On May 26, 2015 Infinity Pharmaceuticals reported new preclinical data for duvelisib (IPI-145), an investigational, oral, dual inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma (Press release, Infinity Pharmaceuticals, MAY 26, 2015, View Source [SID:1234504829]). Schedule your 30 min Free 1stOncology Demo! In vitro studies demonstrated synergy with standard-of-care therapies and emerging agents in development for hematologic malignancies, including duvelisib in combination with venetoclax, in combination with ibrutinib and in combination with dexamethasone. Additionally, in preclinical studies with each of these three combinations, significant inhibition of lymphoma tumor growth was observed compared to each of these agents alone. These data will be presented at the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, Ill. on Sunday, May 31, 2015.
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
"Targeted combinations have the potential to further improve treatment options for patients, and Infinity’s translational research team continues to collaborate with AbbVie, our global partner for duvelisib in oncology, to identify therapies that may be synergistic with duvelisib," stated Vito Palombella, Infinity’s chief scientific officer. "This research supports further development of duvelisib in combination with approved and investigational medicines, including venetoclax."
"Additionally, preclinical research evaluating the activity of PI3K-delta isoform selective inhibitors and PI3K-gamma isoform selective inhibitors together shows that inhibiting both isoforms leads to greater tumor growth inhibition than either isoform alone, suggesting dual inhibition of PI3K-delta and PI3K-gamma has complementary effects on malignant B-cell growth and survival in these preclinical models," Dr. Palombella continued.
Preclinical and Translational Combination Data for Duvelisib (Abstract #8559)
New preclinical and translational research conducted in collaboration with researchers at AbbVie will be reported at ASCO (Free ASCO Whitepaper) 2015 on Sunday, May 31, from 8:00 a.m. – 11:30 a.m. CDT (9:00 a.m. – 12:30 p.m. EDT) in a poster presentation, "High throughput in vitro combination sensitivity screen in hematologic malignancies with the phosphoinositide-3-kinase (PI3K)-delta,gamma inhibitor, duvelisib."
As part of Infinity and AbbVie’s ongoing joint efforts to identify compounds synergistic with duvelisib, researchers conducted an in vitro high-throughput combination screen using a panel of cell lines and various drug combinations. In vitro synergy was observed with standard-of-care therapies and emerging agents in development for hematologic malignancies, including duvelisib in combination with venetoclax, in combination with ibrutinib and in combination with dexamethasone.
Additionally, in preclinical human xenograft studies with each of these three combinations, significant inhibition of lymphoma tumor growth was observed compared to each of these agents alone. These data support the use of duvelisib as part of combination therapy and provide additional rationale for the first clinical study of duvelisib in combination with venetoclax.
Researchers also evaluated the impact of dual inhibition of PI3K-delta and PI3K-gamma using isoform-selective inhibitors in preclinical models. Combined inhibition of PI3K-delta and PI3K-gamma led to greater tumor growth inhibition compared to the inhibition of either PI3K isoform alone, suggesting that dual inhibition of PI3K-delta and PI3K-gamma with duvelisib has complementary effects on malignant B-cell growth and survival in these preclinical models.
Additional Duvelisib Presentations at ASCO (Free ASCO Whitepaper) 2015
In total, four duvelisib presentations will take place on Sunday, May 31, 2015, during a poster session from 8:00 a.m. to 11:30 a.m. CDT in South Hall A at McCormick Place. In addition to the preclinical data reported today, duvelisib presentations at ASCO (Free ASCO Whitepaper) 2015 will include the following:
Phase 1 data describing the clinical activity and pharmacodynamics effects of duvelisib in a cohort of treatment-naïve patients with chronic lymphocytic leukemia (CLL) (Abstract #7074)
Translational data providing insight into the mechanism by which duvelisib disrupts communication between tumor cells and the supporting microenvironment in CLL (Abstract #7072)
A "trials in progress" poster highlighting SYNCHRONY, a Phase 1b study of duvelisib and obinutuzumab in CLL patients whose disease is refractory to or has relapsed while receiving a BTK inhibitor (Abstract #TPS7100)
About Duvelisib
Duvelisib is a dual, oral inhibitor of phosophoinositide-3-kinase (PI3K)-delta and PI3K-gamma that is being jointly developed by Infinity Pharmaceuticals, Inc. and AbbVie Inc. The PI3K pathway is known to play a critical role in regulating the growth and survival of certain types of blood cancers. Duvelisib is designed to block the growth and survival of tumor cells by inhibiting PI3K-delta and PI3K-gamma signaling. The investigational agent is being evaluated in registration-focused studies, including DYNAMOTM, a Phase 2 study in patients with refractory indolent non-Hodgkin lymphoma, DYNAMO+R, a Phase 3 study in patients with previously treated follicular lymphoma, and DUOTM, a Phase 3 study in patients with relapsed/refractory chronic lymphocytic leukemia. Duvelisib is an investigational compound and its safety and efficacy have not been evaluated by the U.S. Food and Drug Administration or any other health authority.
