On July 11, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported an update on a Phase 3 study (DBL3001) of ibrutinib (IMBRUVICA) in untreated (treatment-naïve) diffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin lymphoma (NHL) (Press release, AbbVie, JUL 11, 2018, View Source [SID1234527647]). 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. (Janssen). IMBRUVICA has been available in the U.S. since 2013 and is FDA-approved for use in five B-cell blood cancers, as well as in chronic graft-versus-host-disease for a total of eight FDA-approved indications.

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The DBL3001 study evaluated the addition of ibrutinib to a chemotherapy regimen consisting of five different agents used in combination – rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) – versus R-CHOP plus placebo. R-CHOP is the current standard of care in newly diagnosed DLBCL patients and provided as a first-line therapy for most patients today. The study was conducted in a subset of untreated DLBCL patients identified to have the non-germinal center B cell (GCB) or activated B-cell (ABC) subtypes of this disease. Patients identified with non-GCB or ABC subtypes typically have poorer treatment outcomes and have greater unmet medical need.

At conclusion of the study, data collected found that ibrutinib plus the chemotherapy regimen, R-CHOP, was not superior to R-CHOP alone, and that the study did not meet its primary endpoint of improving event-free survival (EFS) in the targeted patient population. However, clinically meaningful improvements were observed in a patient sub-population that warrant further analysis. Full results from this study will be presented at an upcoming scientific conference and published in a peer-reviewed medical journal.

"Since its first U.S. FDA approval in 2013, IMBRUVICA has redefined standard of care in many different blood cancers – several of which had little to no treatment options available to patients before," said Thorsten Graef, M.D., Ph.D., Head of Clinical Development at Pharmacyclics LLC, an AbbVie company. "These medical achievements reflect our objective of focusing research where there is great unmet patient need and understanding that the nature of research is such that some studies succeed and others do not. We continue to believe that ibrutinib has great untapped potential as a cancer treatment alone or in combination. Together with our global partner Janssen, we are advancing our robust ibrutinib scientific development program and anticipate results from several studies in the future."

About the IMBRUVICA (ibrutinib) Clinical Program
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. IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. 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.

About Diffuse Large B-Cell Lymphoma (DLBCL)
DLBCL is a fast-growing type of non-Hodgkin lymphoma (NHL) that affects B-cell lymphocytes, a type of white blood cell.1 DLBCL is the most common form of NHL in adults, accounting for up to 40 percent of all cases worldwide.2 DLBCL can arise in lymph nodes or outside of the lymphatic system, in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain.1 There are two main subtypes of DLBCL: germinal center B-cell-like (GCB) subtype and non-GCB subtype, which includes unspecific and activated B-cell-like (ABC).3 The disease occurs more commonly in the elderly and is slightly more prevalent in men.1

About the DBL3001 Study
DLB-3001 is a Janssen-sponsored, randomized, double-blind, placebo-controlled Phase 3 study, which evaluated 838 patients with newly diagnosed DLBCL, focusing on those with non-GCB/ABC subtypes. Participants were randomly assigned to receive either placebo plus R-CHOP or ibrutinib plus R-CHOP for 6-8 cycles, 21 days per cycle.

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.4 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).5

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

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.

On July 10, 2018 Advaxis, Inc. (NASDAQ: ADXS), a late-stage biotechnology company focused on the discovery, development and commercialization of immunotherapy products, reported a clinical update, as follows (Press release, Advaxis, JUL 10, 2018, View Source [SID1234527648]):

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Plans to withdraw its Conditional Marketing Authorization Application (MAA) in the European Union for axalimogene filolisbac to treat metastatic cervical cancer in patients who progress beyond first-line therapy

Submission of an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) to study its first ADXS-HOT drug candidate for the treatment of non-small cell lung cancer (NSCLC)

Selection of prostate cancer as the second cancer type within its ADXS-HOT program to move towards the clinic, with an IND filing anticipated within the next six months

Advaxis’ regulatory action in Europe is based on European Medicines Agency (EMA) feedback following its initial review indicating the application will likely need additional data to support a conditional approval. The February 2018 submission included data from the Phase 2 GOG-0265 study in 50 patients, which showed a 12-month overall survival rate (primary efficacy endpoint) of 38% (n=19/50) in women with persistent, recurrent or metastatic carcinoma of the cervix, representing a 55% improvement over a model-predicted 12-month overall survival rate of 24.5%. As more than half of the women treated in this study had received multiple prior lines of therapy including with bevacizumab treatment, the 38% 12-month overall survival rate was unprecedented when compared against historical data.

