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Novartis receives EU approval for Farydak®, the first in its class of anticancer agents approved for patients with multiple myeloma

On September 4, 2015 Novartis reported that the European Commission has approved Farydak (panobinostat, previously known as LBH589) capsules, in combination with bortezomib* and dexamethasone, for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent (IMiD) (Press release, Novartis, SEP 4, 2015, View Source [SID:1234507398]). The approval of Farydak marks the first time a histone deacetylase (HDAC) inhibitor with epigenetic activity is available in the European Union (EU), providing a new treatment option for patients living with multiple myeloma whose disease has progressed after standard-of-care therapy[1,2].

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"Farydak is a welcome advance for people living with relapsed and/or refractory multiple myeloma in Europe," said Philippe Moreau, MD, Department of Hematology, Centre Hospitalier Universitaire de Nantes, France. "Patients with multiple myeloma often relapse or stop responding to treatments; Farydak offers a new mechanism of action, which may improve the effectiveness of response to standard-of-care treatment in patients."

Multiple myeloma is a cancer of the plasma cells, a type of white blood cell present in the bone marrow, and affects approximately 84,000 people in Europe[3,4]. Farydak is the first HDAC inhibitor to show efficacy in multiple myeloma[5]. As an HDAC inhibitor, its epigenetic activity may help restore cell function in patients with multiple myeloma[2].

The EU approval of Farydak is based on efficacy and safety data in a subgroup analysis of 147 patients who had received at least two prior regimens, including bortezomib and an IMiD, during the Phase III, randomized, double-blind, placebo-controlled, multicenter global registration trial, called PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA), evaluating Farydak in combination with bortezomib and dexamethasone against bortezomib and dexamethasone alone in patients with relapsed and/or relapsed and refractory multiple myeloma. The trial found that the median progression-free survival (PFS) benefit in this subgroup increased by 7.8 months in Farydak patients who had received prior treatment with both bortezomib and an IMiD (12.5 months; n=73), as compared to the placebo arm (4.7 months; n=74) (hazard ratio=0.47 [95% confidence interval (CI): 0.31, 0.72])[1].

The most common non-hematological adverse reactions included diarrhea, fatigue, nausea and vomiting. Treatment-emergent hematological toxicities included thrombocytopenia, anemia, neutropenia and lymphopenia. QTc prolongation of >480 and <500 msec was recorded in 1.3% of patients and change from baseline of >60 msec was observed in 0.8% of patients. No patients had an absolute QTc prolongation of >500 msec. Cardiac events (most frequently atrial fibrillation, tachycardia, palpitation and sinus tachycardia) were reported in 17.6% of the Farydak-treated patients versus 9.8% of placebo-treated patients and syncope events were reported in 6.0% versus 2.4%. Discontinuation due to adverse events (AEs), regardless of causality, was observed in 36.2% of patients. The most common AEs leading to treatment discontinuation were diarrhea (4.5%), asthenia and fatigue (2.9% each) and pneumonia (1.3%). On treatment deaths not due to the study indication (multiple myeloma) were reported in 6.8% of Farydak-treated patients versus 3.2% of placebo-treated patients[1].

"With the approval of Farydak in the European Union, we hope to address critically important treatment needs faced by the multiple myeloma community-disease progression and treatment resistance," said Bruno Strigini, President, Novartis Oncology. "This milestone, the approval of a first in its class treatment option for patients in need of new therapies, is the result of more than 13 years of dedicated research, which has helped us better understand the development of multiple myeloma."

Farydak in combination with bortezomib and dexamethasone is also approved in the US, Chile and Japan for certain patients with previously treated multiple myeloma. The exact indication for Farydak varies by country. In the US, Farydak is approved in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an IMiD. Continued approval in the US may be contingent upon verification and description of clinical benefit in confirmatory trials.

About multiple myeloma
Multiple myeloma impacts approximately 84,000 people in Europe[4]. Multiple myeloma is a cancer of the plasma cells, a kind of white blood cell present in bone marrow-the soft, blood-producing tissue that fills the center of most bones. The cancer is caused by the production and growth of abnormal cells within the plasma, which multiply and build up in the bone marrow, pushing out healthy cells and preventing them from functioning normally[3]. Multiple myeloma is an incurable disease with a high rate of relapse (when the cancer returns) and resistance (when the therapy stops working)[6]. Standard-of-care regimens of proteasome inhibitors and IMiDs are often used to treat multiple myeloma, but most patients will stop responding to these treatments creating an unmet need for new options with novel mechanisms of action[6,7,8]. Multiple myeloma typically occurs in individuals 60 years of age or older, with few cases in individuals younger than 40[9].

