On May 22, 2015 Pharmacyclics reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion recommending a change to the terms of the marketing authorization for IMBRUVICA (ibrutinib) in the European Union to indicate the treatment of adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy (Press release, Pharmacyclics, MAY 22, 2015, View Source [SID:1234504625]).1 WM is a rare, slow growing form of blood cancer.2 IMBRUVICA is also the first and only FDA-approved treatment for WM in the United States.3 The CHMP recommendation follows the January 2015 U.S. Food and Drug Administration (FDA) full approval of IMBRUVICA to treat all lines of patients with WM.

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IMBRUVICA is jointly developed and commercialized in the United States by Pharmacyclics and Janssen Biotech, Inc. In Europe, Janssen-Cilag International NV (Janssen) holds the marketing authorization and its affiliates market IMBRUVICA in EMEA (Europe, Middle East, Africa), as well as the rest of the world. IMBRUVICA is already approved in Europe to treat adult patients with relapsed or refractory mantle cell lymphoma (MCL) and adult patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy or in first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy.

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The European Medicines Agency is an agency of the European Union responsible for the scientific evaluation of medicines submitted for approval by pharmaceutical companies for use in the 28 countries of the European Union. The positive CHMP opinion will be reviewed by the European Commission, and a final decision on IMBRUVICA to treat WM is anticipated in the second half of 2015. In addition to European markets, a worldwide regulatory filing program for IMBRUVICA currently is underway.

"We are very pleased that patients with WM in the European Union will have a first-in-class, oral, single-agent, non-chemotherapy treatment option in IMBRUVICA," said Thorsten Graef, M.D., Ph.D., Head of Hematology at Pharmacyclics. "This approval underscores the compelling safety and efficacy profile of IMBRUVICA in hematologic malignancies and we look forward to addressing the unmet medical needs of WM patients across Europe."

WM currently affects approximately 23,000 patients in the G7 countries (United States, France, Germany, Italy, Japan and the United Kingdom).3 The CHMP recommendation was based on a multi-center, Phase II study that evaluated the efficacy and tolerability of IMBRUVICA in 63 patients with previously treated WM. Initial data from the study submitted for review in the EU showed an overall response rate (ORR) of 87.3% after a median duration of treatment of 11.7 months.

Updated results from the study were published on in the April 9, 2015 edition of The New England Journal of Medicine, indicating an ORR of 90.5% after a median duration of treatment of 19.1 months using criteria adopted from the International Workshop on WM. At 24 months, the estimated rate of progression-free survival was 69.1% (95% CI, 53.2 to 80.5), and the estimated rate of overall survival was 95.2% (95% CI, 86.0 to 98.4).

No new safety issues were observed in the clinical trial. The most commonly occurring adverse reactions in WM patients treated with IMBRUVICA ( > 20%) were neutropenia and thrombocytopenia. Other adverse reactions occurred in < 10% of patients (n=5). Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to neutropenia or thrombocytopenia. Of note, IMBRUVICA-related neutropenia and thrombocytopenia were reversible, but required a reduction in dose and/or discontinuation of treatment with IMBRUVICA in three of the four patients who developed these conditions. Overall, IMBRUVICA was well tolerated and there were no unexpected toxicities.

About Waldenström’s macroglobulinemia

WM (a clinically recognized subset of lymphoplasmacytic lymphoma, or LPL) is a slow-growing and rare blood cancer that most commonly originates from B cells, a type of white blood cell (lymphocyte) that develops in the bone marrow.2 WM occurs as the result of a malfunction in the healthy lifecycle of a B cell, causing the cell to become malignant and reproduce at an abnormal rate. The malignant B cells produce large amounts of an abnormal type of antibody protein called immunoglobulin M (IgM). Excess IgM causes the blood to thicken and causes many of the symptoms of WM.2

About IMBRUVICA
IMBRUVICA is currently approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, all CLL patients (including treatment naïve) who have del 17p, a genetic mutation that occurs when part of chromosome 17 has been lost, and all patients (including treatment naïve) with Waldenström’s macroglobulinemia. IMBRUVICA is also approved under accelerated approval for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.3

IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK).3 IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway, and is the only product to have received three Breakthrough Therapy Designations.

BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.3,5 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.3

IMBRUVICA is being studied alone and in combination with other treatments in several blood cancers. More than 6,100 patients have been treated in clinical trials of IMBRUVICA conducted in 35 countries by more than 800 investigators. Currently, 13 Phase III trials have been initiated with IMBRUVICA and 67 trials are registered on www.clinicaltrials.gov.

To learn more about the medical terminology used in this news release, please visit View Source

INDICATIONS

IMBRUVICA is indicated in the U.S. to treat people with:

Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy
Chronic lymphocytic leukemia (CLL) with 17p deletion
Waldenström’s macroglobulinemia
Mantle cell lymphoma (MCL) who have received at least one prior therapy – accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
Patients taking IMBRUVICA for CLL or WM should take 420 mg taken orally once daily (or three 140 mg capsules once daily).

Patients taking IMBRUVICA for MCL should take 560 mg taken orally once daily (or four 140 mg capsules once daily).

Capsules should be taken orally with a glass of water. Capsules should be taken whole. Do not open, break, split or chew the capsules.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections – Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly.

Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification.

Second Primary Malignancies – Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%).

Tumor Lysis Syndrome – Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g., high tumor burden).

Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS

The most common adverse reactions ( > 25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia* (57%, 52%, 43%), neutropenia* (47%, 51%, 44%), diarrhea (51%, 48%, 37%), anemia* (41%, 36%, 13%), fatigue (41%, 28%, 21%), musculoskeletal pain (37%, 28%**, NA***), bruising (30%, 12%**, 16%**), nausea (31%, 26%, 21%), upper respiratory tract infection (34%, 16%, 19%), and rash (25%, 24%**, 22%**).

*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

**Includes multiple ADR terms.

***Not applicable; no associated ADRs.

The most common Grade 3 or 4 non-hematological adverse reactions ( > 5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse events.

Approximately 5% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse events. Most frequent adverse events leading to discontinuation were infections, subdural hematomas, and diarrhea in CLL patients and subdural hematoma (1.8%) in MCL patients

DRUG INTERACTIONS

CYP3A Inhibitors – Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

CYP3A Inducers – Avoid co-administration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

Please see Full Prescribing Information: View Source

On May 22, 2015 Bristol-Myers Squibb reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending that nivolumab, a PD-1 immune checkpoint inhibitor, be granted approval for the treatment of locally advanced or metastatic squamous non-small cell lung cancer (NSCLC) after prior chemotherapy in adults (Press release, Bristol-Myers Squibb, MAY 22, 2015, View Source [SID:1234504622]). The CHMP positive opinion will now be reviewed by the European Commission, which has the authority to approve medicines for the European Union (EU).

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"We are moving at a ground-breaking pace to deliver on a mission that looks to transform cancer treatment options for patients," said Michael Giordano, senior vice president, Head of Development, Oncology. "Last month, we received a CHMP positive opinion for nivolumab for the treatment of advanced melanoma. Today’s announcement of a positive opinion for nivolumab in NSCLC brings us closer to delivering on our promise of changing the standard of care for lung cancer."

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Positive Opinion based on CheckMate -017 and -063

The CHMP positive opinion is based on data from CheckMate -017 and CheckMate -063, two trials that demonstrated the efficacy and safety of nivolumab in patients with advanced or metastatic squamous NSCLC who had progressed following previous chemotherapy treatment. CheckMate -017 was a Phase III, randomized, open-label trial that included patients who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen.

Results from a prespecified interim analysis of CheckMate -017, demonstrated significantly superior overall survival (OS) with nivolumab vs. docetaxel, with a 41% reduction in the risk of death (hazard ratio: 0.59 [95% CI: 0.44, 0.79; p=0.00025]). This benefit was observed regardless of PD-L1 expression status. The estimated one-year survival rate was nearly doubled with nivolumab (42% [95% CI: 34, 50]) compared to docetaxel (24% [95% CI: 17, 31]). The median OS was 9.2 months in the nivolumab arm (95% CI: 7.3, 13.3) and 6 months in the docetaxel arm (95% CI: 5.1, 7.3).

