On July 25, 2016 Celgene Corporation (NASDAQ: CELG) and the Lymphoma Study Association (LYSA) reported that the Lymphoma Academic Research Organisation (LYSARC) reported initial data from a phase III, randomized, double-blind, international clinical study (REMARC) (Press release, Celgene, JUL 25, 2016, View Source [SID:1234514026]). This investigational study evaluated maintenance therapy with REVLIMID (lenalidomide) compared with placebo in diffuse large B-cell lymphoma (DLBCL) patients responding to first-line rituximab plus CHOP chemotherapy (R-CHOP) induction therapy. LYSARC sponsored the study under a Clinical Trial Agreement with Celgene.

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REMARC achieved the primary endpoint of a statistically significant improvement in progression-free survival for patients receiving REVLIMID. The interim analysis of overall survival, a key secondary endpoint, showed no benefit in the REVLIMID arm. Based upon these interim results, Celgene does not currently plan to seek approval for this indication.

"We thank the patients and their families for participating in the REMARC trial and look forward to presenting these important data at a future hematology conference," said Bertrand Coiffier, Professor of Hematology, Hospices de Lyon and University Claude Bernard Lyon 1 and Principal Investigator, REMARC.

"We are continuing to partner with LYSA to complete the analyses of the REMARC study," said Michael Pehl, President Hematology and Oncology of Celgene. "We remain committed to finishing the four ongoing phase III trials evaluating REVLIMID and are confident about its potential as a treatment option across different settings in lymphoma."

A Broad Phase III Program in NHL Underway; Data from Additional Trials Expected in 2017

The REMARC study is part of a broad research program at Celgene focused on multiple areas of non-Hodgkin lymphoma. In addition to the REMARC study, REVLIMID is also being evaluated in:

RELEVANCE, a combination with rituximab in previously untreated follicular lymphoma;
AUGMENT, a combination with rituximab in relapsed/refractory follicular and marginal zone lymphoma;
MAGNIFY, a combination with rituximab in relapsed/refractory follicular, marginal zone and mantle cell lymphoma; and,
ROBUST, a combination with R-CHOP in previously untreated ABC-subtype DLBCL.
Data from RELEVANCE and AUGMENT are expected in the first and second half of 2017, respectively. Beyond REVLIMID, Celgene is also exploring multiple clinical candidates in non-Hodgkin lymphomas and T-cell lymphomas.

REVLIMID is not approved for use in DLBCL.

About REMARC

REMARC is an international, multicentre, randomized, double-blind, placebo-controlled phase III study designed to explore the effect of maintenance therapy with REVLIMID (lenalidomide) versus placebo on progression-free survival (PFS) in 650 patients treated with R-CHOP responding to induction therapy. Patients in REMARC had received at least 6 and up to 8 cycles of the R-CHOP 14 or R-CHOP 21 regimen or 6 R-CHOP-14 or -21 completed by 2 cycles of rituximab alone in accordance to local preferences. Evaluation of the response to R-CHOP was in accordance with Revised Response Criteria for Malignant Lymphoma (2007). The primary endpoint of the study was progression-free survival. The secondary endpoints of the study included overall survival, event-free survival, response at the end of maintenance, improvement in response and safety.

About REVLIMID

In the United States, REVLIMID is approved in combination with dexamethasone for the treatment of patients with multiple myeloma. REVLIMID is also approved in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy in nearly 70 countries, encompassing Europe, the Americas, the Middle East and Asia, and in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy in Australia and New Zealand.

REVLIMID is also approved in the United States, Canada, Switzerland, Australia, New Zealand and several Latin American countries, as well as Malaysia and Israel, for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities and in Europe for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

In addition, REVLIMID is approved in the United States for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

U.S. Regulatory Information for REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)

REVLIMID is indicated for the treatment of patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information
WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity
Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS program (formerly known as the "RevAssist" program).

