparib is well-tolerated. At the recommended Phase Two dose of 600mg BID, the most common treatment-related adverse events (AEs) reported in ≥15 percent of all patients (n=121) included nausea, fatigue, transient ALT/AST elevations, dysgeusia, constipation, anemia/low hemoglobin, decreased appetite, vomiting and diarrhea. These events were mostly Grade 1/2; the only common grade 3/4 toxicity was anemia/low hemoglobin.

The next update of rucaparib clinical data, including outcomes data on the complete Part One ARIEL2 patient population, will be presented in an oral presentation at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in late May/early June.

ARIEL Pivotal Study Program

The ARIEL (Assessment of Rucaparib in Ovarian Cancer Trial) program is a novel, integrated translational-clinical program designed to accurately and prospectively identify patients with tumor genomics associated with benefit from rucaparib therapy.

The global ARIEL2 study, initiated in Q4 2013, has completed enrollment of 206 ovarian cancer patients with relapsed, platinum-sensitive disease. The single-arm, open-label Phase 2 study is designed to prospectively test molecular features that predict sensitivity to rucaparib using DNA sequencing to evaluate each patient’s tumor. ARIEL2 was recently expanded into a registration study (the ARIEL2 extension), which will include an additional approximately 300 women with recurrent disease after at least three prior lines of chemotherapy, and data from this study are planned to serve as the basis of a New Drug Application (NDA) filing for the treatment of ovarian cancer in 2016.

The global ARIEL3 pivotal study is currently enrolling a total of 540 patients, in a randomized, double-blind Phase 3 study that compares the effects of rucaparib versus placebo. The study will evaluate whether maintenance rucaparib treatment in platinum-sensitive, high-grade ovarian cancer patients can extend the period of time for which a response to a prior chemotherapy is maintained. Efficacy is assessed in a pre-specified step-down manner, first in tumor BRCA-mutant patients, then in a larger group of patients with the BRCA-like signature, and finally in all randomized patients. The Company anticipates completing enrollment in the study within the next year.

In addition to the ARIEL program in ovarian cancer, the Company is exploring rucaparib in other solid tumor types with significant BRCA and BRCA-like populations including breast, gastroesophageal and pancreatic.

About Breakthrough Therapy Designation

The Breakthrough Therapy designation was enacted as part of the 2012 FDA Safety and Innovation Act and is intended to expedite development and review of drugs to treat serious or life-threatening medical conditions when preliminary clinical evidence demonstrates that the drug may have substantial improvement on at least one clinically significant endpoint over available therapies. Breakthrough Therapy designation includes all the features of the Fast Track designation, as well as more intensive guidance from the FDA on a drug’s clinical development program.

About Rucaparib

Rucaparib is an oral, potent inhibitor of PARP1 and PARP2 being developed for the treatment of platinum-sensitive ovarian cancer in patients with BRCA mutations (genes that are linked to breast and ovarian cancers) and other DNA repair deficiencies. For information about rucaparib studies in ovarian cancer, please visit www.arielstudy.com.

About Ovarian Cancer

Over 90% of ovarian cancer arises from the uncontrolled growth and replication of epithelial cells which form the surface of the ovary. Cancer involving this type of cell is known as epithelial ovarian cancer. High grade serous carcinoma is a subtype of epithelial ovarian cancer accounting for approximately 70 percent of cases. If detected at a very early stage, ovarian cancers can usually be removed surgically and this can be potentially curative. However, there are often no clearly identifiable initial symptoms and in approximately 90 percent of high grade serous ovarian cancer cases, the cancer has spread to other parts of the body before a person is diagnosed.

On April 6, 2015 Celldex Therapeutics reported the initiation of a Phase 1/2 safety pilot and expansion study examining the investigational combination of varlilumab and ipilimumab (Yervoy; Bristol-Myers Squibb) in patients with Stage III or IV metastatic melanoma (Press release, Celldex Therapeutics, APR 6, 2015, View Source [SID:1234502931]). Varlilumab is Celldex’s fully human monoclonal antibody that targets CD27, a critical co-stimulatory molecule in the immune activation cascade. Ipilimumab, a recombinant, human monoclonal antibody that blocks CTLA-4, is FDA approved for the treatment of unresectable or metastatic melanoma. In the Phase 2 portion of the study, patients with tumors that express NY-ESO-1 will also receive CDX-1401, Celldex’s off-the-shelf antibody-based dendritic cell vaccine that targets tumors expressing the NY-ESO-1 oncoprotein.

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The three agents in this study were specifically selected because they uniquely intervene at key points of immune regulation and because Celldex has observed enhanced activity in preclinical studies when varlilumab is combined with either checkpoint inhibitors or with vaccines. In addition, this study will also build on previous clinical data from the CDX-1401 experience that suggests that CDX-1401 may predispose patients to better outcome on checkpoint inhibitors, including ipilimumab.

