On June 7, 2016 Transgenomic, Inc. (TBIO), (NASDAQ: TBIO), reported that it is unveiling new data at the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2016 Annual Meeting further confirming the utility, speed and efficiency of its ICE COLD-PCR (ICP) technology for liquid biopsy detection of tumor mutations (Press release, Transgenomic, JUN 7, 2016, View Source [SID:1234513122]). The company is distributing a new educational handout at the meeting highlighting expanded concordance data showing that ICP plasma-based liquid biopsies detect all of the mutations identified using conventional tissue samples and also detect additional tumor alterations missed by conventional methods. Another educational handout presents data showing how use of ICP with Thermo Fisher’s Veriti thermal cycler expedites the testing of liquid biopsy samples, producing accurate results rapidly and efficiently.

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TBIO President and CEO Paul Kinnon commented, "As the highest profile cancer meeting of the year, ASCO (Free ASCO Whitepaper) is an excellent venue for presenting our expanded concordance study data further confirming the accuracy and superior performance of ICE COLD-PCR liquid biopsies for tumor detection and monitoring. We also are unveiling new study data highlighting the speed and efficiency of our ICP enrichment technology when used with a leading thermal cycler. We believe ICP’s accuracy, versatility and ease of use have the potential to enable wide adoption of routine genomic testing in cancer research and patient care, and the new data we are discussing at ASCO (Free ASCO Whitepaper) further supports the technology’s near-term clinical and commercial potential."

At the ASCO (Free ASCO Whitepaper) meeting, Transgenomic is distributing an educational report, "CRC Concordance Update – Stage IV CRC Sample Analysis with ICE COLD-PCRTM," which describes the results of an expanded concordance study assessing the ability of its multiplexed ICE COLD-PCR technology to detect a key tumor mutation in matched plasma samples compared to detection in the same patients using tissue and plasma samples analyzed using conventional Sanger sequencing methods. The expanded study included 32 patients with late stage colorectal cancer. Use of ICP-enriched testing resulted in an overall 96.9% concordance rate, with a 94.7% concordance rate for the mutation positive samples. In addition, actionable mutations were detected in two patient samples analyzed using ICP-enriched methods that were missed using conventional PCR with Sanger sequencing. Notably, the missed mutations were detected by ICP in both the plasma and tissue samples from these patients.

The researchers conclude that the high concordance rates achieved in the study and the ability of the ICP-enriched approach to detect relevant mutations missed by conventional methods support the clinical validity and utility of ICP-based liquid and tissue biopsies for mutation detection and monitoring in cancer patients.

Anil Vachani, MD, MS, Associate Professor of Medicine at the Hospital of the University of Pennsylvania and the Veteran’s Administration Medical Center and an investigator working with TBIO, commented, "The ability to accurately and efficiently detect tumor mutations from non-invasive blood-based patient samples is essential for realizing the potential of precision medicine approaches to transform cancer treatment. I welcome studies that increase our confidence in the validity of new technologies such as ICE COLD-PCR to help enable use of targeted and other precision treatment approaches."

A second TBIO educational handout, "Simple and Effective Clinical Testing Protocol Using ICE COLD-PCRTM across Targeted Cancer Gene Panels using the Veriti Thermal Cycler and Sanger Sequencing," details a new study that demonstrates how combining multiplexed ICE COLD-PCR with the Thermo Fisher Veriti thermal cycler expedites mutation detection and monitoring using liquid biopsy samples. It shows that with the Veriti thermal cycler, ICE COLD-PCR amplifications can be grouped based on temperature and primer annealing parameters to enable multiple amplicon enrichments in a single thermal cycler run. By combining the flexibility of the Veriti thermal cycler, the superior enrichment power of ICP and the rapid turnaround time of Sanger sequencing, liquid biopsy test results were generated in about four days, compared to total turnaround times of about four weeks for conventional tissue biopsies. Rapid results are an important advantage in cancer clinical testing and patient monitoring, where critical patient treatment decisions increasingly rely on up-to-date genomic data.

