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Onconova Announces Successful End-of-Phase 2 Meeting with FDA for Oral Rigosertib and Azacitidine Combination

On September 26, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported receipt of the End-of-Phase 2 meeting minutes from the U.S. Food and Drug Administration (FDA) for the combination of oral rigosertib with azacitidine for the treatment of patients with higher-risk myelodysplastic syndromes (HR-MDS) (Press release, Onconova, SEP 26, 2016, View Source [SID:SID1234515367]).

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Based on these discussions, Onconova will design a randomized, controlled Phase 3 clinical trial comparing the combination of oral rigosertib plus azacitidine to azacitidine plus placebo in 1st-line HR-MDS patients. The primary endpoint of this pivotal trial will be overall response rate (ORR); ORR will be a composite of complete remission (CR) and partial remission (PR). Onconova could potentially pursue additional available paths from FDA for accelerated or enhanced review and further input on the development of a final trial protocol. Full details of the protocol will be available following completion of all regulatory discussions.

As part of the End-of-Phase 2 meeting with FDA, Onconova presented updated results from its Phase 2 trial of oral rigosertib and azacitidine. These results are expected to be presented by study investigators at a scientific conference later this year.

"We are encouraged that our interactions with FDA resulted in agreement on the patient population to be evaluated and the selection of overall response as the primary endpoint in this pivotal trial," stated Steven Fruchtman, M.D., Chief Medical Officer of Onconova. "We will provide additional details on the design of this trial and the full Phase 2 data set supporting our pivotal study plans at upcoming meetings and scientific conferences later in 2016."

Onconova is developing rigosertib for patients with MDS where there is a paucity of therapeutic options. Two hypomethylating agents (HMAs), azacitidine and decitabine, the mainstays for eligible 1st-line patients, were approved by the FDA more than a decade ago. In addition to the oral rigosertib and azacitidine combination program, Onconova is currently enrolling patients in the global, pivotal Phase 3 INSPIRE trial of IV rigosertib for 2nd-line MDS patients, who have failed HMA therapy. This trial of 225 patients is now enrolling in the U.S., Europe, Japan and Australia.

About Oral Rigosertib

The oral form of rigosertib provides a more convenient dosing for use where the duration of treatment may extend to multiple years. To date, more than 350 patients have been treated with the oral formulation of rigosertib, either as a single agent or in combination with other drugs. Phase 1 studies with oral rigosertib were conducted in hematological malignancies, lower-risk MDS and solid tumors. Combination therapy of oral rigosertib with azacitidine and chemoradiotherapy has also been explored.

About Trial 09-08 (NCT01926587): Combination therapy with oral rigosertib and azacitidine

The current standard of care for higher-risk MDS patients is one of two approved hypomethylating agents (Azacitidine and Decitabine, approved by the FDA in 2004 and 2006). Although these drugs are currently the mainstays in HR-MDS therapy, their overall response rate and duration of benefit is limited to a subset of eligible patients and all responding patients ultimately progress. Therefore, there is an urgent need for developing therapeutic options for newly diagnosed MDS patients. The 09-08 Phase 1/2 trial tested oral rigosertib in combination with injectable azacitidine in a dose ranging study (Phase 1), followed by an expansion cohort (Phase 2) to evaluate the efficacy and safety of the combination. Interim results from this trial were presented at the 2015 ASH (Free ASH Whitepaper) conference indicating that the combination was generally well tolerated and that clinical responses were observed in 23 of 30 MDS patients evaluable for efficacy assessment.1 Both 1st-line and 2nd-line patients were included in this study.

Corvus Pharmaceuticals Announces Preclinical and Preliminary Clinical Biomarker Data of Lead Oral Checkpoint Inhibitor CPI-444 Presented at Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference

On September 25, 2016 Corvus Pharmaceuticals, Inc. (NASDAQ: CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of novel immuno-oncology therapies, reported preclinical data as well as preliminary biomarker data from its ongoing Phase 1/1b study of CPI-444 as a single agent and in combination with Genentech’s TECENTRIQ (atezolizumab), a fully humanized monoclonal antibody targeting protein programmed cell death ligand 1 (PD-L1) (Filing, 8-K, Corvus Pharmaceuticals, SEP 26, 2016, View Source [SID:SID1234515364]). CPI-444 is a selective and potent inhibitor of the adenosine A2A receptor. The data were presented today in both oral and poster presentations by Stephen Willingham, Ph.D., Corvus senior scientist, at the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (CIMT) (Free CIMT Whitepaper): Translating Science into Survival, which is taking place in New York at the Sheraton New York Times Square Hotel and the New York Hilton Midtown.