About the PANORAMA Clinical Trial Program
PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) is a Phase III, randomized, double-blind, placebo-controlled, multicenter global registration trial to evaluate panobinostat in combination with bortezomib and dexamethasone against bortezomib and dexamethasone alone in patients with relapsed or relapsed and refractory multiple myeloma who failed on at least one prior treatment. The study of 768 patients took place in 215 clinical trial sites worldwide making it the largest global registration trial for multiple myeloma to date. The primary endpoint of the trial was PFS. Data for overall survival, the key secondary endpoint of the trial, are not yet mature. Other secondary endpoints include overall response rate, duration of response and safety[10].

Farydak Important Safety Information
Farydak can cause serious side effects, including diarrhea and heart problems.

Diarrhea is common with Farydak and can be severe. Patients should tell their healthcare provider (HCP) right away if they have abdominal (stomach) cramps, loose stool, diarrhea, or feel like they are becoming dehydrated. HCPs may prescribe medicines to help prevent or treat these side effects. Taking or using stool softeners or laxative medicines may worsen diarrhea, patients should talk to their HCP before taking or using these medicines.

Farydak can cause severe heart problems which can lead to death. Risk of heart problems may be increased with a condition called "long QT syndrome" or other heart problems. Patients should call their HCP and get emergency medical help right away if they have any of the following symptoms of heart problems: chest pain, faster or slower heart beat, palpitations (feel like heart is racing), feel lightheaded or faint, dizziness, blue colored lips, shortness of breath, or swelling in legs.

Farydak can cause severe bleeding which can lead to death. It may take patients longer than usual to stop bleeding while taking Farydak. Patients should tell their HCP right away if they get any of the following signs of bleeding: blood in stools or black stools (look like tar), pink or brown urine, unexpected bleeding or bleeding that is severe or that cannot be controlled, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, feeling dizzy or weak, confusion, change in speech, or headache that lasts a long time.

Farydak is a prescription medicine used, in combination with bortezomib and dexamethasone, to treat people with a type of cancer called multiple myeloma after at least two other types of treatment have been tried. It is not known if Farydak is safe and effective in children.

Patients should tell their HCP about all of the medicines they take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

Patients should take Farydak exactly as the HCP tells them to take it. The HCP will tell patients how much Farydak to take and when to take it. The HCP may change the dose or stop treatment temporarily if patients experience side effects. Patients should not change the dose or stop taking Farydak without first talking with their HCP.

Patients should avoid eating star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice while taking Farydak. These foods may affect the amount of Farydak in the blood.

Low blood cell counts are common with Farydak and can be severe. Low platelet count (thrombocytopenia) can cause unusual bleeding or bruising under the skin. Low white blood cell count (neutropenia) can cause infections. Low red blood cell count (anemia) may make a patient feel weak, tired, or they may get tired easily, look pale, or feel short of breath.

There is an increased risk of infection while taking Farydak. Patients should contact their HCP right away if they have a fever or have any signs of an infection including sweats or chills, cough, flu-like symptoms, shortness of breath, blood in phlegm, sores on body, warm or painful areas on body, or feeling very tired.

Patients should call their HCP right away with any of the following symptoms of liver problems: feel tired or weak, loss of appetite, dark amber colored urine, upper abdominal pain, yellowing of skin or the white of eyes.

The most common side effects of Farydak include tiredness, nausea, swelling in arms or legs, decreased appetite, fever and vomiting. Patients should tell their HCP if they have any side effect that is bothersome or that does not go away.

* Trade name Velcade registered to Millennium Pharmaceuticals, Inc.

10-K – Annual report [Section 13 and 15(d), not S-K Item 405]

(Filing, 10-K, DelMar Pharmaceuticals, SEP 3, 2015, View Source [SID:1234507396])

AstraZeneca to update on leading lung cancer portfolio at WCLC 2015

On September 4, 2015 AstraZeneca reported that data will be reported from across their industry-leading lung cancer portfolio at the World Conference on Lung Cancer (WCLC) 2015, beginning this weekend in Denver, Colorado (Press release, AstraZeneca, SEP 3, 2015, View Source;astrazeneca-to-update-lung-cancer-portfolio-at-wclc [SID:1234507394]). Presentations will feature 25 abstracts (including 9 oral and 4 late breaker presentations) on the company’s lung cancer pipeline, designed to address the unmet needs of patients with different forms of lung cancer.