The study researchers note too that these results provide an opportunity for molecular diagnostic laboratories to reevaluate the use of Sanger sequencing for confirmation of mutation detection results from next-generation sequencing (NGS) platforms, and point out that by using this protocol, Sanger platforms can also be re-considered for front line mutation detection, with the potential to produce accurate results more rapidly and cost effectively than NGS platforms.

ICE COLD-PCR achieves its ultra-high sensitivity through selective amplification of mutant DNA. The result is up to a 500-fold increase in sensitivity in identifying mutations with the most precise sequence alteration detection rates available. ICP was originally developed by the laboratory of Dr. Mike Makrigiorgos at the Dana-Farber Cancer Institute, which has exclusively licensed rights to the technology to Transgenomic.

On June 7, 2016 Blue Earth Diagnostics Ltd., a molecular imaging diagnostics company, and Siemens’ PETNET Solutions, Inc., a wholly-owned subsidiary of Siemens Medical Solutions USA, Inc., reported the commercial availability of Axumin (fluciclovine F 18) injection in the United States (Press release, Blue Earth Diagnostics, JUN 7, 2016, View Source [SID:1234513123]). Axumin is a novel molecular imaging agent indicated for use in positron emission tomography (PET) imaging to identify suspected sites of prostate cancer recurrence in men who have elevated blood levels of prostate specific antigen (PSA) following prior treatment. Axumin was approved by the U.S. Food and Drug Administration (FDA) on May 27, 2016, and is the first FDA-approved F-18 PET imaging agent indicated for use in patients with suspected recurrent prostate cancer.

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"Blue Earth Diagnostics is extremely pleased to be working with Siemens’ PETNET Solutions, the leading supplier of PET radiopharmaceuticals in the United States; we both share a passion for PET molecular imaging, and for providing imaging tools to improve patient management."
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Axumin will be commercially available this month through Blue Earth Diagnostics’ manufacturer and exclusive distributor in the United States, Siemens’ PETNET Solutions. Initial commercial production of Axumin will be underway at certain Siemens’ PETNET Solutions radiopharmacies, with increasingly broader availability planned in the coming months.

"We are tremendously pleased with FDA’s recent approval of Axumin for suspected biochemically recurrent prostate cancer, and hope that this will make a real difference to patients and their physicians," said Jonathan Allis, D. Phil., CEO of Blue Earth Diagnostics Ltd. "Blue Earth Diagnostics is extremely pleased to be working with Siemens’ PETNET Solutions, the leading supplier of PET radiopharmaceuticals in the United States; we both share a passion for PET molecular imaging, and for providing imaging tools to improve patient management."

"This is a significant milestone for the PET industry, as this is the first proprietary F-18 labeled agent for an oncology indication approved by the FDA. And, being F-18 labeled enables efficient distribution and wide patient access," said Barry Scott, head of Siemens’ PETNET Solutions. "Through our broad network of radiopharmacies we are able to increase access to PET tracers, like Axumin, helping healthcare providers to address society’s most challenging diseases. We are proud to work with Blue Earth Diagnostics as the U.S. commercial supplier making Axumin available to imaging centers and their patients."

Blue Earth Diagnostics and Siemens’ PETNET Solutions welcome visitors to the upcoming SNMMI meeting to visit their exhibit booths. Blue Earth Diagnostics is at Booth 337; Siemens’ PETNET Solutions is at Booth 431.

About AxuminTM (fluciclovine F 18)

Axumin (fluciclovine F 18) injection is a novel product indicated for use in positron emission tomography (PET) imaging to identify suspected sites of prostate cancer recurrence in men. Recurrence of prostate cancer is suspected by an increase in prostate specific antigen (PSA) levels following initial therapy. PET imaging with Axumin may identify the location and extent of such recurrence. Axumin was developed to enable visualization of the increased amino acid transport that occurs in many cancers, including prostate cancer. It consists of a synthetic amino acid that is preferentially taken up by prostate cancer cells compared with surrounding normal tissues, and is labeled with the radioisotope F18 for PET imaging. Axumin was approved by the U.S. Food and Drug Administration on May 27, 2016 following Priority Review, and is the first product commercialized by Blue Earth Diagnostics, which licensed the product from GE Healthcare. The molecule is being investigated by Blue Earth Diagnostics for other potential cancer indications, such as glioma.

