PHARMACYCLICS, INC. Early combination data from Phase 1b/2 dose-finding study indicate potential efficacy in previously treated patients with multiple myeloma
This release corresponds to abstract #377
NORTH CHICAGO, IL., December 6, 2015 - Today, AbbVie (NYSE: ABBV), a global biopharmaceutical company, announced preliminary data from the ongoing Phase 1/2b PCYC-1119 trial suggesting that the combination of ibrutinib (IMBRUVICA®) plus carfilzomib with or without dexamethasone was well tolerated in relapsed or refractory patients with multiple myeloma (MM), with an initial objective response rate (ORR) of 62%. These data will be presented today in an oral presentation at the 57th Annual American Society of Hematology (ASH) Meeting and Exposition in Orlando, FL at 5:30 p.m. ET. IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc.
MM is a blood cancer that most commonly arises from B cells, a type of white blood cell (lymphocyte) that originates in the bone marrow. This year, approximately 26,850 people will be diagnosed with the disease and about 11,240 will die.1
"Multiple myeloma can be a very difficult form of cancer to treat and many patients eventually relapse or become resistant to treatment with standard therapies," said Ajai Chari, M.D., Associate Professor of Medicine and Director of Clinical Research in the Multiple Myeloma Program at the Icahn School of Medicine at Mount Sinai, New York, NY, and lead study investigator.* "These initial data are encouraging as they suggest the combination of ibrutinib plus carfilzomib and dexamethasone has promising clinical potential, particularly in the primarily refractory patient population who participated in this study."
Thirty-nine patients were evaluable for efficacy and demonstrated a 62% ORR during early follow-up, with a clinical benefit rate (CBR) of 72%. Overall, the combination was well tolerated, with no dose- limiting toxicities observed during the dose escalation phase.
"As we continue to investigate the use of ibrutinib across a number of hematologic malignancies, multiple myeloma remains an area of great clinical need," said Thorsten Graef, M.D., Ph.D., Head of Hematology & Global Medical Safety at Pharmacyclics. "Many of these patients eventually relapse when treated with other traditional therapies, so new options are greatly needed. We are hopeful ibrutinib may help answer the call for new alternatives and look forward to continuing to follow its promising progress for the treatment of this disease."
The ongoing, multicenter, dose-escalation Phase 1/2b study evaluated the safety and efficacy of ibrutinib in combination with carfilzomib with or without dexamethasone in 40 relapsed or refractory MM patients. Patients received the combination across multiple dose levels during the Phase 1 portion,
with no dose-limiting toxicities observed. Cohorts 2b (n=14; ibrutinib 560mg once daily plus carfilzomib and dexamethasone) and 3b (n=18; ibrutinib 840mg once daily plus carfilzomib and dexamethasone) was determined to be the recommended Phase 2 dose to further assess the safety and efficacy of the combination. In cohort 3b, the ORR was 65% and the CBR was 76%, including three very good partial responses and one stringent complete response.
The most common all grade non-hematologic adverse events (AEs in ≥20% of patients) across all cohorts in this study were diarrhea, constipation, fatigue, cough and nausea. Grade 3 or greater hematologic AEs (≥10% of patients) included hypertension, anemia, pneumonia, thrombocytopenia, diarrhea and fatigue. In addition, 12 patients discontinued treatment due to progressive disease, eight discontinued due to an AE and nine discontinued due to investigator or patient decision.
About IMBRUVICAIMBRUVICA is currently approved for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, CLL patients who have del 17p and patients with Waldenström's macroglobulinemia.2 IMBRUVICA is also approved for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. 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.2
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase (BTK).2 IMBRUVICA was one of the first medicines to receive a U.S. FDA approval after being granted a Breakthrough Therapy Designation, and IMBRUVICA is one of the few therapies to receive three separate 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.2,3 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.2
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, 16 Phase 3 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 http://stedmansonline.com/.
INDICATIONSIMBRUVICA 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
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 swallowed whole with a glass of water. Do not open, break or chew the capsules.
IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONSHemorrhage - 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.
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.
CYP3A Inhibitors - Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.
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: http://www.imbruvica.com/downloads/Prescribing_Information.pdf.
Pharmacyclics Inc. issued this content on 2016-01-07 and is solely responsible for the information contained herein. Distributed by Public, unedited and unaltered, on 2016-01-07 20:35:04 UTC
Original Document: http://www.pharmacyclics.com/docs/librariesprovider4/press-releases/2015/4_pcyc-abbv-ash-mm-press-release-12-6-15.pdf?sfvrsn=4
