On June 25, 2018 Sophiris Bio Inc. (NASDAQ: SPHS) (the "Company" or "Sophiris"), a biopharmaceutical company studying topsalysin (PRX302), a first-in-class, pore-forming protein, in late stage clinical trials for the treatment of patients with urological diseases, reported top-line interim safety and biopsy data following a single administration of topsalysin from its ongoing open-label, Phase 2b clinical trial (Press release, Sophiris Bio, JUN 25, 2018, View Source [SID1234527461]). A single administration of topsalysin continues to demonstrate an ability to ablate targeted prostate cancer cells with 10 of 35 patients (29%) demonstrating a clinical response of which 6 patients had a complete ablation with no detectable cancer on targeted biopsy of the treated area. Separately, Sophiris was recently notified that a patient death occurred on the same day as their second administration. The company is currently investigating the cause and as a precaution no additional patients will receive a second administration of topsalysin.

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"We are extremely saddened by the death of a patient after receiving a second administration of topsalysin," said Randall E. Woods, president and CEO of Sophiris. "Understanding the cause of the patient’s death is our first priority and essential to determining the potential for re-administration of topsalysin in future clinical trials."

To date, over 450 patients have received a single administration of topsalysin at various doses. The drug continues to appear to be well-tolerated in patients who received a single administration, with no new safety signals reported. In addition, biopsy data from the Phase 2b trial demonstrated that 29% (10/35) of patients sustained a clinical response at six-month follow-up – defined as no detectable tumor following targeted biopsy of the treated lesion or a reduction in the tumor to clinically insignificant.

"We are very encouraged by the safety and biopsy results from a single administration of topsalysin in the Phase 2b study. Biopsy results improved from what we saw in the Phase 2a proof of concept trial and safety and tolerability remains in-line with what we have seen historically," stated Mr. Woods. "We believe that the safety and biopsy data from the first administration of topsalysin supports moving forward into potential registration studies. We will continue to evaluate whether future clinical development will include an option to administer a second dose as we receive more information about the patient death and additional information from the 10 patients who received a second dose. We will be able to evaluate this towards the end of this year."

Top-Line Interim Safety Results from a Single Administration of Topsalysin:

The primary objective of this trial is to evaluate the safety and tolerability of a single, and if applicable, a second administration of topsalysin, when used to focally ablate a histologically-proven, clinically-significant lesion in patients with localized prostate cancer.

To date, a single administration of topsalysin continues to appear safe and well tolerated by patients. No hypersensitivity reactions or other serious systemic reactions to study medication were observed after a single administration. Adverse events considered related to topsalysin and occurring in more than one patient were: dysuria (n=3 patients), urinary retention (n=3 patients), nocturia (n=2 patients), micturition urgency (n=2 patients) and strangury (n=2 patients). All adverse events were considered mild and typically resolved within the same day. One event of micturition urgency was considered severe and resolved the same day and one event of urinary retention was considered moderate and the event was considered resolved after the patient underwent a transuretheral resection of the prostate.

In May 2018, an independent data monitoring committee (IDMC) met to review the safety data from all 38 patients administered a single dose of topsalysin as well the safety data available on the first seven patients who received a second administration of topsalysin. At that time, the IDMC unanimously recommended the clinical trial continue without changes to the protocol.

Top-Line Interim Biopsy Results From a Single Administration of Topsalysin:

A secondary objective of the study is to evaluate the efficacy of a single administration of topsalysin and, if applicable, a second administration of topsalysin to selectively target and focally ablate a pre-identified lesion.

In the Phase 2b clinical trial, 38 patients with pre-identified, clinically-significant low-to-intermediate risk localized prostate cancer received a single administration of topsalysin. Six months after administration, patients received a follow-up targeted biopsy of the treated lesion. At the time of this release, targeted follow-up biopsies have been undertaken and evaluated from 35 of 38 patients treated with a single dose of topsalysin. Two of the remaining patients are expected to receive follow-up biopsies in the coming weeks.