AZD92911: Targeting resistance mechanisms in lung cancer

AZD9291 will be the focus of six oral presentations on its clinical activity in both first-line and previously-treated patients with epidermal growth factor receptor mutation (EGFRm) T790M advanced non-small cell lung cancer (NSCLC). The data are consistent with previously reported efficacy and safety results of AZD9291 in these treatment settings.

Antoine Yver, Head of Oncology, Global Medicines Development at AstraZeneca said: "The data presented at WCLC illustrate the breadth of our lung cancer research across multiple disease settings and lines of therapy, as we aim to develop a comprehensive portfolio of effective and durable treatments for patients. AZD9291 is moving through clinical development with unprecedented speed, and was recently granted US Priority Review designation in recognition of its potential to target the mutation that drives resistance to current treatments for EGFR mutation positive advanced non-small cell lung cancer in the majority of patients."

In addition to AZD9291, AstraZeneca will also present results from the IRESSA (gefitinib) Clinical Access Programme (ICAP), which provides data on the long-term safety and tolerability of the EGFR tyrosine kinase inhibitor in 188 US cancer patients outside the clinical trial setting. IRESSA was approved by the US Food and Drug Administration (FDA) as a first-line treatment for EGFRm metastatic NSCLC in July 2015, and is already available in 91 countries worldwide.

Immuno-oncology (IO): Update on key clinical trials

Trial designs for the ongoing IO late-stage studies that will be presented at WCLC include:

ATLANTIC (NCT02087423): A Phase II trial of durvalumab (PD-L1 mAb) as third-line treatment in patients with PD-L1 positive, locally advanced or metastatic NSCLC
ARCTIC (NCT 02352948): A Phase III trial of durvalumab monotherapy and in combination with tremelimumab (CTLA-4 mAb) versus standard of care in third-line metastatic NSCLC
PACIFIC (NCT02125461): A Phase III placebo-controlled trial of durvalumab compared to placebo in patients with locally advanced, unresectable, NSCLC following completion of treatment with chemoradiotherapy and no evidence of tumour progression.
Robert Iannone, Head of Immuno-Oncology, Global Medicines Development, at AstraZeneca said: "WCLC provides another opportunity for us to update the medical community on our extensive immuno-oncology development programme in lung cancer. We have made tremendous progress in developing immuno-oncology-based combination approaches, with nine pivotal studies planned or underway in NSCLC alone, which will provide us with a steady stream of research milestones in the coming months."

The FDA has granted Fast Track designation to tremelimumab for the treatment of mesothelioma, an aggressive, rare form of cancer that affects the lining of the lungs and abdomen. Durvalumab was also granted Fast Track designation for patients with advanced NSCLC, who have received at least two prior systemic-treatment regimens, who do not have EGFR mutations or anaplastic lymphoma kinase (ALK) alterations, and have tumours that are determined to be PD-L1 positive.

AstraZeneca Pivotal Studies in Lung Cancer

Data presented at WCLC are part of AstraZeneca’s rapidly advancing lung cancer programme, which includes the following pivotal clinical trials and upcoming milestones.

CytRx Announces the Presentation of its Phase 2b Clinical Trial Design in Small Cell Lung Cancer at the World Conference on Lung Cancer in Denver, Colorado

On Septenber 3, 2015 CytRx Corporation (Nasdaq: CYTR), a biopharmaceutical research and development company specializing in oncology, reported that the Phase 2b clinical trial design of its clinical trial in small-cell lung cancer (SCLC) will be presented in the P3.07 Poster Session on SCLC at the 16th World Conference on Lung Cancer in Denver, Colorado, September 6 – 9, 2015 (Press release, CytRx, SEP 3, 2015, View Source;p=RssLanding&cat=news&id=2085122 [SID:1234507391]). Entitled "Phase 2 Study of Aldoxorubicin versus Topotecan for Relapsed/Refractory Small Cell Lung Cancer" (Poster # 1736), the poster will be available starting at 9:30 AM MDT, on September 9, 2015. Additionally, aldoxorubicin will be discussed in the Novel SCLC Therapies Mini Symposium (MS 16) on September, 8, 2015.