Indication and Important Safety Information About Axumin

INDICATION

Axumin (fluciclovine F 18) injection is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated blood prostate specific antigen (PSA) levels following prior treatment.

IMPORTANT SAFETY INFORMATION

Image interpretation errors can occur with Axumin PET imaging. A negative image does not rule out recurrent prostate cancer and a positive image does not confirm its presence. The performance of Axumin seems to be affected by PSA levels. Axumin uptake may occur with other cancers and benign prostatic hypertrophy in primary prostate cancer. Clinical correlation, which may include histopathological evaluation, is recommended.
Hypersensitivity reactions, including anaphylaxis, may occur in patients who receive Axumin. Emergency resuscitation equipment and personnel should be immediately available.
Axumin use contributes to a patient’s overall long-term cumulative radiation exposure, which is associated with an increased risk of cancer. Safe handling practices should be used to minimize radiation exposure to the patient and health care providers.
Adverse reactions were reported in ≤ 1% of subjects during clinical studies with Axumin. The most common adverse reactions were injection site pain, injection site erythema and dysgeusia.
To report suspected adverse reactions to Axumin, call 1-855-AXUMIN1 (1-855-298-6461) or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Full Axumin prescribing information is available at www.axumin.com.

About Prostate Cancer/Recurrent Prostate Cancer

Prostate cancer is the second leading cause of cancer death in men. While most primary prostate cancer can be successfully treated, the disease recurs in up to one-third of patients. In some patients recurrent disease is detectable only by a rise in prostate specific antigen (PSA) levels, yet the location of the recurrence cannot consistently be located by conventional imaging, severely limiting treatment guidance for these patients.

On June 6, 2016 Galera Therapeutics, Inc., a clinical-stage biotechnology company developing new treatments for cancer patients, reported the presentation of data from a Phase 1b/2a clinical trial of GC4419, an investigational drug candidate for the reduction of chemoradiotherapy-induced oral mucositis (OM), at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL (Press release, Galera Therapeutics, JUN 7, 2016, View Source [SID:1234513124]). Study results suggest that GC4419 may reduce the incidence, severity and duration of severe OM in patients receiving chemoradiation therapy for the treatment of head and neck cancer, particularly when GC4419 is administered for the duration of chemoradiation therapy.

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The Phase 1b/2a trial assessed the safety and pharmacokinetics of GC4419, administered intravenously prior to each dose of intensity modulated radiotherapy (IMRT) and cisplatin therapy, in 43 patients evaluable for OM. Study endpoints also included assessments of the incidence, time to onset, duration, and severity of OM and initial tumor outcomes for several dosing schedules of GC4419. The study demonstrated that, compared to historic controls, GC4419 appeared to delay onset, shorten the duration and decrease the incidence of severe OM (defined as WHO Grades 3 and 4 OM). The data also showed that the effect of GC4419 was greater if the treatment was administered for the entire duration of IMRT, with larger reductions in all grades of OM experienced by patients receiving full therapy (6-7 weeks) compared to patients receiving partial therapy (3 weeks). For example, investigators reported that the cumulative overall incidence of Grade 4 OM was 25 percent in patients in the 3 week cohort, while patients receiving full therapy had 0 percent. The median duration of severe OM was 2.5 days in patients receiving full therapy, far shorter than the 3-4 week duration in matched historical controls. Patients who received partial therapy still experienced less than 25 percent of the duration of severe OM than reported for matched historical controls.

GC4419 had a safety profile consistent with the IMRT and cisplatin regimen. The most common adverse events were attributable to chemotherapy or head and neck cancer. The plasma half-life of GC4419 was approximately 1.5 hours, with minimal accumulation after repeated dosing. Only 4.3 percent of patients required breaks in IMRT of 5 consecutive fractions or more, as opposed to 15% in published reports of other studies of OM in comparable patients. Patients followed for up to 12 months after completion of IMRT have showed no evidence of tumor protection from GC4419 treatment, with follow-up ongoing.