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)
REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism
REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. 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 the fetus

Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

Females of Reproductive Potential: See Boxed WARNINGS
Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID
REVLIMID REMS Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. MDS: Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or dose reduction. Please see the Black Box WARNINGS for further information. MCL: Patients taking REVLIMID for MCL should have their CBCs monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID, an increase of invasive SPM notably AML and MDS have been observed. Monitor patients for the development of SPMs. Take into account both the potential benefit of REVLIMID and risk of SPMs when considering treatment

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID/dex. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered

Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose; risk-benefit of treatment should be evaluated in patients with lactose intolerance

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of lenalidomide for CLL and lymphoma. Monitoring and evaluation of TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment ( > 4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection

ADVERSE REACTIONS

Multiple Myeloma

In newly diagnosed: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or RD18
The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash, (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms (20%), and thrombocytopenia (20%)
After at least one prior therapy the most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%)
Myelodysplastic Syndromes

Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%), thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)
Adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): thrombocytopenia (61.5%), neutropenia (58.8%), diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)
Mantle Cell Lymphoma

Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%)
Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)
DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels is recommended due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin

NURSING MOTHERS

Discontinue drug or nursing taking into consideration the importance of the drug to the mother

PEDIATRIC USE

Safety and effectiveness in patients below the age of 18 have not been established

RENAL IMPAIRMENT

REVLIMID is primarily excreted unchanged by the kidneys; adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis

Please see full Prescribing Information, including Boxed WARNINGS.

About LYSARC

The Lymphoma Academic Research Organisation (LYSARC), located in Lyon, France, is an academic clinical research organization running international clinical lymphoma trials in affiliation with the LYSA and in collaboration with other renowned, international cooperative groups. For more information, please visit www.lysarc.org.

About LYSA

The Lymphoma Study Association (LYSA), is a French association leader in international clinical and translational research in lymphoma, with a network of 130 centers in France, Switzerland, Portugal and Belgium. For more information, please visit www.lysa-lymphoma.org

On July 25, 2016 KaloBios Pharmaceuticals, Inc. (OTC:KBIO), a biopharmaceutical company focused on advancing medicines for patients with neglected and rare diseases, reported that the first patient has been dosed in its open-label, multi-center Phase 1 clinical trial with lenzilumab (formerly KB003) focused on patients with previously-treated Chronic Myelomonocytic Leukemia (CMML) (Press release, KaloBios, JUL 25, 2016, View Source [SID:1234514144]).

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This multi-center Phase 1 dose escalation trial is being conducted to evaluate the safety, maximum tolerated dose, and preliminary activity of single-agent lenzilumab in subjects with CMML who are relapsed/refractory to, and/or intolerant to, standard-of-care treatments.

"The new KaloBios is now in action mode, and the first dosing of a patient in the lenzilumab study highlights our pivot to swift execution in advancing our pipeline assets," said Cameron Durrant, MD, KaloBios chairman and CEO. "CMML is a rare and devastating disease for which there are limited effective treatment options currently available. We anticipate this trial will demonstrate lenzilumab’s potential to help patients who need new treatment options and support its continued clinical advancement."

The study will enroll up to 18 patients and is designed to identify the maximum tolerated dose, or recommended Phase 2 dose, of lenzilumab in subjects with previously-treated CMML. It will also assess preliminary efficacy of single-agent lenzilumab and to provide additional data on pharmacokinetics, pharmacodynamics and safety.

"The first patient to receive treatment in this study also signifies the first of many important clinical milestones ahead for KaloBios, as we seek to tackle neglected and rare diseases through innovative and responsible business models," added Dr. Durrant.

About Lenzilumab

Lenzilumab is a monoclonal antibody that targets and is an antagonist of soluble Granulocyte Macrophage – Colony Stimulating Factor (GM-CSF), a cytokine suggested to be central to the inflammation and activation of certain immune cells. Lenzilumab has been studied for its ability to limit hypersensitivity to GM-CSF signaling, which appears to be a key feature to many CMML patients and its inhibition may affect the growth of leukemic cells in patients. Lenzilumab has been tested in more than 90 subjects in previous clinical trials in rheumatoid arthritis, asthma and healthy volunteers, and was found to be well tolerated. Data also suggest lenzilumab may have the potential to treat other diseases, including juvenile myelomonocytic leukemia (JMML).