"We are very encouraged by the early data showing that CPI-444 is well tolerated and by the biomarker data indicating that treatment with CPI-444 as a single agent is associated with activation of T-cells detected in the blood. We believe this is the first demonstration of immune modulation in cancer patients receiving an adenosine antagonist," said Richard A. Miller, M.D., an oncologist and co-founder, president and chief executive officer of Corvus. "Patient enrollment in our CPI-444 Phase 1/1b study is on schedule, and we anticipate completing the dose-selection portion of the study and reporting interim safety and efficacy data at a scientific conference later this year. That data will enable us to choose the best dose for testing in disease-specific expansion cohorts, which we expect to initiate before year end."

According to preclinical study results presented at the Conference:

· CPI-444 has been shown to be active, both as a single agent and in combination with anti-PD-1 and anti-PD-L1 antibodies, in stimulating various immune cells, generating anti-tumor immunity, suppressing tumor growth, delaying tumor progression and generating complete tumor rejection in multiple animal models of cancer.
· Results from mechanism of action studies indicate that CD8+ cytotoxic T-lymphocytes are necessary for CPI-444’s activity in animal models.
· Long-term immunity was demonstrated upon tumor re-challenge in animals previously treated with CPI-444.

Preliminary biomarker data from ongoing analyses of patients with various solid tumors treated to date in the ongoing Phase 1/1b study presented at the Conference demonstrated:

· In the first 11 patients analyzed, 40-100 percent blockade of peripheral blood lymphocyte A2A receptors was achieved in a dose-dependent manner with CPI-444 treatment.
· All three patients receiving CPI-444 100 mg twice daily for 28 days achieved 90-100 percent continuous, sustained blockade of peripheral blood lymphocyte A2A receptors.
· Pharmacodynamic markers on peripheral blood lymphocytes showed evidence of activation of T-cell mediated immunity in all three patients treated with CPI-444 100 mg twice daily for 28 days. In these patients, increases in cytotoxic T-lymphocytes that were both PD-1-positive and CD8-positive (double positive) were seen in the blood following 28 days of treatment compared to baseline pretreatment. Previous research from others has shown that PD-1, CD8 double positive T-cells are associated with anti-tumor immune responses.
· CPI-444 has been well tolerated to date, with no drug-related dose limiting toxicities or serious adverse events observed.
· The trial is currently enrolling patients at 25 sites in the United States, Canada and Australia with 39 patients enrolled to date.

About the Phase 1/1b Trial
The Phase 1/1b trial is designed to examine the activity of CPI-444 as a single agent and in combination with Genentech’s TECENTRIQ (atezolizumab), an anti-PD-L1 antibody. The first part of the study (dose-selection) includes four cohorts of 12 patients each — three cohorts treated with single agent CPI-444 (100 mg twice daily for 14 days; 100 mg twice daily for 28 days; 200 mg once daily for 14 days) and one cohort treated with the combination (CPI-444 50 mg or 100 mg twice daily for 14 days combined with TECENTRIQ). A treatment cycle is 28 days. Patients with non-small cell lung cancer, melanoma, renal cell cancer, triple-negative breast cancer, colorectal cancer, head and neck cancer, bladder cancer and prostate cancer who have failed all standard therapies are eligible. Based on safety and biomarker analyses, an optimum single agent and combination dose will be selected. The second part of the study will evaluate CPI-444 as a single agent in five disease-specific cohorts, and CPI-444 in combination with TECENTRIQ in five additional matched disease-specific cohorts. Corvus expects that each of these 10 cohorts will initially enroll 14 patients, but each cohort may be expanded based on efficacy.