Regeneus receives approval for personalised cancer immunotherapy trial
On May 25, 2015 Regeneus (ASX: RGS), a clinical stage regenerative medicine company, reported that it has received ethics approval to commence its first-in-human trial for a personalised therapeutic cancer vaccine that is aimed at harnessing the body’s own immune system to fight cancer cells (Press release, Regeneus, MAY 25, 2015, View Source [SID1234519521]). Schedule your 30 min Free 1stOncology Demo! The vaccine, known as RGSH4K, is produced from a patient’s own cancer cells and, combined with a proprietary immunostimulant, is designed to activate the immune system against the cancer cells to initiate a body-wide response. The immune system’s memory should recognise and respond to both existing and new tumours.
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
The trial has its genesis in promising results in canines. In canine trials, Regeneus worked with the Bill Walsh Translational Cancer Research Laboratory at Royal North Shore Hospital. The vaccines, created using a dog’s own tumour, resulted in the majority of treated dogs outliving the average expected survival time for their particular type of cancer.
"We are hopeful that the success we have seen with the vaccine in treating a wide variety of cancers in dogs translates to humans" said Regeneus CEO, John Martin.
Cancer immunotherapies represent a treatment option without many of the side effects of standard chemotherapy. Cancer vaccines interfere minimally with most chemotherapeutic drugs making them likely helping agents to traditional therapies. The RGSH4K vaccine is simple to manufacture and contains no live cancer cells.
The study known as the ACTIVATE trial, is a single centre, open label, first in-human, Phase 1 dose escalating study to evaluate the safety, tolerability and preliminary efficacy of RGSH4K, administered in 21 patients with advanced cancers.
To facilitate the trial, Regeneus has established an ethics-approved tumour bank. Participants in the trial will need to have stored a tumour sample which then may be used to produce an autologous cancer vaccine for individual patient’s use in the trial. Further detail in relation to the trial and the tumour bank can be found on the Australian New Zealand Clinical Trials Registry website
The Principal Investigators for the trial are leading medical oncologists, Professor Stephen Clarke and Associate Professor Nick Pavlakis from University of Sydney‘s Northern Clinical School at the Kolling Institute of Medical Research located at Royal North Shore Hospital in St Leonards, Sydney. The trial will be conducted through the Northern Cancer Institute in St Leonards.
The cancer vaccine technology was developed at the Bill Walsh Translational Cancer Research Laboratory which is part of the Kolling Institute of Medical Research and is the research arm of the Medical Oncology Department, Royal North Shore Hospital. "It’s exciting to see world-class innovative cancer research done at the Kolling Institute translated into clinical application as a potential new therapeutic cancer vaccine," Professor Clarke said.
Regeneus has the exclusive worldwide rights to develop and commercialise the vaccine technology for human and veterinary applications.
Additional information on the human trials
In this trial, adult patients with a variety of advanced cancer types will be treated using this revolutionary technology. The process will work as follows:
Suitable patients will have their tumour removed and stored (known as tumour banking) prior to commencing first-line treatment;
If the patient relapses, and there are no other useful treatment options available, they will move into the next stage of the trial and, using their excised tumour, have a personalised vaccine produced;
The personalised, or autologous vaccine, will be injected at staged intervals and patients monitored for a response.
Professor Clarke says the aim will be for the cancer to be stabilised and the tumour to shrink. Ideally this would then lead to an extended life expectancy for the patient, similar to the results obtained in the canine research.