A second study, CheckMate -063, was a Phase II single-arm, multinational, multicenter trial that included patients with metastatic squamous NSCLC who had progressed after receiving a platinum-based therapy and at least one additional systemic treatment regimen (65% of patients had received ≥ 3 prior therapies). In CheckMate -063, confirmed objective response rate, the study’s primary endpoint, was 14.5% (17/117) (95% CI = 8.7, 22.2) with an estimated one-year survival rate of 40.8% (95% CI: 31.6, 49.7) and median overall survival of 8.2 months (95% CI: 6.1, 10.9).

In both CheckMate -017 and -063, there was consistent nivolumab dosing of 3 mg/kg every two weeks. The safety profile of nivolumab has been evaluated in thousands of patients enrolled in the broader clinical program and treatment-related adverse events (AEs) were generally managed using established safety algorithms. In CheckMate -017, the safety profile of nivolumab was consistent with prior studies and favorable versus docetaxel. Treatment-related adverse events occurred less frequently with nivolumab than docetaxel (grade 3–4, 6.9% vs. 55%, respectively).

About Nivolumab

Bristol-Myers Squibb has a broad, global development program to study nivolumab in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.

Nivolumab became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the U.S. Food and Drug Administration (FDA) granted its first approval for nivolumab for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. On March 4, 2015, nivolumab received its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

In addition, nivolumab is being investigated in patients with advanced non-squamous NSCLC. On April 17, 2015, an open-label, randomized Phase III study (CheckMate -057) evaluating nivolumab versus docetaxel in previously treated patients with advanced non-squamous NSCLC was stopped early because an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the study met its endpoint, demonstrating superior overall survival in patients receiving nivolumab compared to docetaxel. The company plans to share these data with health authorities.

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year, according to the World Health Organization. NSCLC is one of the most common types of the disease and accounts for approximately 85 percent of cases. Survival rates vary depending on the stage and type of the cancer when it is diagnosed. Globally, the five-year survival rate for Stage I NSCLC is between 47 and 50 percent; for Stage IV NSCLC, the five-year survival rate drops to two percent.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.
Immune-Mediated Colitis

In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.
Immune-Mediated Hepatitis

In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.
Immune-Mediated Nephritis and Renal Dysfunction

In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.
Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.
Other Immune-Mediated Adverse Reactions

In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.
Embryofetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.
Lactation

It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.
Serious Adverse Reactions

In Trial 1, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.
In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.
Common Adverse Reactions

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

On May 21, 2015 Kite Pharma reported that the first patient in its Phase 1/2 clinical trial of KTE-C19 in patients with refractory aggressive NHL has been treated (Press release, Kite Pharma, MAY 21, 2015, View Source [SID:1234504619]). KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a CAR designed to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

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"This is a very exciting time for Kite, and we’re grateful to the patients and clinical researchers who greatly contribute to the progress of our KTE-C19 program," said Arie Belldegrun, M.D., FACS, Chairman, President and Chief Executive Officer. "We are at a pivotal moment for our Company and for the industry as a whole as we initiate the first company-sponsored clinical trial of CAR T-cell therapy in patients with refractory diffuse large B-cell lymphoma (DLBCL)."

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Dr. Belldegrun continued, "Kite has met its goal of initiating the first company-sponsored clinical trial of KTE-C19 in the first half of this year and plans to commence an additional three trials of KTE-C19 before year-end. Our first study is expected to provide pivotal results in 2016, leading to the potential launch and commercialization of KTE-C19 in 2017."

Kite’s Phase 1/2 clinical trial of KTE-C19 is a single arm, open-label, multi-center study, designed to determine the safety and efficacy of KTE-C19 in patients with refractory DLBCL, primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL). Upon completion of the Phase 1 portion of the study, Kite expects to proceed with the Phase 2 portion that will include a total of approximately 112 patients. Additional information about Kite’s Phase 1/2 study may be found at ClinicalTrials.gov, using Identifier NCT: 02348216.

On May 21, 2015 CytRx reported positive updated results from its ongoing Phase 2 clinical trial with aldoxorubicin for the treatment of unresectable glioblastoma multiforme (GBM), a deadly form of brain cancer (Press release, CytRx, MAY 21, 2015, View Source [SID:1234504616]). The open-label, multisite trial is designed to investigate the preliminary efficacy and safety of aldoxorubicin in patients whose tumors have progressed following prior treatment with surgery, radiation and temozolomide.