Idera Pharmaceuticals Reports Promising Data from Ongoing Phase 1 Dose Escalation in Clinical Trial of Intra-tumoral IMO-2125 in Combination with Ipilimumab in Patients with PD-1 Refractory Metastatic Melanoma

On September 26, 2016 Idera Pharmaceuticals, Inc. (NASDAQ:IDRA), a clinical-stage biopharmaceutical company developing Toll-like receptor and RNA therapeutics for patients with cancer and rare diseases, reported initial clinical data from its ongoing Phase 1/2 clinical trial of intra-tumoral IMO-2125, a Toll-like receptor (TLR) 9 agonist (Press release, Idera Pharmaceuticals, SEP 26, 2016, View Source [SID:SID1234515362]). In this arm of the Phase 1 portion of the trial, IMO-2125 is being evaluated in combination with ipilimumab for treatment of patients with metastatic melanoma who have failed prior PD-1 therapy. These early results indicate that IMO-2125 is demonstrating promising clinical activity and is being well tolerated in a patient population with minimal options and low expectation of clinical response with ipilimumab treatment alone. Further clinical information from the ongoing dose escalation portion of the trial, as well as detailed information on the translational results, will be presented during an oral session at the 2016 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting beginning November 9th in Maryland.

"We have completed extensive pre-clinical work in a broad scope of tumor types to test the hypothesis of intra-tumoral administration of IMO-2125 inducing a meaningful effect on the tumor microenvironment and potentiating local and systemic tumor regression in patients. This work gave us confidence to test the ability of IMO-2125, beginning with this current study in PD-1 refractory metastatic melanoma patients," stated Vincent Milano, Idera’s Chief Executive Officer.

"We are energized by the early results from this ongoing trial and have been solidifying our plans to accelerate the program as we believe there is a clear path to bring IMO-2125 to melanoma patients who have not benefited from checkpoint inhibition alone and open an opportunity to establish IMO-2125 as the agent of choice to activate the tumor microenvironment and potentially improve outcomes for patients," Milano added. "Following a full strategic review, we have decided to prioritize the IMO-2125 program and explore strategic options for IMO-8400 in B-cell lymphoma."

Current Data Analysis

Safety

10 patients in 3 dosing cohorts (4mg, 8mg and 16mg) have been dosed and are assessable for safety, as of the September 19, 2016 cutoff date;

IMO-2125 in combination with ipilimumab is being generally well tolerated at all 3 dose levels studied to date;

Immune related adverse events have been observed in 3 subjects: 2 responding patients have experienced hypophysitis and 1 patient has discontinued the study due to a recurrence of immune related hepatitis previously observed on prior therapy with ipilimumab;

No dose limiting toxicities (DLTs) have been identified to date and the study is currently enrolling at the highest (32mg) dosing cohort in combination with ipilimumab.
Clinical activity

6 patients treated in the first 2 dosing cohorts (4mg and 8mg) are assessable for initial clinical activity, as of the September 19, 2016 cutoff date;

3 of the 4 patients with cutaneous melanoma are responders with one Complete Response (CR) and 2 Partial Responses (PR);

2 patients with mucosal melanoma experienced Progressive Disease (PD).
Translational observations

Translational data seen through the first two dosing cohorts is promising relative to the induction of immune responses;

Detailed information on the translational findings from biopsies taken in the first 2 dosing cohorts and the relationship of these to clinical response is the subject of an accepted oral presentation on November 11, 2016 at the 2016 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting by Cara Haymaker, Ph.D., University of Texas, MD Anderson Cancer Center.
"The degree of activity we’ve seen so far in this trial is very exciting as these patients are very unlikely to respond to other therapies. All three responses that we’ve seen are clinically meaningful, and these patients continue to do well following treatment," stated Adi Diab, M.D., Assistant Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center.

These early results are from the Phase 1 portion of study IMO-2125-204 (NCT02644967) in which cohorts of patients with metastatic melanoma unresponsive to PD-1 inhibitor therapy are being administered escalating doses of IMO-2125 ranging from 4 mg/kg through 32 mg/kg. IMO-2125 is injected intra-tumorally into a designated tumor lesion together with a standard dosing regimen of ipilimumab given intravenously. Following determination of the recommended Phase 2 dose (RP2D) additional patients will be treated in an expansion Phase 2 portion of the study. The primary objective of the Phase 1 portion of the trial is to characterize the safety and determine a RP2D of IMO-2125 when administered intra-tumorally in combination with ipilimumab. The primary objective of the Phase 2 portion is to assess the clinical activity of IMO-2125 in combination with ipilimumab at the respective RP2D in patients. Assessment will be based on the immune-related response criteria (irRC) and additionally the traditional RECIST criteria. Serial biopsies are being taken of selected injected and non-injected tumor lesions to assess immune changes and correlate with clinical response assessments. The trial will enroll approximately 60 patients. The study is being conducted at The University of Texas MD Anderson Cancer Center and is being led by Adi Diab, M.D., Assistant Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, MD Anderson as part of a strategic research alliance announced by Idera and MD Anderson in 2015.