"We believe sophisticated combination approaches centered on immunotherapy hold significant promise for the treatment of cancer and, to this end, are committed to exploring novel combinations across a broad array of mechanisms and indications. This latest trial marks the third Phase 1/2 combination study that varlilumab has entered and the first three-drug combination study," said Thomas Davis, MD, Executive Vice President and Chief Medical Officer of Celldex Therapeutics.

The Phase 1 portion of the study will assess the safety and tolerability of varlilumab at 0.3 and 3.0 mg/kg in combination with ipilimumab at 3 mg/kg administered every three weeks to identify a recommended dose for the Phase 2 portion of the study. The Phase 2 study will include two cohorts—one comprised of patients who are NY-ESO-1 positive and one comprised of patients who are NY-ESO-1 negative. Patients who are NY-ESO-1 positive will also receive CDX-1401 dosed at 1 mg (with poly-ICLC at 2 mg given as an adjuvant) every three weeks in addition to varlilumab and ipilimumab. In total, up to four doses of study treatment will be administered. The primary objective for both cohorts is objective response rate up to 24 weeks (ORR6) using standard, modified World Health Organization response criteria. Secondary objectives for the Phase 2 study include safety and tolerability, immunogenicity, pharmacokinetics and further assessment of anti-tumor activity across a broad range of endpoints.

About Varlilumab

Varlilumab is a fully human monoclonal antibody that targets CD27, a critical molecule in the activation pathway of lymphocytes. CD27 can be effectively manipulated with activating antibodies to induce potent anti-tumor responses and may result in fewer toxicities due to its restricted expression and regulation. Varlilumab is a potent anti-CD27 agonist that induces activation and proliferation of human T cells when combined with T cell receptor stimulation. In lymphoid malignancies that express CD27 at high levels, varlilumab may have an additional mechanism of action through a direct anti-tumor effect. Varlilumab has completed a Phase 1 dose-escalation study, demonstrating potent immunologic activity consistent with its mechanism of action and anti-tumor activity in patients with advanced, refractory disease. No maximum tolerated dose was reached and minimal toxicities were observed. Celldex has initiated a broad development program for varlilumab to explore its role as an immune activator in combination with a number of complementary investigational and approved oncology drugs. Varlilumab is currently being studied in three Phase 1/2 combination studies and several additional combination studies will be initiated in 2015.

About CDX-1401

CDX-1401 is a next-generation, off-the-shelf cancer vaccine designed to activate the patient’s immune system against cancers that express the tumor marker, NY-ESO-1. CDX-1401 consists of a fully human monoclonal antibody with specificity for the dendritic cell receptor DEC-205 genetically linked to the NY-ESO-1 tumor antigen. Celldex has accessed NY-ESO-1 through a licensing agreement with the Ludwig Institute for Cancer Research. By selectively delivering the NY-ESO-1 antigen to dendritic cells in the body, CDX-1401 is intended to induce robust immune responses against the antigen-expressing cancer cells.

On April 6, 2015 ARIAD Pharmaceuticals reported that Health Canada has approved the use of Iclusig (as ponatinib hydrochloride) in Canada for the treatment of adult patients with all phases of chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom other tyrosine kinase inhibitor (TKI) therapy is not appropriate, including CML or Ph+ ALL that is T315I mutation positive, or where there is prior TKI resistance or intolerance (Press release, Ariad, APR 6, 2015, View Source [SID:1234502927]).

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"Patients with CML or Ph+ ALL can become resistant to their therapies over time," said Professor Jeffrey Lipton, Ph.D., M.D., staff physician at The Princess Margaret Cancer Centre and one of the PACE trial investigators. "Iclusig will be a valuable new therapeutic option in Canada for patients with refractory CML and Ph+ ALL, where we have a proven unmet medical need."

Iclusig is approved under the Notice of Compliance with Conditions (NOC/c) policy based on promising evidence of clinical effectiveness following review by Health Canada. Products approved under this policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness, and have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, these products either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies.

"Throughout the development of Iclusig, we have worked closely with leading academic centers and clinical investigators in Canada. Iclusig is the only TKI that has been approved in Canada for indications that include CML and Ph+ ALL patients with the T315I mutation," stated Harvey J. Berger, M.D., chairman and chief executive officer of ARIAD. "We will strive to make Iclusig available as quickly as possible to appropriate patients with Ph+ leukemias throughout Canada."

Iclusig will be made available through a controlled distribution program. Under this program, prescribers who have completed the certification procedure are able to prescribe Iclusig. Trained pharmacies will verify the prescriber’s certified status prior to dispensing Iclusig to the patient.

"Iclusig provides a new treatment option for patients with difficult-to-treat CML or Ph+ ALL who previously had limited therapies available to them," said Cheryl-Anne Simoneau, president and chief executive officer at the Chronic Myelogenous Leukemia Society of Canada. "For appropriate patients, this can be an important new treatment option."