"We are pleased to share the promising results of the Phase 1b/2a trial, which offer early insight into the potential safety profile and clinical benefit of GC4419 in reducing severe oral mucositis in patients with head and neck cancer," said J. Mel Sorensen, MD, President and CEO of Galera. "These findings support the continued clinical development of GC4419, as well as our pipeline of breakthrough drugs targeting oxygen metabolic pathways. Enrollment in a randomized Phase 2 trial of GC4419 is currently underway. In addition, we are conducting IND-enabling work on orally active dismutase mimetics."

About Oral Mucositis (OM)
OM is a common debilitating side effect of radiation treatment in head and neck cancer (HNC) patients. Severe OM, defined as Grade 3 or 4 OM on the World Health Organization Oral Mucositis Scale, occurs in 60 to 80 percent of HNC patients who receive radiation therapy. Importantly, severe OM may result in interruptions in radiation treatment, which can compromise the otherwise good prognosis for tumor control in many of these patients. In addition, patients suffer significant pain, may develop serious infections, and may be unable to eat solid food or even drink liquids. Further, the costs of managing these side effects are substantial, particularly when hospitalization and/or surgical placement of PEG tubes to maintain nutrition and hydration is required. There is currently no drug approved to prevent or treat severe OM in head and neck cancer patients.

About GC4419
GC4419 is a superoxide dismutase mimetic, a small molecule drug that selectively targets the superoxide pathway by supplementing the activity of the superoxide dismutase enzyme family to accelerate the conversion of superoxide to hydrogen peroxide. This mechanism is thought to block the large burst of superoxide induced by radiotherapy, the initiating step in the development of OM, and has been shown to be protective of normal tissue but not tumor. In preliminary clinical studies, GC4419 markedly delayed the onset, shortened the duration and decreased the incidence of severe OM when administered intravenously prior to each dose of intensity modulated radiotherapy (IMRT) and cisplatin. GC4419 has now entered randomized Phase 2 development for the reduction of severe OM associated with chemoradiotherapy in head and neck cancer.

On June 6, 2016 Celator Pharmaceuticals, Inc. (Nasdaq: CPXX) reported results from its Phase 3 trial of VYXEOS (cytarabine: daunorubicin) Liposome for Injection (also known as CPX-351) in patients with high-risk (secondary) acute myeloid leukemia (AML) were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2016 Annual Meeting (Press release, Celator Pharmaceuticals, JUN 6, 2016, View Source [SID:1234513035]). As previously reported, the trial met its primary endpoint demonstrating a statistically significant improvement in overall survival. The Phase 3 trial compared to the standard of care regimen of cytarabine and daunorubicin known as 7+3.

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The median overall survival for patients treated with VYXEOS in the study was 9.56 months compared to 5.95 months for patients receiving 7+3, representing a 3.61 month improvement in favor of VYXEOS. The hazard ratio (HR) was 0.69 (p=0.005) which represents a 31% reduction in the risk of death versus 7+3. The percentage of patients alive 12 months after randomization was 41.5% on the VYXEOS arm compared to 27.6% on the 7+3 arm. The percentage of patients alive 24 months after randomization was 31.1% on the VYXEOS arm compared to 12.3% on the 7+3 arm.

Event-free survival was also statistically significant in favor of VYXEOS. The HR was 0.74 (p-value=0.021). The median event-free survival was 2.53 months in the VYXEOS arm compared to 1.31 months in the 7+3 arm.

"We believe the promising primary efficacy results of CPX-351 in high risk AML, across multiple parameters, support its use as the new standard of care in a difficult-to-treat population," said Jeffrey E. Lancet, M.D., senior member and chief of the Leukemia/Myelodysplasia Program at Moffitt Cancer Center and the principal investigator for the study. "This is an important step forward in the treatment of a terrible disease, and hopefully this platform for synergistic drug delivery will continue to advance the field."