About CMML

CMML is a rare and aggressive cancer of the blood with approximately 1,500-3,000 new cases per year in the United States. The cancer interferes with normal blood cell production, including red blood cells, white blood cells and platelets. CMML patients have shortened life expectancies, with a median survival rate of one to two years, and approximately 15-30 percent of patients will go on to develop acute leukemia.

On July 25, 2016 Shire plc (LSE: SHP, NASDAQ: SHPG) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending the marketing authorization for the use of ONIVYDE (irinotecan pegylated liposomal formulation) also known as nal-IRI or MM-398, for the treatment of metastatic adenocarcinoma of the pancreas, in combination with 5-fluorouracil (5-FU) and leucovorin (LV), in adult patients who have progressed following gemcitabine based therapy (Press release, Shire, 25 7/, 2016, View Source [SID:1234514015]).

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"There has been little improvement in the prognosis for patients with metastatic pancreatic cancer in over 20 years. We therefore welcome the CHMP positive opinion for ONIVYDE, a regulatory milestone which brings us a step closer to helping patients with this devastating disease." said Philip J. Vickers, Ph.D., Head of R&D, Shire. "At Shire, we are committed to research and development through innovation in order to identify unique methodologies for treating patients with high unmet needs."

Pancreatic cancer is the third leading cause of cancer death in the region and there are limited treatment options available. In September 2015, the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) stated that use of MM-398 (ONIVYDE) when available in all countries, may be the best option for second-line treatment of these patients following gemcitabine-based therapy. Gemcitabine-based therapy is commonly used as a first-line treatment for patients with metastatic disease or locally advanced disease who cannot be treated with surgery, or as adjuvant therapy.

"Guidance from ESMO (Free ESMO Whitepaper) indicates the use of ONIVYDE for the treatment of metastatic pancreatic cancer in patients who have progressed following gemcitabine-based treatment," said Volker Heinemann, M.D., Ph.D., a professor of medical oncology at the University of Munich, Germany. "The CHMP positive opinion for ONIVYDE is an important step for patients with this devastating disease."

The CHMP positive opinion is based on pivotal, Phase 3 NAPOLI-1 data that demonstrated nal-IRI combined with 5-FU and LV improved overall survival (OS) (primary endpoint), as well as progression-free survival (PFS) and objective response rate (ORR) relative to the 5-FU and LV control arm (secondary endpoints). The most common Grade 3 or higher adverse events with greater than five percent difference in patients receiving nal-IRI and 5-FU and LV were neutropenia, fatigue and diarrhoea, and vomiting.

"The CHMP positive opinion confirms the strength of the Phase 3 NAPOLI-1 data for the use of ONIVYDE to treat metastatic pancreatic cancer patients in the post-gemcitabine setting." said Professor Thomas Seufferlein, M.D., University of Ulm, Germany. "This data will allow physicians to better evaluate options for extending overall survival of patients diagnosed with a very difficult-to-treat cancer."

The CHMP’s positive opinion will be submitted to the European Commission (EC), which is responsible for granting marketing authorizations for medicines in the European Union (EU). We anticipate a final decision later this year.

J. Marc Pipas, M.D., Senior Medical Director at Merrimack Pharmaceuticals Inc. commented: "We applaud the CHMP’s positive opinion on ONIVYDE as it acknowledges the clinical significance of this therapy for a patient population with few treatment options. We look forward to continuing our work with Shire to expand the global availability of this important therapy to patients facing metastatic pancreatic cancer."