The Company continues to believe that the results from the GOG-0265 study are clinically meaningful and provide proof-of-concept that axalimogene filolisbac demonstrated clinical activity in metastatic cervical cancer. The withdrawal of this application does not impact the ongoing clinical trials of axalimogene filolisbac. As previously communicated, Advaxis is actively seeking a partner to support the late-stage cervical cancer program.

The Company also announced that it has submitted an IND with the FDA to study its first product candidate from the ADXS-HOT program, ADXS-503, for the treatment of NSCLC. Upon allowance of the IND for ADXS-503, the Company plans to initiate an open-label, Phase 1/2 clinical trial. Further details of the study design will be provided after the IND is allowed. Advaxis expects the first patient will be dosed by the end of 2018. Additionally, Advaxis anticipates submitting a second IND from the ADXS-HOT program within the next six months, for its drug candidate referred to as ADXS-504, for the treatment of prostate cancer.

"We are pleased to submit the ADXS-503 IND and look forward to advancing our ADXS-HOT NSCLC drug candidate into the clinic. Our ADXS-HOT program leverages both the benefits of our Lm technology platform, which has shown clinical activity in earlier generation drug candidates, and the use of neoantigen targets. We believe that neoantigen-based treatments have the potential to transform cancer care, and the ADXS-HOT program allows us to develop cancer-type specific therapies across a broad range of tumor types," said Kenneth A. Berlin, President and Chief Executive Officer of Advaxis. "With our announcement today of plans for a second IND submission for an ADXS-HOT construct in prostate cancer, we feel confident we can reach proof-of-concept for these off-the-shelf therapeutics in a relatively rapid and cost-effective manner."

Advaxis affirms plans to submit a total of four INDs for drug candidates from its ADXS-HOT program by the end of calendar year 2019, resulting in Phase 1/2 studies evaluating safety, immune responses and preliminary clinical activity of four different constructs addressing four different tumor types. Beyond NSCLC and prostate cancer, the next two ADXS-HOT product candidates will be selected from breast, colorectal, bladder, ovarian and head and neck cancers.

About ADXS-HOT
ADXS-HOT is a program that leverages the Company’s proprietary Lm technology to target hotspot mutations that commonly occur in specific cancer types. ADXS-HOT drug candidates are designed to target acquired shared or "public" mutations in tumor driver genes along with other cancer-testes and oncofetal tumor-associated antigens that also commonly occur in specific cancer types. Although ADXS-HOT drug candidates have not yet been tested in patients, each product candidate has been designed to potentially treat all patients with a specific cancer type, without the need for pre-treatment biomarker testing, biopsy, DNA sequencing or diagnostic testing.

On July 10, 2018 Aravive Biologics, Inc. reported that the company has completed both the single ascending dose and repeat dose portions of its Phase 1 study of AVB-S6-500 in healthy volunteers (Press release, Aravive Biologics, JUL 10, 2018, View Source [SID1234528276]).

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The study met the safety and tolerability endpoints for the trial. As previously announced, the study also demonstrated clinical proof-of-mechanism for AVB-S6-500 in neutralizing GAS6, based on analysis of the single ascending dose portion of the study which demonstrated a dose-dependent decrease in measurable, circulating free GAS6 in serum. Aravive plans to submit full results of the study for potential presentation at a major medical meeting later in 2018. Also during the second half of 2018, the company expects to initiate the Phase 1b portion of a Phase 1b/Phase 2 trial combining AVB-S6-500 with standard-of care-therapies in patients with platinum-resistant ovarian cancer.