VYXEOS also demonstrated a statistically significant improvement in induction response rate (CR+CRi of 47.7% versus 33.3%; p=0.016) and this significance was maintained for the analysis of CR alone (CR of 37.3% versus 25.6%, p=0.040).

Thirty-four percent of VYXEOS treated patients received a stem cell transplant (SCT) compared to 25% of 7+3 treated patients. In a landmark survival analysis of patients receiving a SCT, VYXEOS patients had significantly improved survival post-transplant (HR was 0.46 (p-value=0.0046)). The median overall survival had not been reached in the VYXEOS treated patients compared to 10.25 months in the 7+3 treated patients.

Thirty-day and sixty-day all-cause mortality favored VYXEOS. Thirty-day mortality was 5.9% compared to 10.6% and sixty-day mortality was 13.7% versus 21.2%.

Grade 3-5 non-hematologic and hematologic adverse events were similar between the VYXEOS and 7+3 arms.

The company expects to submit a New Drug Application (NDA) for VYXEOS with the U.S. Food and Drug Administration (FDA) by the end of the third quarter of 2016 and submit a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) in the first quarter of 2017.

"We are very pleased to have this opportunity to share the data from our Phase 3 trial with the oncology community. This successful outcome represents an important advance for AML patients, their families and clinicians," said Scott Jackson, Chief Executive Officer of Celator Pharmaceuticals. "We thank the patients and investigators who participated in this study and we will work closely with regulatory authorities to make this new treatment available to the AML community as soon as possible."

The clinical trial was conducted in partnership with The Leukemia & Lymphoma Society (LLS) through its Therapy Acceleration Program (TAP), which has supported the clinical development of VYXEOS beginning in Phase 2.

Phase 3 Trial Design

The randomized, controlled, Phase 3 trial (Protocol NCT01696084), enrolled 309 patients at 39 sites in the United States and Canada, and compared VYXEOS to the conventional cytarabine and daunorubicin treatment regimen (commonly referred to as 7+3) as first-line therapy in older (60-75 years of age) patients with high-risk (secondary) AML. Patients were stratified for age (60 to 69 and 70 to 75 years of age) and AML type; treatment-related AML, AML with documented history of myelodysplastic syndrome (MDS) with prior treatment with hypomethylating agent therapy, AML with documented history of MDS without prior hypomethlyating agent therapy, AML with a documented history of chronic myelomonocytic leukemia (CMMoL), and de novo AML with a karyotype characteristic of MDS.

Patients were randomized 1:1 to receive either VYXEOS or 7+3. Patients could receive one or two inductions, and responding patients could receive one or two consolidations. First induction for VYXEOS was 100u/m2; days 1, 3, and 5 by 90-minute infusion and for the control arm was cytarabine 100mg/m2/day by continuous infusion for 7 days and daunorubicin 60mg/m2 on days 1, 2, and 3 (7+3). Second induction for VYXEOS-treated patients was 100u/m2 on days 1 and 3, and the control arm was cytarabine 100mg/m2/day by continuous infusion for 5 days and daunorubicin 60mg/m2 on days 1 and 2 (5+2).

Only patients with documented CR or CRi were eligible to receive chemotherapy consolidation. Consolidation for VYXEOS-treated patients was 65u/m2 on days 1 and 3 and the control arm was cytarabine 100mg/m2/day by continuous infusion for 5 days and daunorubicin 60mg/m2 on days 1 and 2 (5+2).

About VYXEOS

VYXEOS (cytarabine:daunorubicin) Liposome for Injection, also known as CPX-351, is a nano-scale co-formulation of cytarabine and daunorubicin at a synergistic 5:1 molar ration. VYXEOS represents a novel approach to developing combinations of drugs in which molar ratios of two drugs with synergistic anti-tumor activity are encapsulated in a nano-scale liposome in order to maintain the desired ratio following administration. The FDA granted Breakthrough Therapy designation to VYXEOS for the treatment of adults with therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). VYXEOS was granted orphan drug status for the treatment of AML by the FDA and the European Commission. VYXEOS was also granted Fast Track designation for the treatment of elderly patients with secondary AML by the FDA.