The Health Canada decision was based on two-year data from the pivotal Phase 2 PACE trial in patients with CML or Ph+ ALL who were resistant or intolerant to prior TKI therapy, or who had the T315I mutation of BCR-ABL. Iclusig demonstrated anti-leukemic activity, achieving a major cytogenetic response (MCyR) in 56 percent of chronic-phase CML patients and in 70 percent of patients with the T315I mutation. MCyR within the first 12 months of treatment was the primary endpoint of the PACE trial for chronic-phase patients.

In patients with advanced disease, 57 percent of accelerated-phase CML patients and 31 percent of blast-phase CML patients achieved a major hematologic response (MaHR) with Iclusig. MaHR within the first 6 months was the primary endpoint in the trial for patients with advanced disease. In patients with Ph+ ALL, 41 percent achieved MaHR.

ARIAD’s upcoming dose-ranging trial to evaluate three starting doses of Iclusig in patients with refractory, chronic-phase CML who are resistant to at least two approved TKIs — planned to begin in mid-2015 — will serve as the confirmatory trial for the Health Canada approval.

About CML and Ph+ ALL

CML is a cancer of the white blood cells that according to the Chronic Myelogenous Leukemia Society of Canada affects 1 in 100,000, with about 5,500 Canadians living with the disease. In 2010, more than 550 people in Canada were expected to be diagnosed with CML, and 480 people were expected to be diagnosed with ALL.

CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality that produces the BCR-ABL protein. After a chronic phase of production of too many white blood cells, CML typically evolves to the more aggressive phases referred to as accelerated phase and blast crisis. Ph+ ALL is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than CML and is often treated with a combination of chemotherapy and TKIs. The BCR-ABL protein is expressed in both of these diseases.

About Iclusig (as ponatinib hydrochloride)

Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD’s computational and structure-based drug design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs.

Indications

ICLUSIG is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) for whom other tyrosine kinase inhibitor (TKI) therapy is not appropriate, including CML or Ph+ ALL that is T315I mutation positive or where there is prior TKI resistance or intolerance.

Marketing authorization with conditions is based on response rate. There are no trials demonstrating increased survival or improvement in symptoms with ICLUSIG. In the pivotal trial, the majority of the hematological responses occurred within 1 month. Consider discontinuing ICLUSIG if a hematological response has not been achieved by 3 months (90 days).

ICLUSIG for this indication has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Patients should be advised of the conditional nature of the authorization.

Contraindications

Do not use in patients who are hypersensitive to ponatinib or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
Do not use in patients who have unmanaged cardiovascular risk factors, including uncontrolled hypertension. Hypertension may contribute to the risk of arterial thrombotic events. Blood pressure should be monitored and managed to avoid hypertension.
Do not use in patients who are not adequately hydrated and with uncorrected high uric acid levels.

Serious Warnings and Precautions

Iclusig has serious warnings and precautions for: vascular occlusion, heart failure, hemorrhage, hepatotoxicity, myelosuppression, and pancreatitis.

ICLUSIG should only be prescribed and monitored by a physician who has completed the certification with the ICLUSIG Controlled Distribution Program and who is experienced in the use of antineoplastic therapy and in the treatment of CML or Ph+ ALL.

Vascular Occlusion (arterial and venous thrombosis and occlusions), occurred in 24% (129/530) of ICLUSIG-treated patients with and without cardiovascular risk factors (including patients less than 50 years old). In clinical trials, serious treatment-emergent arterial thrombosis (cardiovascular, cerebrovascular, and peripheral vascular) and occlusions were seen in 14% of the ICLUSIG-treated patients including fatal myocardial infarction, fatal cerebral infarction, stroke, disseminated intravascular coagulation, and arterial stenosis sometimes requiring urgent revascularization procedures. Some of these events occurred within 2 weeks of starting treatment with ICLUSIG. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or consider discontinuation in patients who develop arterial thrombotic events.
Heart Failure (in some cases, fatal), including left ventricular dysfunction and ejection fraction decreases, occurred in 8% of ICLUSIG-treated patients, 5% of which were serious.
Hemorrhage events (some fatal) including intracranial hemorrhage, hemorrhagic gastritis, (fatal), hemorrhagic cerebral infarction (fatal). Most hemorrhagic events, but not all, occurred in patients with grade 4 thrombocytopenia.
Hepatotoxicity (including fatal acute hepatic failure) has been reported. Monitor hepatic function prior to and during treatment. Consider ICLUSIG dose interruption followed by dose reduction or discontinuation in patients with hepatotoxicity.
Myelosuppression (thrombocytopenia, neutropenia, and anemia).
Pancreatitis (7%) and elevations in amylase (2% grade 3 or greater) or lipase (12% grade 3 or greater) have been reported.