Based on the six-month follow-up biopsy results, 29% of patients (10/35) demonstrated a clinical response, defined in this study as no detectable tumor on targeted biopsy of the treated lesion or a sufficient reduction to deem the lesion clinically-insignificant (cancer lesion of Gleason Score 6 (3+3) and a Maximum Cancer Core Length (MCCL) of less than 6 millimeters). This compares favorably to 17% of patients (3/18) moving to clinically-insignificant disease in the previously completed Phase 2a localized prostate cancer study. Of the 10 clinical responders in the Phase 2b trial, six experienced a complete ablation with no histological evidence of the tumor remaining.

Additionally, the Phase 2b single administration follow-up biopsy data show that:

37% of patients (13/35) experienced a partial response, defined as a reduction in MCCL and/or Gleason pattern, but the targeted lesion was still deemed clinically-significant.
34% (12/35) of patients did not respond to treatment defined as no change in the targeted lesion or an increase in MCCL and/or Gleason pattern
"The initial biopsy results released today, following a single intraprostatic administration of topsalysin are highly encouraging and definitely improve upon the Proof of Concept study results with a greater proportion of patients experiencing successful treatment of their treated lesion," stated Dr. Hashim Ahmed, the study’s chief investigator and chair of urology & consultant urological surgeon, Imperial College Healthcare NHS Trust & professor urology Imperial College. "Importantly, we have shown that the targeted intraprostatic injection of a single administration of topsalysin continues to appear safe and well tolerated. Furthermore, targeted focal therapy with topsalysin in this patient population is transferable to other clinicians with at least half of the clinical sites observing patients with no detectable lesion on re-biopsy of the targeted tumor and all eight sites observing patients in which lesions were at least partially ablated."

"Advances in the imaging of the prostate – by virtue of MRI – and the precise risk-stratification that this now permits has opened up new therapeutic opportunities for men with low-intermediate risk prostate cancer," stated Professor Mark Emberton, Dean University College London Faculty of Medical Sciences. "Men truly welcome the opportunity to undergo a targeted treatment of their prostate cancer (often in an ambulatory setting) without exposure to the commonly occurring side-effects of urinary incontinence, sexual dysfunction and rectal symptoms that have tended to accompany the more traditional approaches of surgery and radiotherapy. Topsalysin is beginning to show the spectrum of attributes we would want to see in a prostate cancer treatment of the future."

Administration of a Second Topsalysin Dose:

The Phase 2b prostate cancer study represents the first trial designed to allow qualified patients to receive a second administration of topsalysin six months after initial treatment. To be eligible to receive a second administration, patients could not have experienced a clinically-significant adverse event attributable to either topsalysin or the dosing procedure. Additionally, patients must have demonstrated evidence of a response to treatment with topsalysin, either through a reduction in lesion size, Gleason pattern, or MCCL. The objective of re-administering topsalysin is to determine if additional clinical benefit is observed.

Eleven patients elected to receive a second dose of topsalysin. The patients will continue to be monitored per the trial’s protocol and data are expected to be available in the fourth quarter of 2018.

Webcast scheduled for today at 11:00 a.m. Eastern Time

The Sophiris management team will host a conference call and webcast today, June 25, at 11:00 a.m. Eastern Time to review the topsalysin prostate cancer data. Dr. Hashim Ahmed, Chair of Urology, Imperial College of London & Imperial College Healthcare NHS Trust and investigator for the Phase 2b clinical trial will also participate in the call.

A live audio webcast will be accessible on the "Investor Relations" page of the Sophiris corporate website at www.Sophirisbio.com. A replay will be available at the same location.

About Localized Prostate Cancer

Prostate cancer is the second most common form of cancer in men in the US with an estimated 161,000 new cases in 2017. Approximately 80 percent of patients in the US are diagnosed with localized disease. Research has shown that patients with early, localized disease have a low likelihood of the cancer spreading beyond the confines of the prostate; however, many men with clinically significant localized disease choose to undergo radical treatment. Radical therapies include surgery to remove the entire prostate and/or radiation. Potential toxicities from radical treatments can be significant and permanent and include erectile dysfunction, urinary incontinence, and rectal toxicity.