Positive Phase I Results from CAR-T CD30 Immuno-Oncology Clinical Development Program
On May 22, 2015 Cellular Biomedicine Group reported encouraging clinical data from its Chimeric Antigen Receptor (CAR-T) CD30-positive Hodgkin’s lymphoma immuno-oncology clinical development program (Press release, Cellular Biomedicine Group, MAY 22, 2015, View Source [SID:1234504630]). The results of this trial to date demonstrated that five out of seven patients responded to the treatment. CD30-directed CAR-T cell therapy was demonstrated in this trial to be safe, feasible and efficient. Schedule your 30 min Free 1stOncology Demo! The data was presented by Dr. William (Wei) Cao, PhD, BM, Chief Executive Officer of Cellular Biomedicine Group, at the 10th Annual World Stem Cells & Regenerative Medicine Congress in London, UK on May 21, 2015. Know more, wherever you are: Dr. Cao commented, "We are very encouraged by the efficacy and toxicity profile of our CAR-T CD30 technology, given that the cancer patients in the trials were diagnosed with Stage III and IV Hodgkin’s lymphoma. The patient selection criteria of our CAR-T studies are very stringent, as the participants enrolled are advanced, relapsed, and refractory to other standard-of-care therapies. The results of this study has led us to move forward with this protocol into the treatment of relapsed/refractory CD30 positive lymphoma patients."
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
Latest on CAR/TCR Therapies in Oncology, book your free 1stOncology demo here.
"We previously announced positive clinical data from our Phase I clinical trials for CD19 and CD20 constructs and expect to announce clinical data from our EGFR-HER1-positive advanced lung cancer trial in the third quarter of this year. We look forward to additional progress in advancing our Immuno-Oncology platform with further clinical developments of our CD19, CD20, CD30 and EGFR-HER1 constructs."
About the Trial
The CAR-T trial was designed and conducted by Chinese PLA General Hospital ("PLAGH", Beijing, also known as "301 Hospital"), led by Principal Investigator Wei Dong Han, MD, PhD, head of PLAGH’s cancer immunotherapy department. It assessed the feasibility, safety and efficacy in subjects with progressive relapsed/refractory Hodgkin’s lymphoma following the administration of CD30-targeting CAR-T cells. The study recruited male and female subjects who had a heavy treatment history (16 previous treatments, ranging from 8-24) and/or multiple tumor lesions with no available curative treatment options (such as autologous or allogeneic SCT) that had limited prognosis (several months to < 2 year survival) with currently available therapies.
This trial was a Phase I, open-label trial (NCT02259556) whereby enrolled patients received escalating doses of autologous T cells transduced with a CD30-directed chimeric antigen receptor moiety for a consecutive 3-5 days. The level of CAR transgenes in peripheral blood and biopsied tumor tissues were measured periodically according to assigned protocol by Quantitative PCR.
CAR-T CD30 for Hodgkin’s Lymphoma Data Analysis
Seven adult patients with relapsed/refractory Hodgkin’s lymphoma were enrolled in this CAR-CD30 T cell therapy trial. Results showed that 2 out of 7 patients achieved partial response (PR) and 3 out of the 7 patients obtained stable disease (SD), therefore the therapy resulted in an overall disease control rate of 71.4% (5/7) and an objective response rate of 28.6% (2/7) in the patients with relapsed/refractory Hodgkin’s lymphoma. Neither conditioning chemotherapy nor subsequent allogeneic-HSCT (hematopoietic stem cell transplant) was applied. Only one out of seven patients experienced an adverse effect with a 5-day self-limiting arthralgias, myalgias and dual knee swelling 2 weeks after cell infusion.
This study is registered at View Source
Further details of the clinical data may be viewed in the Company’s most recent presentation filed on Form 8k with the SEC, which can be found on the Company’s website at the following link, View Source under SEC filings or presentations.
Merck Receives Positive CHMP Opinion for KEYTRUDA® (pembrolizumab) for the Treatment of Advanced Melanoma
On May 22, 2015 Merck reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of advanced (unresectable or metastatic) melanoma, as both first-line therapy and in previously treated patients (Press release, Merck & Co, MAY 22, 2015, View Source [SID:1234504626]). The CHMP positive opinion for KEYTRUDA, which is based on data in more than 1,500 adult patients with advanced melanoma, will now be reviewed by the European Commission for central marketing authorization in the European Union (EU). Schedule your 30 min Free 1stOncology Demo! "Merck is committed to bringing KEYTRUDA to people with advanced melanoma in Europe as rapidly as possible, and the positive CHMP opinion marks a significant step forward," said Roger Dansey, therapeutic area head and senior vice president, oncology late stage development, Merck Research Laboratories. "We have established a broad data set for KEYTRUDA in the treatment of advanced melanoma, and have demonstrated improvements in progression free survival compared to chemotherapy and a survival benefit compared to ipilimumab. We look forward to working with European health authorities to make KEYTRUDA available to patients." Know more, wherever you are: Pembrolizumab, which will be marketed under the worldwide brand name of KEYTRUDA, is one of the first of a new generation of immunotherapies that works by blocking the PD-1 pathway. KEYTRUDA was the first anti-PD-1 therapy approved in the United States and the first medicine to be accepted under the UK’s Early Access to Medicines Scheme (EAMS), which was introduced to help patients benefit from promising, innovative treatments before a European license has been granted.