Business Update
Idera is also reporting that the company has chosen to suspend the clinical development of IMO-8400 for B-cell lymphomas, including studies in Waldenstroms Macroglobulinemia (WM) and Diffuse Large B-Cell Lymphoma (DLBCL), and will explore strategic options in these indications. This decision was based upon the prioritization of the clinical development plans for IMO-2125 and our assessment that the level of clinical activity seen in the WM trial does not support monotherapy, the very slow enrollment rate in DLBCL and our commercial assessment. No safety concerns have been observed with IMO-8400 in the B-cell Lymphoma program. The development of IMO-8400 in dermatomyositis continues and is not impacted by this decision.

Investor Event and Webcast
Idera will host a conference call and live webcast on Monday, September 26 at 9:00 A.M. EST to review the data being presented along with a discussion of the next steps for the IMO-2125 development program in melanoma. To participate in the conference call, please dial (844) 882-7837 (domestic) and (574) 990-9824 (international). The webcast can be accessed live or in archived form in the "Investor’s" section of the company’s website at www.iderapharma.com. The company has also posted a slide presentation to the Idera corporate website in the "Investors" section which will be referenced during the conference call. Additionally the company has updated its corporate presentation which has also been posted to the Idera corporate website in the "Investors" section.

About Toll-like Receptors and Idera’s Immuno-Oncology Research Program
Toll-like receptors (TLRs) play a central role in the innate immune system, the body’s first line of defense against invading pathogens, as well as damaged or dysfunctional cells including cancer cells. The innate immune system is also involved in activating the adaptive immune system, which marshals highly specific immune responses to target pathogens or tissue. Cancer cells may exploit regulatory checkpoint pathways to avoid being recognized by the immune system, thereby shielding the tumor from immune attack. Checkpoint inhibitors such as agents targeting CTLA4 or programmed cell death protein 1 (PD1) are designed to enable the immune system to recognize tumor cells. In this setting, intra-tumoral TLR9 agonist administration may increase the tumor-infiltrating lymphocytes (TILs), and thereby potentiate anti-cancer activity of checkpoint inhibitors in the injected tumor as well as systemically.

Idera’s TLR9 agonist, IMO-2125 has been created using the company’s proprietary chemistry-based discovery platform. IMO-2125 has been shown to activate dendritic cells and induce interferon. Idera selected IMO-2125 to advance into clinical development in combination with checkpoint inhibitors based on this immunological profile. In previously completed clinical trials, subcutaneous administration of IMO-2125 was generally well tolerated in about 80 patients with hepatitis C. Idera has conducted further preclinical research evaluating the potential of IMO-2125 to enhance the anti-tumor activity of other checkpoint inhibitors in cancer immunotherapy with data being presented at several medical conferences during the past twelve months. The posters from these presentations can be found at View Source

About Metastatic Melanoma
Melanoma is a type of skin cancer that begins in a type of skin cell called melanocytes. As is the case in many forms of cancer, melanoma becomes more difficult to treat once the disease has spread beyond the skin to other parts of the body such as by through the lymphatic system (metastatic disease). Melanoma accounts for only one percent of skin cancer cases, but causes a large majority of skin cancer deaths. The American Cancer Society estimates that in 2016, there will be 76,380 new cases of melanoma in the U.S., and about 10,130 will die of this disease.

MD Anderson Cancer Center and Adaptimmune Form Strategic Alliance to Advance Development of Immunotherapies Targeting Multiple Cancers

On September 26, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, and The University of Texas MD Anderson Cancer Center reported that they have entered into a multi-year strategic alliance designed to expedite the development of novel adoptive T-cell therapies for multiple types of cancer (Press release, Adaptimmune, SEP 26, 2016, View Source [SID:SID1234515360]).

The alliance pairs MD Anderson’s preclinical and clinical teams with Adaptimmune’s scientists and proprietary SPEAR (Specific Peptide Enhanced Affinity Receptor) T-cell technology platform, which enables Adaptimmune to identify targets expressed on solid and hematologic cancers and to develop affinity enhanced T-cell receptors (TCRs) with optimal potency and specificity against them.