About Topsalysin

Topsalysin (PRX302), an innovative, "First-in-Class" transmembrane pore-forming protein, was genetically modified to be activated only by enzymatically-active PSA, which is produced in large quantities within the prostate of men with prostate cancer. The targeted focal treatment of prostate cancer is in line with current treatment trends for solid tumors such as breast and liver, where the goal is to remove the tumor and preserve as much of the organ and organ function as possible.

Topsalysin has the potential to provide a targeted focal therapy for the ablation of localized prostate cancer lesions while potentially avoiding many of the complications and side effects associated with whole gland radical treatments. The increasing use of multiparametric magnetic resonance imaging (mpMRI) and advances in software to co-register previously obtained mpMRI images with real-time three-dimensional ultrasound images enables urologists to more accurately locate tumors within the prostate when taking biopsies. This increases the accuracy with which men with clinically significant lesions are identified. It also enables the injection of an ablative agent, such as topsalysin, directly into previously identified clinically significant tumors located within the prostate.

On June 25, 2018 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations with a primary focus in hematology and oncology, reported the company will hold a conference call on Friday, June 29th at 8:30 a.m. EDT/5:30 a.m. PDT to discuss the ROLONTIS Phase 3 ADVANCE study data being presented at Multinational Association of Supportive Care in Cancer (MASCC) 2018 annual meeting (Press release, Spectrum Pharmaceuticals, JUN 25, 2018, http://investor.sppirx.com/news-releases/news-release-details/spectrum-pharmaceuticals-host-conference-call-highlighting [SID1234527459]). The call will feature a presentation from ADVANCE study lead investigator, Lee S. Schwartzberg, M.D., FACP Professor of Medicine and Division Chief, Hematology Oncology, The University of Tennessee Health Science Center, and Executive Director, UT/West Cancer Center.

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Conference Call Details

Friday, June 29, 2018 @ 8:30 a.m. Eastern/5:30 a.m. Pacific

Domestic: (877) 837-3910, Conference ID# 6798817

International: (973) 796-5077, Conference ID# 6798817

The conference call will also be webcast live. To access the webcast and additional documents related to the call, please visit the Investor Relations page of the Spectrum Pharmaceutical website at View Source

For interested individuals unable to join the call, a webcast replay will be available online from June 29, 2018, @ 11:30 a.m. ET/8:30 a.m. PT through July 6, 2018 until 11:30 a.m. ET/8:30 a.m. PT.

Domestic Replay Dial-In #: (855) 859-2056, Conference ID# 6798817

International Replay Dial-In #: (404) 537-3406, Conference ID# 6798817

On June 25, 2018 Pfizer reported overall survival (OS) results from the Phase 3 PALOMA-3 trial, which evaluated IBRANCE (palbociclib) in combination with fulvestrant compared to placebo plus fulvestrant in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer whose disease has progressed after prior endocrine therapy (Press release, Pfizer, JUN 25, 2018, View Source [SID1234527458]). The results demonstrated a positive trend in the hazard ratio favoring the IBRANCE combination, although this trend did not reach statistical significance. Overall survival is a secondary endpoint of the PALOMA-3 trial and, as such, the trial design was not optimized to detect a statistically significant difference in OS.

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"While the difference in overall survival narrowly missed the threshold for statistical significance – a high bar for any trial in this patient population – it is similar, in absolute terms, to the improvement in median progression-free survival previously demonstrated in this trial.1 We are encouraged by these results, which build on the compelling clinical benefit delivered by IBRANCE," said Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development. "IBRANCE in combination with endocrine therapy has transformed the treatment landscape for patients with HR+, HER2- metastatic breast cancer."

PALOMA-3 met its primary endpoint of progression-free survival (PFS) at interim analysis and results were published in The New England Journal of Medicine in June 2015; updated PFS data were later presented at the 2016 San Antonio Breast Cancer Symposium. The trial demonstrated a statistically significant and clinically meaningful improvement in PFS for IBRANCE plus fulvestrant compared to placebo plus fulvestrant. PFS is a well-established measure of clinical benefit in metastatic breast cancer trials.2 IBRANCE in combination with fulvestrant has been approved in more than 80 countries around the world based on the PFS demonstrated in PALOMA-3.