About Pancreatic Cancer

Pancreatic cancer is a significantly underserved disease in Europe and almost always fatal. Half of people diagnosed with pancreatic cancer are diagnosed at Stage 4, which is advanced metastatic disease and no longer curable. The disease has a five-year overall survival (OS) rate of three percent, and a median OS typically less than a year, as supported by real-world European systematic review. The only curative treatment for pancreatic cancer is surgical resection in the primary stage, which can improve five-year survival to 10 percent.

The signs and symptoms of pancreatic cancer are non-specific, (common presenting symptoms include jaundice, abdominal pain, weight loss, steatorrhoea, and new-onset diabetes) and may not appear until the disease has spread locally or metastasized. Therefore, approximately 80 percent of patients are not candidates for surgery upon diagnosis.

Even though it accounts for less than three percent of all cancer cases, pancreatic cancer is the seventh leading cause of cancer death worldwide, and the third in Europe. Worldwide, pancreatic cancer prognosis is typically poor, with an estimated 337,900 new cases and 330,400 deaths each year.

About ONIVYDE (nal-IRI)

ONIVYDE is a first-of-its-kind formulation (encapsulation) of irinotecan in a long-circulating liposomal form designed to improve delivery and the length of exposure of irinotecan. Studies have suggested that encapsulation helps to improve delivery of irinotecan to tumors, such as metastatic pancreatic cancer.

In the pivotal Phase 3 NAPOLI-1 study, nal-IRI demonstrated improved survival in patients with metastatic pancreatic cancer after previous gemcitabine-based therapy. Gemcitabine, both as monotherapy as well as in combination, is commonly used in the first-line treatment of locally advanced and/or metastatic pancreatic adenocarcinoma, as well as in the adjuvant (treatment after surgery) and neo-adjuvant (treatment before surgery) settings.

Shire is responsible for the development and commercialization of ONIVYDE outside of the United States and Taiwan under an exclusive licensing agreement with Merrimack Pharmaceuticals, Inc. (NASDAQ: MACK). Merrimack currently markets ONIVYDE in the United States after having received US Food and Drug Administration (FDA) approval in October 2015 for the treatment of patients with metastatic adenocarcinoma of the pancreas who have progressed following treatment with gemcitabine-based therapy. Approval of ONIVYDE in Taiwan was also received in October 2015, where PharmaEngine holds the commercialization rights.

About NAPOLI-1

NAPOLI-1 is the first global, randomized open-label Phase 3 trial to show extended overall survival in metastatic pancreatic ductal adenocarcinoma cancer after gemcitabine-based therapy through treatment with nal-IRI combined with 5-FU and LV. NAPOLI-1 was the largest Phase 3 study in this setting to date. Patients were enrolled at 76 sites in 14 countries across North America, Europe, Asia, South America, and Australia. The study evaluated nal-IRI (80mg/m2) in combination with 5-FU and LV administered intravenously every two weeks and as a monotherapy (120 mg/m2) administered every three weeks. Each nal-IRI containing arm was compared to a control arm of 5-FU and LV.

NAPOLI-1 met the following primary and secondary endpoints by demonstrating that nal-IRI combined with 5-FU and LV significantly improved OS,progression-free survival (PFS) and objective response (OR) compared to 5-FU/LV alone in patients with metastatic pancreatic cancer. In a pivotal analysis, nal-IRI plus 5-FU/LV demonstrated a significant increase in median overall survival versus 5-FU and LV alone: 6.1 months vs 4.2 months (based on a non-stratified hazard ratio [HR] of 0.67; 95% CI 0.49-0.92, p=0.012).

The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nal-IRI plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]).

Important Safety Information

The most common adverse reactions (incidence ≥20 percent) seen with nal-IRI in combination with 5-FU and LV compared with 5-FU and LV alone were: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anaemia, stomatitis, and pyrexia. Early-onset (within 1 day of treatment) diarrhoea occurred in 30 percent of patients on nal-IRI combined with 5-FU and LV and was usually transient. Early-onset diarrhoea was accompanied by cholinergic symptoms in three percent of patients taking nal-IRI in combination with 5-FU and LV. Median time to late-onset diarrhoea was eight days following the nal-IRI dose. Alopecia occurred in 14 percent of patients in the nal-IRI combined with 5-FU and LV arm versus five percent of patients in the 5-FU and LV arm. Of patients taking nal-IRI combined with 5-FU and LV, 11 percent of patients discontinued treatment versus seven percent of patients receiving 5-FU and LV alone. No significant deterioration in quality of life was observed in patients in either arm of the study compared to baseline.

