On September 14, 2015 Janssen Biotech reported a supplemental New Drug Application (sNDA) for IMBRUVICA (ibrutinib) has been submitted to the U.S. Food and Drug Administration (FDA) for front-line use in patients with chronic lymphocytic leukemia (CLL) (Press release, Johnson & Johnson, SEP 14, 2015, View Source [SID:1234507468]). The filing is based on data from the randomized, multi-center, open-label Phase 3 RESONATE-2 (PCYC-1115) trial assessing the use of ibrutinib versus chlorambucil in patients with treatment-naïve CLL or small lymphocytic lymphoma (SLL) aged 65 years or older. IMBRUVICA is jointly developed and commercialized by Janssen and Pharmacyclics LLC, an AbbVie company.

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Pharmacyclics is the investigational new drug (IND) holder for IMBRUVICA in the U.S. and submitted the application to the FDA on behalf of the companies.

"Treatment-naïve patients with this disease typically relapse or become refractory to standard chemotherapy, so new options are greatly needed to potentially change the CLL/SLL treatment paradigm," said Jan Burger, M.D., Ph.D., Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX and study lead investigator.

The RESONATE-2 trial enrolled 269 patients with treatment-naïve CLL/SLL aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive either ibrutinib 420 mg orally, once daily until progression or toxicity or chlorambucil 0.5 to 0.8 mg/kg on days 1 and 15 of each 28-day cycle for up to 12 cycles. At the time of the final analysis, the primary endpoint was met, with ibrutinib shown to be superior to chlorambucil in terms of progression-free survival (PFS). In addition, ibrutinib demonstrated significant improvements in key secondary efficacy endpoints, including overall survival (OS), overall response rate (ORR) and in hematologic function.

"This submission to expand the use of IMBRUVICA for patients with treatment-naïve CLL is very significant, as this patient population represents the largest group of patients with CLL," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen Research & Development, LLC. "The submission highlights our commitment to developing medicines that truly transform treatment paradigms and patient outcomes, as well as our commitment to further develop IMBRUVICA in hematologic malignancies."

The RESONATE-2 trial was sponsored by Pharmacyclics. The data have been submitted for presentation at an upcoming medical conference and for publication in a peer-reviewed journal. More information about the study can be found on www.clinicaltrials.gov.

Janssen Research & Development, LLC and Pharmacyclics are continuing an extensive clinical development program for IMBRUVICA, including Phase 3 study commitments in multiple patient populations.

About CLL
CLL is a slow-growing blood cancer that most commonly arises from B cells, a type of white blood cell (lymphocyte) that originates in the bone marrow.1,2 CLL is predominantly a disease of the elderly, with a median age of 71 at diagnosis.3

About IMBRUVICA (ibrutinib)
IMBRUVICA was one of the first therapies to receive U.S. approval after having received the FDA’s Breakthrough Therapy Designation. IMBRUVICA works by blocking a specific protein called Bruton’s tyrosine kinase (BTK).1 The BTK protein transmits important signals that tell B cells to mature and produce antibodies and is needed by specific cancer cells to multiply and spread.1,4 IMBRUVICA targets and blocks BTK, inhibiting cancer cell survival and spread.1 For more information, visit www.IMBRUVICA.com.

Additional Information about IMBRUVICA

INDICATIONS

IMBRUVICA is indicated 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 (WM)
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.
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 IIMBRUVICA 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 September 14, 2015 Kite Pharma, Inc. (Kite) (Nasdaq:KITE) reported that it has expanded its collaboration with the Netherlands Cancer Institute (NKI) (Press release, Kite Pharma, SEP 14, 2015, View Source [SID:1234507467]). Kite and the NKI have entered into an agreement under which Kite will receive from the NKI the exclusive option to license multiple T cell receptor (TCR) gene sequences for the development and commercialization of cancer immunotherapy candidates targeting solid tumors (Press release, Kite Pharma, SEP 14, 2015, View Source. Kite has also expanded its access to additional resources and research facilities through a master services agreement with the NKI.