The teams will collaborate in a number of areas including preclinical and clinical development of Adaptimmune’s SPEAR T-cell therapies targeting MAGE-A10 and future clinical stage first and second generation SPEAR T-cell therapies such as MAGE-A4 across a number of cancers, including bladder, lung, ovarian, head and neck, melanoma, esophageal and gastric cancers. The alliance will also drive research and development of other new SPEAR TCR therapies to targets in other tumor types such as breast cancers and facilitate clinical study participation by MD Anderson in other Adaptimmune trials. Access to MD Anderson’s tumor repository will guide further target selection and clinical trial design, while its cancer immunology cores and expertise in performing translational medicine studies may help optimize the efficacy and safety of SPEAR T-cell therapies.

"At MD Anderson, we are focused on providing the best possible care for cancer patients, including implementing important new technologies and treatment modalities," said Elizabeth Mittendorf, M.D., Ph.D., associate professor of Breast Surgical Oncology.

David Hong, M.D., associate professor of Investigational Cancer Therapeutics at MD Anderson added, "It is our hope this alliance will allow us to address numerous solid tumors and augment the patient’s immune system, directing it against tumors based on their specific molecular makeup."

"We believe that this strategic alliance will provide a strong partnership for the development of multiple new first and subsequent generation SPEAR T-cell therapies against many intractable solid tumors in our near-term clinical programs," commented Rafael Amado, Adaptimmune’s chief medical officer. "It will also generate invaluable data from patient samples that will help us understand these therapies and design the next generation of studies. We are very proud to form this alliance with the outstanding team of cancer immunologists at MD Anderson, and are confident that together we can move these novel immunotherapeutic candidates forward for patients who are fighting a variety of cancers."

AbbVie Announces Submission of a Supplemental New Drug Application for Ibrutinib (IMBRUVICA®) for Treatment of Marginal Zone Lymphoma

On September 26, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported that it submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for ibrutinib (IMBRUVICA) to treat patients with marginal zone lymphoma (MZL) (Press release, AbbVie, SEP 26, 2016, View Source [SID:SID1234515359]). MZL is a slow-growing form of non-Hodgkin’s lymphoma. The Company’s sNDA submission is based on data from a multi-center, open-label Phase II PCYC-1121-CA trial assessing ibrutinib as a single-agent treatment for MZL. If approved, MZL will be the fifth unique type of blood cancer indication for IMBRUVICA. IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company and Janssen Biotech, Inc.

"We continue to explore the use of ibrutinib in non-Hodgkin’s lymphoma, including marginal zone lymphoma and its three sub-types, given its unique mechanism of action and ability to target the B-cell receptor pathway," said Darrin Beaupre, M.D., Ph.D., Head of Early Development and Immunotherapy at Pharmacyclics. "MZL in its advanced stages is currently an incurable form of hematologic cancer and new treatment options are needed. We look forward to working with the FDA and our partners at Janssen to bring this promising treatment to patients with MZL."

The Phase II PCYC-1121-CA trial is a Pharmacyclics-sponsored study that enrolled 63 previously treated patients with MZL, including splenic MZL (SMZL), nodal MZL (NMZL) and extranodal MZL (EMZL), in the U.S., EU and other regions. Patients received monotherapy ibrutinib orally, once daily until progression or unacceptable toxicity. The primary endpoint of the study was overall response rate as assessed by an Independent Review Committee. A key secondary endpoint was safety.

These clinical data have been submitted for publication in a peer-reviewed journal and presentation at an upcoming medical conference. More information about the study can be found on www.clinicaltrials.gov.

IMBRUVICA is currently approved to treat patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including patients with 17p deletion, patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia (WM).

About Marginal Zone Lymphoma
Marginal zone lymphoma (MZL) is a slow-growing B-cell lymphoma arising from white blood cells (lymphocytes) at the edges of lymphoid tissue.1 MZL accounts for approximately 12 percent of all cases of non-Hodgkin’s lymphoma in adults, and the median age of diagnosis is 65 years old.2 There are currently no approved treatments or standards of care specifically indicated for patients with MZL.2

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK). 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.3,4 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.3

IMBRUVICA is approved to treat patients with CLL/SLL including patients with 17p deletion, patients with MCL who have received at least one prior therapy and patients with WM. 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.3

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 and other serious illnesses. 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 postsurgery 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.

Please see Full Prescribing Information: View Source