ICLUSIG has not been studied in patients with renal impairment.

Most Common Adverse Reactions

Overall, the very common adverse reactions (≥ 10%) were platelet count decreased, rash, dry skin, abdominal pain, neutrophil count decreased, headache, lipase increased, fatigue, constipation, myalgia, arthralgia, nausea, anemia, ALT increased, hypertension, and AST increased.

On April 6, 2015 Advaxis reported that it is entering into a clinical trial collaboration agreement with the Radiation Therapy Oncology Group (RTOG) Foundation to evaluate the safety and efficacy of Advaxis’s lead cancer immunotherapy, ADXS-HPV (ADXS11-001), in a pivotal Phase 2/3 anal cancer trial, which will be run by NRG Oncology (Press release, Advaxis, APR 6, 2015, View Source [SID:1234502925]). ADXS-HPV is an investigational Lm-LLO immunotherapy bioengineered to generate an immune response to the HPV-associated tumor specific oncogene.

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Under the proposed collaboration, RTOG Foundation, through its partnership with NRG Oncology, will conduct an adequate and well-controlled Phase 2/3 clinical trial of concurrent chemotherapy of mitomycin C/5FU and radiation therapy (CCRT) compared to CCRT combined with ADXS-HPV in the adjuvant treatment of high-risk locally advanced anal cancer.

Walter J. Curran, Jr., MD, RTOG Foundation Chairman of the Board and NRG Oncology Group Chair, commented, "The ability of ADXS-HPV to generate an immune response to the HPV-associated tumor specific oncogene offers the potential to benefit multiple cancers that are known to be caused by the HPV infection, including cervical cancer and anal cancer. We look forward to initiating this Phase 2/3 study in anal cancer and mirroring the encouraging results that the Gynecologic Oncology Group, now a part of NRG Oncology, has had in its clinical study of ADXS-HPV in cervical cancer."

David J. Mauro, MD, PhD, Executive Vice President and Chief Medical Officer of Advaxis, stated, "We are excited to enter this collaboration agreement with NRG Oncology and look forward to building on the initial results observed in the ongoing Phase 1/2 study of ADXS-HPV in anal cancer being conducted by Professor Howard Safran MD of Brown University Oncology Group. Although a relatively rare tumor, virtually all cases of squamous cell cancer of the anus are caused by HPV infection, and ADXS-HPV offers the potential to treat this often fatal malignancy."

About RTOG Foundation, Inc.

The Radiation Therapy Oncology Group (RTOG) has been an international leader in conducting Phase 2 and 3 multi-institutional clinical trials with a focus on radiation oncology issues. During its forty-plus year history, the group has repeatedly defined new standards of cancer care to improve the survival and quality of life of cancer patients and developed new processes for the study and application of innovative radiotherapy technologies. RTOG Foundation, Inc. is a Philadelphia based 501(c)(3) organization that continues its National Cancer Institute (NCI) funded research activities through NRG Oncology as one of its three founding members. RTOG also joins with corporate partners to conduct multicenter clinical trials systematically testing novel radiotherapy approaches combined with new classes of anti-cancer therapies and targeted agents. The group has completed a number of practice- and paradigm-changing trials in its primary disease sites: central nervous system, head & neck, lung, gastrointestinal (esophagus, stomach, pancreas, anal canal, and rectum), genitourinary (bladder and prostate), breast, and cervix.

About NRG Oncology

NRG Oncology conducts practice-changing, multi-institutional clinical and translational research to improve the lives of patients with cancer. Founded in 2012, NRG Oncology is a Pennsylvania-based nonprofit corporation that integrates the research strengths of the National Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG) and the Gynecologic Oncology Group (GOG). The research organization seeks to carry out clinical trials with emphases on gender-specific malignancies including gynecologic, breast, and prostate cancers and on localized or locally advanced cancers of all types. NRG Oncology’s extensive research organization is comprised of multidisciplinary investigators including medical oncologists, radiation oncologists, surgeons, physicists, pathologists, and statisticians and encompasses more than 1300 research sites located world-wide with predominance in the United States and Canada. NRG Oncology is supported primarily through grants from the National Cancer Institute (NCI) and is one of five research groups in the NCI’s National Clinical Trials Network.

About ADXS-HPV

ADXS-HPV is Advaxis’s lead Lm-LLO immunotherapy product candidate for the treatment of HPV-associated cancers. It is currently under investigation in three HPV-associated cancers: invasive cervical cancer, head and neck cancer, and anal cancer. In cervical cancer, a completed Phase 2 study, ADXS-HPV demonstrated prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of this Lm-LLO immunotherapy. The U.S. Food and Drug Administration granted an orphan drug designation for ADXS-HPV for HPV-associated Stage II-IV cervical cancer, head and neck cancer, and for anal cancer.