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
Latest on Melanoma, book your free 1stOncology demo here.
Data Supporting the CHMP Positive Opinion
The positive opinion was based on data from more than 1,500 patients with advanced melanoma treated with KEYTRUDA as monotherapy in three studies – from a large Phase 1b study, KEYNOTE-001; from a randomized, controlled study KEYNOTE-002; and an interim analysis from a second, randomized, controlled study, KEYNOTE-006. In KEYNOTE-001, the largest Phase 1b study to date of an anti-PD-1 antibody, KEYTRUDA demonstrated durable objective responses in patients with advanced melanoma. KEYNOTE-002, a Phase 2 study, showed KEYTRUDA was superior to chemotherapy for progression-free survival in ipilimumab refractory advanced melanoma. KEYNOTE-006, a Phase 3 study, showed KEYTRUDA was superior to ipilimumab for overall survival, progression-free survival, and overall response rate. The trial was stopped early in March 2015 based on the recommendation of the study’s independent Data Monitoring Committee as it had met its two primary endpoints. The CHMP recommended approval of KEYTRUDA monotherapy at a dose of 2 mg/kg every three weeks, which is the currently approved dose for advanced melanoma in the U.S.
About Melanoma
Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The incidence of melanoma has been increasing over the past four decades. In 2012, approximately 232,130 new cases were diagnosed worldwide, and the incidence in Europe was estimated to be 100,300. The five-year survival rates for advanced or metastatic melanoma (Stage IV) are estimated to be 15 to 20 percent.
About KEYTRUDA (pembrolizumab)
KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.
KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 85 clinical trials – across more than 30 tumor types and over 14,000 patients – both as a monotherapy and in combination with other therapies.
Selected Important Safety Information for KEYTRUDA
Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.
Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.
Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.
Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.
Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.
Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.
Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic neuritis, and rhabdomyolysis.
For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.
For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.
The most common adverse reactions (reported in ≥20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).
The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.
European Medicines Agency Issues Positive Opinion, Recommends Full Approval of IMBRUVICA® (ibrutinib) to Treat Waldenstrom’s Macroglobulinemia
On May 22, 2015 Pharmacyclics reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion recommending a change to the terms of the marketing authorization for IMBRUVICA (ibrutinib) in the European Union to indicate the treatment of adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy (Press release, Pharmacyclics, MAY 22, 2015, View Source [SID:1234504625]).1 WM is a rare, slow growing form of blood cancer.2 IMBRUVICA is also the first and only FDA-approved treatment for WM in the United States.3 The CHMP recommendation follows the January 2015 U.S. Food and Drug Administration (FDA) full approval of IMBRUVICA to treat all lines of patients with WM. Schedule your 30 min Free 1stOncology Demo! IMBRUVICA is jointly developed and commercialized in the United States by Pharmacyclics and Janssen Biotech, Inc. In Europe, Janssen-Cilag International NV (Janssen) holds the marketing authorization and its affiliates market IMBRUVICA in EMEA (Europe, Middle East, Africa), as well as the rest of the world. IMBRUVICA is already approved in Europe to treat adult patients with relapsed or refractory mantle cell lymphoma (MCL) and adult patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy or in first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy. Know more, wherever you are: The European Medicines Agency is an agency of the European Union responsible for the scientific evaluation of medicines submitted for approval by pharmaceutical companies for use in the 28 countries of the European Union. The positive CHMP opinion will be reviewed by the European Commission, and a final decision on IMBRUVICA to treat WM is anticipated in the second half of 2015. In addition to European markets, a worldwide regulatory filing program for IMBRUVICA currently is underway.
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
Latest on Hematological Cancers, book your free 1stOncology demo here.
"We are very pleased that patients with WM in the European Union will have a first-in-class, oral, single-agent, non-chemotherapy treatment option in IMBRUVICA," said Thorsten Graef, M.D., Ph.D., Head of Hematology at Pharmacyclics. "This approval underscores the compelling safety and efficacy profile of IMBRUVICA in hematologic malignancies and we look forward to addressing the unmet medical needs of WM patients across Europe."