"The duration of the survival in hormone receptor-positive metastatic breast cancer patients, and the potential for subsequent therapies to confound overall survival outcomes, make demonstrating statistically significant improvement in overall survival extremely difficult," said Nicholas Turner, M.D., Ph.D., professor of molecular oncology at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden NHS Foundation Trust, as well as principal investigator of the PALOMA-3 trial. "The results from this overall survival analysis support the strong progression-free survival results from PALOMA-3 and, while not statistically significant, are encouraging for physicians and patients. We look forward to presenting the detailed data at an upcoming medical meeting."

The most common adverse reactions in PALOMA-3 included neutropenia, leukopenia, infections, fatigue and nausea; no new safety signals were identified as part of this final OS analysis.

IBRANCE in combination with endocrine therapy is a standard of care for HR+, HER2- metastatic breast cancer. IBRANCE has been prescribed to more than 120,000 patients globally to date.

The full prescribing information for IBRANCE can be found at www.pfizer.com.

About IBRANCE (palbociclib) 125 mg capsules

IBRANCE is an oral inhibitor of CDKs 4 and 6,3 which are key regulators of the cell cycle that trigger cellular progression.4,5 In the U.S., IBRANCE is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy.

IMPORTANT IBRANCE (palbociclib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Neutropenia was the most frequently reported adverse reaction in PALOMA-2 (80%) and PALOMA-3 (83%). In PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 15 of first 2 cycles and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (80% vs 6%), infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis (30% vs 14%), diarrhea (26% vs 19%), anemia (24% vs 9%), rash (18% vs 12%), asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting (16% vs 17%), decreased appetite (15% vs 9%), dry skin (12% vs 6%), pyrexia (12% vs 9%), and dysgeusia (10% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and anemia (5% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were decreased WBC (97% vs 25%), decreased neutrophils (95% vs 20%), anemia (78% vs 42%), decreased platelets (63% vs 14%), increased aspartate aminotransferase (52% vs 34%), and increased alanine aminotransferase (43% vs 30%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (66% vs 1%) and leukopenia (31% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), decreased platelets (62% vs 10%), increased aspartate aminotransferase (43% vs 48%), and increased alanine aminotransferase (36% vs 34%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg. The pharmacokinetics of IBRANCE have not been studied in patients requiring hemodialysis.

On June 25, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, and Calibr, a nonprofit drug discovery division of Scripps Research, reported a collaboration to develop T-cell therapies aimed primarily at cancer, including solid tumors (Press release, AbbVie, JUN 25, 2018, View Source [SID1234527457]).

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This collaboration broadens AbbVie’s oncology research to access advanced precision medicine technology to expand the development of potentially life-changing treatments for patients with cancer.

Chimeric Antigen Receptor T-cell (CAR-T) therapies harness the power of a cancer patient’s own immune system to attack and destroy cancer cells. Despite promising results in hematological malignancies, current CAR-T therapies in development for solid tumors have demonstrated limitations due to rapid activation and expansion of CAR-T cells that can lead to serious adverse events. Calibr’s novel cell therapy program, led by Travis Young, Ph.D., director of protein sciences at Calibr, is designed to enhance safety, versatility and efficacy through a proprietary modular "switchable" CAR-T cell that uses antibody-based switch molecules to control the activation and antigen specificity of CAR-T cells.1 Calibr’s proprietary technology may enable the development of universal CAR-T-based treatments across several types of hematological and solid tumor indications.

"Calibr has assembled a premier scientific team and developed an innovative cell therapy technology that can take us to the next frontier of cancer treatment," says Mohit Trikha, Ph.D., vice president and head of Oncology Early Development at AbbVie. "The combination of AbbVie’s oncology discovery and early development expertise and Calibr’s novel switchable CAR-T therapy platform aims to advance the current standard of care, with the potential rapidly advancing new treatment options for patients."

"We’re delighted to work together with a strong partner like AbbVie to expand the impact of the CAR-T cell field to a broader range of cancers," says Peter Schultz, Ph.D., chief executive officer of Calibr and Scripps Research.