On July 25, 2016 Medigene AG (MDG1, Frankfurt, Prime Standard), a clinical stage immune-oncology company focusing on the development of T cell immuno-therapies for the treatment of cancer, reported the grant of US patent US9,341,617B2 (Press release, MediGene, JUL 25, 2016, View Source [SID:1234514024]). The patent, with an expected life-span until 2030, claims a method for the identification of antigens recognized by CD4+ T cells, including tumor infiltrating CD4+ T cells.

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This patent expands Medigene’s T-cell receptor (TCR) platform technology with an additional fast and efficient method for the direct identification of antigens and respective epitopes recognized by CD4+ tumor infiltrating lymphocytes and opens the way to identify immune relevant patient-specific neoantigens. Rapid definition of epitopes recognized by CD4+ T helper cells for generation of tumor vaccines also becomes potentially possible.

Prof. Dolores Schendel, CEO and CSO of Medigene, explains: "This newly patented method provides the company with a potential additional source for new TCR candidates and also allows us to identify patient-specific neoantigens seen by CD4+ T cells. While CD4+ tumor infiltrating T cells have been known in the past, finding the antigens for which these T cells are specific was very time-consuming and complex. With the covered method we are now able to overcome these problems and it helps us to provide expanded options for adoptive T-cell therapies with transgenic T-cell receptors."

Medigene holds an exclusive license to the patent that was issued to Helmholtz Zentrum München (German Research Center for Environmental Health). Patents within the same patent family have already been granted in Europe, Australia and Canada.

About Medigene’s TCR patent portfolio: Medigene’s IP-portfolio relating to the TCR platform comprises 4 patent families covering methods for the identification of tumor-antigen specific T cell receptors and T cell receptors targeting specific tumor antigens. The 4 patent families in turn comprise 47 granted patents (including validations in Europe) and 14 pending applications. In addition, Medigene is constantly expanding its IP portfolio by filing applications for new methods and newly identified T-cell receptors specific for various tumor-antigens.

About CD4+ T cells in tumor biology: Recent advances in cellular immunotherapy show that cancer cells can be efficiently eliminated by adoptive transfer of modified patient T cells. The main effector functions can be provided by genetically engineered lymphocytes expressing T-cell receptors isolated from tumor antigen-specific cytotoxic CD8+ lymphocytes, which recognize tumor-associated antigens presented on HLA class I molecules. Nevertheless, CD4+ T lymphocytes play a critical role for efficient and sustained cytotoxic CD8+ T cell responses and memory function. Multifunctional CD4+ T cells are essential to activate, control and maintain immune responses. CD4+ T cells recognize antigens presented on HLA class II molecules; thereby HLA class II tumor antigen-positive cells may be efficiently eliminated also by direct CD4+ cytotoxic mechanisms. It was demonstrated that adoptive transfer of tumor antigen-specific CD4+ T cells alone can lead to substantial regression of epithelial tumors (Science. 2014 May 9;344(6184):641-5).

About Medigene’s TCR technology:
The TCR technology aims at arming the patient’s own T cells with tumor-specific T-cell receptors. The receptor-modified T cells are then able to detect and efficiently kill tumor cells. This immunotherapy approach attempts to overcome the patient’s tolerance towards cancer cells and tumor-induced immunosuppression by activating and modifying the patient’s T cells outside the body (ex-vivo). A large number of specific T cells to fight the tumor is thereby made available to patients within a short period of time.