WM currently affects approximately 23,000 patients in the G7 countries (United States, France, Germany, Italy, Japan and the United Kingdom).3 The CHMP recommendation was based on a multi-center, Phase II study that evaluated the efficacy and tolerability of IMBRUVICA in 63 patients with previously treated WM. Initial data from the study submitted for review in the EU showed an overall response rate (ORR) of 87.3% after a median duration of treatment of 11.7 months.
Updated results from the study were published on in the April 9, 2015 edition of The New England Journal of Medicine, indicating an ORR of 90.5% after a median duration of treatment of 19.1 months using criteria adopted from the International Workshop on WM. At 24 months, the estimated rate of progression-free survival was 69.1% (95% CI, 53.2 to 80.5), and the estimated rate of overall survival was 95.2% (95% CI, 86.0 to 98.4).
No new safety issues were observed in the clinical trial. The most commonly occurring adverse reactions in WM patients treated with IMBRUVICA ( > 20%) were neutropenia and thrombocytopenia. Other adverse reactions occurred in < 10% of patients (n=5). Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to neutropenia or thrombocytopenia. Of note, IMBRUVICA-related neutropenia and thrombocytopenia were reversible, but required a reduction in dose and/or discontinuation of treatment with IMBRUVICA in three of the four patients who developed these conditions. Overall, IMBRUVICA was well tolerated and there were no unexpected toxicities.
About Waldenström’s macroglobulinemia
WM (a clinically recognized subset of lymphoplasmacytic lymphoma, or LPL) is a slow-growing and rare blood cancer that most commonly originates from B cells, a type of white blood cell (lymphocyte) that develops in the bone marrow.2 WM occurs as the result of a malfunction in the healthy lifecycle of a B cell, causing the cell to become malignant and reproduce at an abnormal rate. The malignant B cells produce large amounts of an abnormal type of antibody protein called immunoglobulin M (IgM). Excess IgM causes the blood to thicken and causes many of the symptoms of WM.2
About IMBRUVICA
IMBRUVICA is currently approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, all CLL patients (including treatment naïve) who have del 17p, a genetic mutation that occurs when part of chromosome 17 has been lost, and all patients (including treatment naïve) with Waldenström’s macroglobulinemia. IMBRUVICA is also approved under accelerated approval for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.3
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK).3 IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway, and is the only product to have received three Breakthrough Therapy Designations.
BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.3,5 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.3
IMBRUVICA is being studied alone and in combination with other treatments in several blood cancers. More than 6,100 patients have been treated in clinical trials of IMBRUVICA conducted in 35 countries by more than 800 investigators. Currently, 13 Phase III trials have been initiated with IMBRUVICA and 67 trials are registered on www.clinicaltrials.gov.
To learn more about the medical terminology used in this news release, please visit View Source
INDICATIONS
IMBRUVICA is indicated in the U.S. to treat people with:
Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy
Chronic lymphocytic leukemia (CLL) with 17p deletion
Waldenström’s macroglobulinemia
Mantle cell lymphoma (MCL) who have received at least one prior therapy – accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
Patients taking IMBRUVICA for CLL or WM should take 420 mg taken orally once daily (or three 140 mg capsules once daily).
Patients taking IMBRUVICA for MCL should take 560 mg taken orally once daily (or four 140 mg capsules once daily).
Capsules should be taken orally with a glass of water. Capsules should be taken whole. Do not open, break, split or chew the capsules.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.
The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.
Infections – Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly.
Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly.
Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification.
Second Primary Malignancies – Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%).
Tumor Lysis Syndrome – Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g., high tumor burden).
Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
ADVERSE REACTIONS
The most common adverse reactions ( > 25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia* (57%, 52%, 43%), neutropenia* (47%, 51%, 44%), diarrhea (51%, 48%, 37%), anemia* (41%, 36%, 13%), fatigue (41%, 28%, 21%), musculoskeletal pain (37%, 28%**, NA***), bruising (30%, 12%**, 16%**), nausea (31%, 26%, 21%), upper respiratory tract infection (34%, 16%, 19%), and rash (25%, 24%**, 22%**).
*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).
**Includes multiple ADR terms.
***Not applicable; no associated ADRs.
The most common Grade 3 or 4 non-hematological adverse reactions ( > 5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).
Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse events.
Approximately 5% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse events. Most frequent adverse events leading to discontinuation were infections, subdural hematomas, and diarrhea in CLL patients and subdural hematoma (1.8%) in MCL patients
DRUG INTERACTIONS
CYP3A Inhibitors – Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.
CYP3A Inducers – Avoid co-administration with strong CYP3A inducers.
SPECIFIC POPULATIONS
Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.
Please see Full Prescribing Information: View Source