About AML

Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood characterized by the uncontrolled proliferation of immature blast cells in the bone marrow. AML is generally a disease of older adults, and the median age of a patient diagnosed with AML is about 67 years. The American Cancer Society estimates that there will be 19,950 new cases of AML and 10,430 deaths from AML in the U.S. in 2016. In Europe the number of new cases is estimated to be 18,000 and in Japan the number is 5,500. The Company estimates that nearly 70 percent of AML patients are over the age of 60, and approximately 75% are intermediate or high risk. Furthermore, approximately half of those patients are considered suitable for intensive treatment.

Even with current treatment, overall survival for AML is poor. In patients over 60 years of age, the 5 year survival rate is less than 10%. In high-risk (secondary) AML, overall survival is lower, resulting in an acute need for new treatment options for these patients.

On June 6, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported longer-term follow-up results from Phase 3 studies of IMBRUVICA (ibrutinib) in chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) (Press release, AbbVie, JUN 6, 2016, View Source [SID:1234513058]). Findings include an analysis of outcomes from the RESONATETM (PCYC-1112) and RESONATETM-2 (PCYC-1115) trials, which showed IMBRUVICA was associated with favorable progression-free survival (PFS) and overall survival (OS) regardless of line of therapy (previously treated or treatment-naïve; abstract 7520). Other data include first-ever presentation of longer-term follow-up data from the HELIOS (CLL3001) trial showing IMBRUVICA in combination with bendamustine and rituximab (BR) continued to demonstrate superiority over time versus placebo plus BR in relapsed/refractory CLL/SLL patients (abstract 7525), along with improvements in quality of response.

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These data showcasing additional clinical evidence of IMBRUVICA in CLL/SLL will be presented today in a poster session at the Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago from 8:00 – 11:30 a.m. CDT. The RESONATE and RESONATE-2 analysis will also be featured as a poster discussion today from 1:15 – 2:45 p.m. CDT. IMBRUVICA is jointly developed and commercialized in the U.S. by Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc.

"Our clinical data presented at this year’s ASCO (Free ASCO Whitepaper) from several randomized studies demonstrate solid durability of response with IMBRUVICA in patients with CLL/SLL with additional follow-up of up to three years," said Danelle James, M.D., M.S., Head of Oncology at Pharmacyclics. "This evidence of deepening responses with continued therapy and long-term survival with IMBRUVICA over time, used either as a single agent or in combination, positions this therapy as a potentially beneficial treatment option for a variety of patients with CLL or SLL, regardless of when it is prescribed in the treatment journey."

An analysis of the RESONATE and RESONATE-2 trials showed IMBRUVICA was associated with favorable PFS and OS outcomes, as well as a high overall response rate (ORR) in previously treated and treatment-naïve patients with CLL/SLL, regardless of line of therapy. The median PFS and OS were not reached in treatment-naïve or previously-treated patients; 89-92% of patients treated with ibrutinib at first or second line of therapy remained progression-free at two years. Additionally, ORR was high in both previously treated and treatment-naïve patients (92% and 91%, respectively). The safety profile was similar for both patient groups1 and was consistent with previously-reported outcomes. Data from the RESONATE and RESONATE-2 studies served as the basis for the 2014 and 2016 FDA approvals of IMBRUVICA for patients with CLL/SLL.

The most commonly occurring adverse reactions (? 20%) in studies that supported the FDA approvals for patients with CLL/SLL were neutropenia, thrombocytopenia, anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, pyrexia and hemorrhage. Four to 10% of patients receiving IMBRUVICA discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each). Adverse reactions leading to dose reduction occurred in approximately 6% of patients.