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"We are excited with the progress of the TCR research programs with Kite and look forward to further advancements of the programs and our collaboration," said Professor René Medema, Director of NKI. "NKI believes that TCR technologies hold great potential for cancer care, and we are committed to making these new therapies a reality for patients."

Kite Pharma EU, based in Amsterdam, will be conducting preclinical research related to candidates under the agreement with NKI. Kite Pharma EU is comprised of a leading team of immuno-oncology researchers and collaborators, including Professor Dr. Ton N. M. Schumacher, who serves as Chief Scientific Officer of Kite Pharma EU. Professor Dr. Schumacher, a pioneer in T cell biology and gene therapy, is a developer of Kite’s proprietary TCR-GENErator discovery platform, an industry-leading R&D engine for rapid, high-throughput identification of TCR-based product candidates.

"With Kite Pharma EU, we have established a central hub of cancer immunotherapy efforts in Europe, attracting leading scientific experts, researchers and collaborators in this field," said Arie Belldegrun, M.D., FACS, Chairman, President and Chief Executive Officer of Kite. "Kite’s relationship with the NKI, an internationally renowned cancer research and clinical institution, provides an important operational platform, as we advance TCR-based immuno-oncology product candidates."

On September 14, 2015 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies,reported that the U.S. Food and Drug Administration’s (FDA) Office of Orphan Products Development (OOPD) awarded a grant totaling $1.1 million over three years to Baylor College of Medicine in support of an ongoing Phase 2 trial of Advaxis’s lead Lm Technology immunotherapy, axalimogene filolisbac (ADXS-HPV), in HPV-associated oropharynx (throat) cancer, a type of head and neck cancer (Press release, Advaxis, SEP 14, 2015, View Source [SID:1234507466]).

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The grant was administered through the FDA’s Orphan Products Grants Program, created more than 30 years ago by the Orphan Drug Act to promote the development of products for rare diseases. It is a competitive program that receives approximately 100 applications per year, from which typically 10 to 15 applications are selected for funding each fiscal year.

"Applications to the Orphan Products Grants Program undergo rigorous review for scientific and technical merit by a panel of experts to compete for funding," said Daniel J. O’Connor, President and Chief Executive Officer of Advaxis. "We are encouraged to see axalimogene filolisbac recognized as viable by being awarded a grant for its clinical research that could ultimately contribute to market approval."

The Phase 2 study will be led by Andrew G. Sikora, M.D., Associate Professor of Otolaryngology at BCM and co-director of the Head and Neck Cancer Program in the NCI Comprehensive-Designated Dan L. Duncan Cancer Center at Baylor, and is supported by key investigators Brett Miles, M.D. and Marshall Posner, M.D. at the Icahn School of Medicine at Mount Sinai. The study is designed to evaluate the efficacy of axalimogene filolisbac as neoadjuvant treatment prior to robot-assisted surgery in patients with HPV-associated oropharyngeal cancer.

"We hope to improve outcomes in HPV-associated head and neck cancer by exploring axalimogene filolisbac in this indication, where existing treatment options are associated with risk of long-term morbidity," said Dr. Sikora. "If successful, this trial could pave the way for immunotherapy to become a standard treatment for HPV-associated cancers."

HPV-Associated Oropharynx (Throat) Cancer

Human papillomavirus (HPV) is an important cause of cancers worldwide, including cancers of the oropharynx (throat), cervical cancer, and other cancers. HPV-related throat cancer is currently the fastest-growing type of head and neck cancer, with an incidence of approximately 15,500 new cases of HPV-associated oropharynx cancer in the U.S. per year.

About Axalimogene Filolisbac

Axalimogene filolisbac (ADXS-HPV) is Advaxis’s lead Lm Technology immunotherapy candidate for the treatment of HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer. In a completed randomized Phase 2 study in recurrent/refractory cervical cancer, axalimogene filolisbac showed apparent prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of the company’s Lm Technology.