Medigene’s technology for T-cell receptor-modified T cells is one of the company’s highly innovative and complementary immunotherapy platforms for adoptive T-cell therapy. The TCR therapy is designed to treat patients with high tumor loads. Medigene is preparing the clinical development of its first TCR candidates and is developing a library of recombinant T-cell receptors. Moreover, a Good Manufacturing Practice (GMP)-compliant process for their combination with patient-derived T cells is currently being established. Medigene plans to commence its first own clinical TCR trials in 2017 and a second in 2018.

On July 21, 2016 DelMar Pharmaceuticals, Inc. (NASDAQ: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that it will present an abstract at the 12th Meeting of the European Association of Neuro-Oncology (EANO) taking place in Mannheim, Germany from October 12 – 16, 2016 (Press release, DelMar Pharmaceuticals, JUL 21, 2016, View Source [SID:1234513983]).

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DelMar will present an abstract entitled: "Dianhydrogalactitol (VAL-083) causes bifunctional alkylation leading to irreparable DNA double-strand breaks, S/G2 phase cell-cycle arrest and tumor cell death in an MGMT independent manner offering a unique treatment paradigm for GBM."

The Company’s EANO presentation will further elucidate how VAL-083 attacks cancer cells utilizing a mechanism of action distinct from other chemotherapies used in the treatment of glioblastoma multiforme (GBM), the most common and aggressive form of brain cancer. Specifically, DelMar will present data supporting the potential of VAL-083 to treat patients whose tumors exhibit features correlated with resistance to the chemotherapies currently used in the treatment of GBM.

About VAL-083

VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments.

VAL-083 has received an orphan drug designation in Europe for the treatment of malignant gliomas; and the U.S. FDA Office of Orphan Products has granted an orphan designation to VAL-083 for the treatment of glioma, medulloblastoma and ovarian cancer.

DelMar presented data from a recently completed Phase I/II clinical trial in refractory GBM at the 2016 American Association of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual meeting. In summary, the Company reported that:

Median survival of 22 patients receiving an assumed therapeutic dose of VAL-083 (≥20mg/m2) was 8.35 months following bevacizumab (Avastin) failure compared to published literature where survival of approximately three to five months has been reported.
A dose of 40 mg/m2/day VAL-083 administered on the first three days of every three-week cycle is well tolerated in refractory GBM patients and has been selected for study in subsequent clinical trials.
DelMar believes that these data support the potential of VAL-083 as a new chemotherapy that may offer improved outcomes in the treatment of GBM. The Company recently announced the completion of a successful end of Phase II meeting with the U.S. FDA and plans to advance VAL-083 into a pivotal clinical trial for GBM patients following bevacizumab failure.

DelMar’s advanced development program will feature a single randomized Phase III study measuring survival outcomes compared to a "physicians’ choice" control, which, if successful, would serve as the basis for a New Drug Application (NDA) submission for VAL-083. The control arm will consist of a limited number of salvage chemotherapies currently utilized in the treatment of Avastin-failed GBM. The final pivotal trial design will be confirmed with the FDA following further discussions with the Company’s clinical advisors.

In addition to the pivotal trial, DelMar also plans to initiate two separate Phase II clinical trials in earlier-stage GBM patients.

In collaboration with the University of Texas MD Anderson Cancer Center: A non-comparative, biomarker-driven, Phase II study to determine if treatment of MGMT-unmethylated recurrent GBM with VAL-083 or CCNU improves overall survival at 9 months, compared to historical control in bevacizumab naïve patients. (clinicaltrials.gov identifier: NCT02717962)
In collaboration with Sun-Yat Sen University and Guangxi Wuzhou Pharmaceutical (Group) Co.: A single arm Phase II clinical trial to confirm the tolerability of DelMar’s dosing regimen in combination with radiotherapy (XRT) and to explore the activity of VAL-083 in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high levels of MGMT.
DelMar believes that data from these clinical trials, if successful, will form the basis of a new paradigm in the treatment for all GBM patients who fail, or whose tumors exhibit features that make them unlikely to respond to, currently available chemotherapy.