"We are pleased to present the aldoxorubicin Phase 2b clinical trial design in SCLC at the World Conference on Lung Cancer," said Steven A. Kriegsman, Chairman and Chief Executive Officer. "We believe this will raise awareness of aldoxorubicin’s potential to treat patients with relapsed or refractory SCLC, a devastating disease with a large unmet need. In prior Phase 1 trials, we have seen encouraging evidence of SCLC patients with tumor shrinkage and prolonged stable disease. Our previous data in relapsed or refractory solid tumor patients indicates that the dose of aldoxorubicin being administered to these patients is well tolerated and without any treatment-limiting side effects. Up to 21 cycles (4.8 grams/m2) have been given to one patient with small cell lung cancer with minimal side effects and good anti-tumor activity."

The Phase 2b trial is currently enrolling 132 patients at 37 sites in the USA, Hungary and Spain. Patients with metastatic small cell lung cancer who have either relapsed or were refractory to prior chemotherapy will receive either aldoxorubicin or topotecan in a 1:1 randomization. The primary endpoint for the trial is progression-free survival. Overall survival and safety are secondary endpoints.

About Small Cell Lung Cancer

An estimated 1.6 million new cases of lung cancer are diagnosed worldwide each year. In the Western world, approximately 13-15% of cases are SCLC, a deadly form of lung cancer associated with tobacco use. The five year survival rate is less than 7%, in part because an estimated 70% of patients have extensive disease at diagnosis. According to the National Cancer Institute, more than 30,000 new cases were diagnosed in the USA in 2014. The estimated 2014 SCLC incidences for Europe and Asia are over 58,000 and 136,000, respectively.

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.

MD Anderson Cancer Center and Cellectis Announce a Broad Preclinical and Clinical Strategic Alliance in Cancer Immunotherapy

On September 3rd 2015 Cellectis (Alternext: ALCLS – Nasdaq: CLLS), the gene editing company employing proprietary technologies to develop best-in-class CAR Tcell products in adoptive immunotherapy for cancer, and The University of Texas MD Anderson Cancer Center reported that they have entered into a research and development alliance aimed at bringing novel cellular immunotherapies to patients suffering from different types of liquid tumors (Press release, Cellectis, SEP 3, 2015, View Source [SID:1234507393]).

The alliance is aimed at developing novel cancer immunotherapies based on Cellectis’ allogeneic chimeric antigen receptor (CAR) platform. MD Anderson Cancer Center’s leukemia and myeloma teams will work with Cellectis to bring better treatments to patients suffering from cancers with high unmet needs, particularly multiple myeloma (MM), acute lymphocytic leukemia (ALL), T-cell acute lymphocytic leukemia (ALL) and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

The alliance will build on MD Anderson’s outstanding translational and state-of-the-art preclinical and clinical teams in leukemia and myeloma, coupled with Cellectis’ first-in-class allogeneic CAR T-cell therapy approach and manufacturing capabilities, to pursue the development of Cellectis’ candidate products UCARTCS1, UCART22, UCART38 in T-cell ALL and UCART123 in a rare non curable disease BPDCN. Cellectis has built an allogeneic CAR T-cell approach based on proprietary gene editing technologies, aimed at developing off-the-shelf cellular therapies for cancer treatment.

At MD Anderson, the alliance will be brought forward under the direction of Hagop Kantarjian, MD, Chair, Department of Leukemia, and Robert Orlowski, MD, PhD, Department Ad Interim Chair, Department of Lymphoma/Myeloma. MD Anderson’s Leukemia Department is known for its clinical trials and patient treatment using chemotherapies, tyrosine kinase inhibitors and monoclonal antibodies.

"We are extremely proud to have our research teams partnering with MD Anderson as we aim to address treatments for different types of liquid tumors," said Mathieu Simon, MD, Executive Vice President and Chief Operating Officer at Cellectis. "This alliance could potentially drive to 5 clinical developments within a time horizon of 3 years. Together, we are confident that we will quickly bring new therapeutic solutions to patients."

"Our efforts are always focused on providing more effective care for our patients," said Kantarjian. "Alliances such as this one are one more way that we can explore how to bring the latest therapies to the patients who need them."

"Significant unmet medical need exists in many types of liquid tumors. Cellectis is committed to changing patient expectations as we’re building a portfolio of candidate products in immune-oncology through our own research and key collaborations such as with MD Anderson," said André Choulika, Ph.D., Chief Executive Officer and Chairman of Cellectis.

"We’re highly encouraged by the potential of our product candidate pipeline to deliver innovative, best-in-class treatment options to patients."

"Immunotherapy is increasingly a significant element in cancer treatment," said Orlowski. "It is my hope that patients with multiple myeloma and other cancers will benefit through this alliance."