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Study subjects (n=18) have received between 1 and 14 cycles of aldoxorubicin, with 4 subjects continuing to receive aldoxorubicin treatment. Subjects received either 350 mg/m2 (260 mg/m2 doxorubicin equivalent) (n=6) or 250 mg/m2 (185 mg/m2 doxorubicin equivalent) (n=12) of aldoxorubicin intravenously on Day 1, and every 21 days thereafter until discontinuation. Notably, 2 subjects (11%) diagnosed with tumor progression following aldoxorubicin treatment (1 and 5 cycles, respectively) demonstrated no microscopic evidence of tumor tissue, a pathological complete response, when tissue was examined after resection. Fourteen of 18 subjects discontinued aldoxorubicin treatment, although there is a significant possibility that some of the patients experienced pseudo-progression. Pseudo-progression refers to post-treatment imaging changes in the tumor where the tumor appears larger compared to the pre-treatment baseline images. These changes can be misleading in that the tumor appears to get worse (true progression), when in fact the changes may be the result of tumor destruction and related swelling around the tumor bed. Following discontinuation of aldoxorubicin treatment, 10 of 14 subjects received treatment with bevacizumab (Avastin) for 1 to 14 cycles. Deaths have occurred in only 4 of 18 subjects (22%) to date, with survival duration so far of up to 10 plus months.

Aldoxorubicin was well tolerated at both dose levels with all adverse events consistent with known doxorubicin toxicities, but not cardiotoxity. Grade 3 or 4 adverse events were comprised primarily of neutropenia, anemia and fatigue and occurred mainly in the 350 mg/m2 dose group and were resolved before the next dose. Only two aldoxorubicin-related serious adverse events have occurred in the trial, and both resolved successfully.

"GBM is the most common and aggressive malignant primary brain cancer in humans and carries an extremely poor prognosis for the vast majority of diagnosed patients. Prognosis at recurrence is especially poor," said Morris D. Groves, M.D., Neuro-Oncologist, Texas Oncology-Austin Brain Tumor Center and co-principal investigator of the trial. "Pseudo-progression is commonly seen in CNS malignancies undergoing radiation therapy, and it mimics tumor progression, but it is thought to be a treatment-related reaction that could represent an active, inflammatory response against the tumor. The findings from this trial are early but exciting; the finding of no tumor cells in the resected GBM tumor samples after treatment with aldoxorubicin is worth further investigation. This suggests, somewhat paradoxically, that by binding to albumin, aldoxorubicin may allow doxorubicin to cross the blood:brain barrier and into the malignancy."

"These results suggest the possibility that the administration of Avastin after treatment with aldoxorubicin could prolong survival in patients with relapsed GBM, and patient follow up is currently ongoing," said Daniel Levitt, M.D., Ph.D., CytRx Executive Vice President and Chief Medical Officer. "At the upcoming 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, we will be convening with the study investigators to discuss the potential for a pivotal trial evaluating aldoxorubicin in combination with Avastin for the treatment of relapsed GBM, with survival as the primary endpoint. We also look forward to submitting the results from this ongoing Phase 2 clinical trial for presentation at a neuro-oncology-focused medical meeting in 2015."

The primary objective of this Phase 2 trial is to determine progression-free survival (PFS) at 6 months and overall survival (OS) in patients with recurrent glioblastoma multiforme. The principal secondary objective is to evaluate the safety of aldoxorubicin in study patients as assessed by the frequency and severity of adverse events. Only patients who have not received prior treatment with bevacizumab (Avastin) are eligible to participate in the trial. The clinical trial is expected to enroll up to 28 patients randomly assigned equally to receive either 350 mg/m2 (260 mg/m2 doxorubicin equivalent) or 250 mg/m2 (185 mg/m2 doxorubicin equivalent) of aldoxorubicin intravenously on Day 1, and every 21 days thereafter until evidence of tumor progression, unacceptable toxicity or withdrawal of consent. Tumor response is monitored every 6 weeks by MRI until disease progression occurs. The trial is being conducted at the John Wayne Cancer Center/Sarcoma Oncology Center in Santa Monica, CA, City of Hope in Duarte, CA, the Louisiana State University Health Sciences Center in New Orleans, LA, and Texas Oncology in Austin, TX.