Under the terms of the license agreement, AbbVie will pay Calibr an upfront license fee and gain exclusive access to Calibr’s switchable CAR-T platform for a term of up to four years. The two organizations will work together to develop T-cell therapies directed to solid tumor targets identified by AbbVie. AbbVie also has the option to develop additional cell therapies toward AbbVie-nominated targets and license existing Calibr cell therapy programs under development for hematological and solid cancers, including Calibr’s lead program. Calibr plans to enter this lead candidate into clinical studies for lymphoma in 2019. In addition, the agreement provides AbbVie with an option to acquire an exclusive license to Calibr’s switchable CAR-T platform and programs within the first four years of the collaboration. The companies will share responsibility for preclinical development, with AbbVie responsible for clinical development and commercialization, and Calibr eligible to receive success-based milestone payments and royalties. The transaction is subject to clearance under the Hart-Scott-Rodino Antitrust Improvements Act.

On June 25, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported the U.S. Food and Drug Administration (FDA) has accepted for Priority Review a supplemental New Drug Application (sNDA) for IMBRUVICA (ibrutinib) in combination with rituximab (RITUXAN) as a new treatment option for Waldenström’s macroglobulinemia (WM), a rare and incurable form of blood cancer (Press release, AbbVie, JUN 25, 2018, View Source [SID1234527455]).1 If approved, the sNDA would expand the prescribing information of IMBRUVICA in WM beyond its current approved use as a single agent for all lines of therapy to include combination use with rituximab. As a single-agent therapy, IMBRUVICA is the first and only FDA-approved treatment available for patients with WM. IMBRUVICA is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

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"We are excited about the data from the Phase 3 iNNOVATE study, which indicate that IMBRUVICA plus rituximab was able to improve progression-free survival, versus rituximab alone, across all lines of therapy and Waldenström’s macroglobulinemia patient subgroups that were studied," said Thorsten Graef, M.D., Ph.D., Head of Clinical Development at Pharmacyclics LLC, an AbbVie company. "These promising findings build on our commitment to exploring the full potential of IMBRUVICA alone and in combination with other treatments. If approved, this chemotherapy-free combination will provide another treatment opportunity for patients living with this rare disease, which continues to have very limited treatment options."

The sNDA is supported by data from the Phase 3 iNNOVATE (PCYC-1127) trial assessing IMBRUVICA in combination with rituximab, versus rituximab alone, in patients with previously untreated and relapsed/refractory WM. These data were recently presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting and simultaneously published in The New England Journal of Medicine.

Waldenström’s macroglobulinemia is a rare and incurable form of non-Hodgkin’s lymphoma (NHL). There are about 2,800 new cases of WM in the U.S. each year.1 In January 2015, IMBRUVICA received FDA approval for all lines of treatment in WM and as the first and only FDA-approved therapy specifically indicated for this disease.

About iNNOVATE
iNNOVATE is a Pharmacyclics-sponsored, randomized, placebo-controlled, double-blind, Phase 3 study, which enrolled 150 patients with relapsed/refractory and treatment-naïve Waldenström’s macroglobulinemia. Patients were randomized to receive intravenous rituximab 375 mg/m2 once weekly for four consecutive weeks, followed by a second four-weekly rituximab course following a three-month interval. All patients received either ibrutinib 420 mg or placebo once daily continuously until criteria for permanent discontinuation were met. The primary endpoint was progression-free survival, with secondary objectives including overall response rate, hematological improvement measured by hemoglobin, time-to-next treatment, overall survival and number of participants with adverse events as a measure of safety and tolerability within each treatment arm.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking 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 as well as other serious, debilitating conditions.2 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).3

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with previously treated CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.4 IMBRUVICA was one of the first medicines to receive 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. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, 100,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

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 non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0 to 1% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 0 to 6% of patients. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias 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 anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (range, 3 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, 2 to 13%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., 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. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (62%)*, neutropenia (61%)*, diarrhea (43%), anemia (41%)*, musculoskeletal pain (30%), bruising (30%), rash (30%), fatigue (29%), nausea (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%)*, thrombocytopenia (16%)*, and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9 % (WM [6%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustment may be recommended.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS
Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.