Additionally, after a median follow-up of 25.4 months, data from the HELIOS trial showed the combination of IMBRUVICA plus BR continued to demonstrate a significant improvement in investigator-assessed PFS (the primary endpoint) (74.8%) versus placebo plus BR (20.9%) in patients with relapsed/refractory CLL/SLL (median not reached versus 14.2 months, respectively; HR [95% CI]: 0.199 [0.15, 0.26], P<0.0001). The updated investigator-assessed ORR for IMBRUVICA plus BR was 87.2%, as compared with 66.1% for placebo plus BR (P<0.0001) and the rate of complete responses (CRs) and CRs with incomplete bone marrow recovery (CRi) improved in the IMBRUVICA plus BR arm (33.9% versus 7.2% in the placebo plus BR arm). OS was not reached in either arm (HR [95% CI]: 0.670 [0.44, 1.02], P=0.587). Safety was consistent with the first analysis.2 Notably, positive results from the initial analysis (median follow-up: 17 months) supported the May 2016 update to the IMBRUVICA U.S. Prescribing Information.

The prevalence of CLL is approximately 115,000 patients in the U.S.3 with approximately 15,000 newly diagnosed patients every year.4 SLL is a slow-growing lymphoma biologically similar to CLL in which too many immature white blood cells cause lymph nodes to become larger than normal.5 CLL and SLL are predominately diseases of the elderly, with a median age of 71 at diagnosis.3

About the RESONATE Study
RESONATE is a Pharmacyclics-sponsored randomized, multi-center, open-label, international Phase 3 study that examined ibrutinib versus ofatumumab in relapsed/refractory patients with CLL/SLL who had received at least one prior therapy and were not considered appropriate candidates for treatment with a purine analog (n=391). Patients were administered either 420 mg oral ibrutinib (n=195) once-daily until progression or unacceptable toxicity or intravenous ofatumumab for up to 24 weeks (n=196, initial dose of 300 mg followed by 11 doses at 2,000 mg per dose and schedule consistent with local labeling). The study met its primary endpoint, demonstrating improved PFS.

Results from RESONATE were featured in the official press program at ASCO (Free ASCO Whitepaper) in Chicago in June 2014 and simultaneously published in The New England Journal of Medicine.

About the RESONATE-2 Study
RESONATE-2 is a Pharmacyclics-sponsored, randomized, multi-center, open-label, Phase 3 study which enrolled 269 treatment-naïve patients with CLL/SLL aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive either IMBRUVICA 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg. The study met its primary endpoint, demonstrating improved PFS, as assessed by an independent review committee (IRC).

Results from RESONATE-2 were first presented in an oral session at the American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in Orlando, FL in December 2015 and simultaneously published in The New England Journal of Medicine. The results were also part of the official press program at ASH (Free ASH Whitepaper) 2015.

About the HELIOS Study
HELIOS is a Janssen-sponsored, randomized, multi-center, double-blind, placebo-controlled, Phase 3 study which enrolled 578 CLL/SLL patients who had received at least one prior systemic therapy. Patients were randomized to receive IMBRUVICA or placebo, once daily continuing until disease progression or unacceptable toxicity with six cycles of BR. The study met its primary endpoint, demonstrating improved IRC assessed PFS.

Data from an interim analysis of HELIOS were first presented during the official press program at ASCO (Free ASCO Whitepaper) in Chicago in May 2015. The results were also published in The Lancet Oncology in December 2015.

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK).6 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.7 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably. 7

IMBRUVICA is approved to treat patients with CLL/SLL, patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.7

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers. More than 6,000 patients have been treated with IMBRUVICA in clinical trials. Currently, 14 Phase 3 trials have been initiated with IMBRUVICA and more than 90 trials are registered on www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including 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 and patients should be monitored for signs of bleeding. 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 nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.

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%) based on laboratory measurements occurred in patients treated with single agent 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, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension – Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies – Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).

Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

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 and for 1 month after cessation of therapy. 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 (?20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia* (64%), thrombocytopenia* (63%), diarrhea (43%), anemia* (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia (21%).

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

The most common Grade 3 or 4 non-hematologic 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 reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

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

CYP3A Inducers – Avoid coadministration 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.

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