This Phase 2 study follows positive confirmatory results reported in 2013 from a preclinical study in which aldoxorubicin demonstrated statistically significant efficacy (p<.0001) in the treatment of rapidly growing human brain (glioblastoma) cancer in the brains of animals. In that study, animals treated with aldoxorubicin had median survival of more than 63 days, compared with approximately 25 days for animals treated with doxorubicin or saline. In addition, because aldoxorubicin uptake was confined to the tumor in the brain rather than normal brain tissue, the principal investigator concluded that aldoxorubicin has the potential to safely shrink glioblastoma tumors, which could dramatically prolong patient survival.

About Glioblastoma Multiforme

Glioblastoma is the most common and most malignant primary brain tumor in adults and afflicts more than 12,000 new patients in the U.S. annually. The median survival after diagnosis is approximately 14 months, despite patients subsequently receiving surgical resection, radiotherapy and chemotherapy. Limited efficacy of chemotherapeutic agents has been attributed to several contributing factors including insufficient drug delivery to the tumor site through the blood:brain barrier.

About Aldoxorubicin

The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows for greater doses (3 ½ to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.

On May 21, 2015 Celsion reported data from a preclinical study confirming that the Company’s TheraSilence technology platform can safely and effectively deliver RNA to the lungs in non-human primates (Press release, Celsion, MAY 21, 2015, View Source [SID:1234504615]). TheraSilence is designed to enable the delivery of synthetically-generated mRNA, inhibitory RNA (RNAi) such as small inhibitory RNAs (siRNAs), microRNAs, microRNA mimics, and related molecules that can regulate protein expression at the transcript level by exploiting endogenous cell mechanisms.

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"The findings from this study are consistent with the data observed in earlier preclinical studies and underscore the differentiating and widespread potential of our TheraSilence RNA delivery platform," stated Dr. Khursheed Anwer, Celsion’s Executive Vice President and Chief Scientific Officer. "Development for RNA therapeutics has been significantly limited due to the delivery challenges associated with nucleic acid-based therapies, with development efforts in the space focused primarily on diseases of the liver. Our chemically-flexible approach offers the opportunity to significantly expand the development of RNA therapies to include major unmet medical needs affecting the lung, such as lung cancer, asthma and pulmonary hypertension."

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The study was designed to evaluate the expression profile and safety of RNA formulated with Celsion’s TheraSilence delivery system in non-human primates. Three primates were dosed in the study, receiving either TheraSilence-formulated RNA intravenously at one of two doses, or intravenous RNA formulated with a liver-directed formulation used as a positive control. Following the treatment, an analysis for safety and RNA expression was performed.

In the study, TheraSilence-formulated signaling RNA resulted in preferential expression in the lungs, with expression in the liver at less than 15% of expression levels observed in the lungs. Expression levels in tissues other than the lung, spleen and liver were very low or at background levels. The TheraSilence-formulated RNA was well-tolerated at both dose levels as determined by safety analysis including complete blood cell count, blood chemistry, histopathology, interferon response and compliment activation. A liver-directed delivery system, used as a positive control for the study, yielded preferential expression in liver and spleen, with only background expression levels observed in the lung.

These data build on previous preclinical studies indicating the preferential delivery of RNA to the lung using the TheraSilence RNA delivery system. A murine study evidenced that the delivery of TheraSilence-formulated siRNA molecules targeting anti-vascular endothelial receptor 2 (VEGF2), a protein that is critical for the growth of new blood vessels in tumors, significantly inhibit lung tumor growth. Additionally, delivery of a TheraSilence-formulated anti-micro RNA molecule into rats with experimentally induced pulmonary arterial hypertension appeared to normalize vascular remodeling that occurs in the lung and help restore cardiac function that is compromised as a result of the disease.

"The data highlights the great potential of our TheraSilence technology platform to provide unique treatment options for lung diseases that are not addressable by conventional drugs," said Michael H. Tardugno, the Company’s Chairman, President and Chief Executive Officer. "TheraSilence has significant potential in a wide variety of indications, including those that fall outside our core focus of oncology. Our strategy is to seek to maximize the value of this platform in the near-term by pursuing collaborations and licensing agreements, while focusing internal development efforts on our two clinical stage candidates, ThermoDox and GEN-1, our DNA-based immunotherapy for the localized treatment of ovarian and brain cancers."