Elevated GAS6 levels have been associated with poor prognosis in cancer. As a decoy molecule, AVB-S6-500 has been shown to neutralize GAS6 activity by binding to that molecule with very high affinity. In doing so, AVB-S6-500 selectively inhibits triggering of the GAS6-AXL signaling pathway. In preclinical studies, GAS6-AXL inhibition has shown activity, whether achieved by a single agent (including AVB-S6-500) or through combinations of a variety of anticancer therapies including radiation therapy, immuno-oncology agents, and drugs that affect DNA replication and repair. Inhibition of the GAS6-AXL pathway has also shown potential as a strategy for the treatment of certain fibrotic diseases.

"We are pleased with the positive outcome of this first study of AVB-S6-500 in humans. The results not only demonstrated initial safety and tolerability for this therapeutic candidate but clearly showed a dose-related reduction of circulating free GAS6, a measurement that we anticipate will be highly useful as a biomarker of drug activity in future clinical studies," said Gail McIntyre Ph.D., DABT, Senior Vice President of R&D at Aravive. "We look forward to our anticipated initiation of the Phase 1b portion of our planned Phase 1b/Phase 2 studies in ovarian cancer during the second half of this year, which are designed to evaluate the anti-cancer effects of lowering of GAS6 in patients with ovarian cancer."

On July 10, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported that it will announce its second-quarter 2018 financial results on Friday, July 27, 2018, before the market opens (Press release, AbbVie, JUL 10, 2018, View Source [SID1234527630]).

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AbbVie will host a live webcast of the earnings conference call at 8 a.m. Central time (9 a.m. Eastern). It will be accessible through AbbVie’s Investor Relations website investors.abbvie.com. An archived edition of the session will be available later that day.

On July 10, 2018 Celgene Corporation (NASDAQ:CELG) reported that the Phase III IMpassion130 study, which was sponsored by Roche, met its co-primary endpoint of progression-free survival (PFS) (Press release, Celgene, JUL 10, 2018, View Source [SID1234527631]). This is the first phase III study to demonstrate a statistically significant PFS improvement in first-line metastatic or unresectable locally advanced triple negative breast cancer (TNBC), a type of breast cancer with high unmet need.

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Results demonstrated that the investigational combination of TECENTRIQ (atezolizumab) plus ABRAXANE (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) compared to ABRAXANE monotherapy, as an initial (first-line) treatment, significantly reduced the risk of disease worsening or death (PFS) in patients with metastatic or unresectable locally advanced TNBC in the intention-to-treat (ITT) and PD-L1 positive populations. Overall survival is encouraging in the PD-L1 positive population at this interim analysis, and follow up will continue until the next planned analysis. Safety in the TECENTRIQ plus ABRAXANE arm appeared consistent with the known safety profiles of the individual medicines, and no new safety signals were identified with the combination.

"The IMpassion130 results are extremely encouraging for patients with this highly aggressive form of breast cancer for which there are limited options," said Jay Backstrom, M.D., Chief Medical Officer for Celgene. "This is the third positive Phase III study to demonstrate a clinical benefit with TECENTRIQ plus ABRAXANE as part of a treatment regimen; the other studies evaluated this investigational combination in non-small cell lung cancer patients. These data demonstrate the potential role of ABRAXANE as a preferred chemotherapy partner for immunotherapy combinations."

Results will be presented at an upcoming medical meeting.

ABRAXANE is not approved in combination with TECENTRIQ for any indication in any geography.

About the IMpassion130 Study

IMpassion130 is a Phase III multicenter, randomized, double-blind study evaluating the efficacy, safety, and pharmacokinetics of TECENTRIQ and ABRAXANE compared with placebo in combination with ABRAXANE in people with locally advanced or metastatic TNBC who have not received prior systemic therapy for metastatic breast cancer. The study enrolled 902 people who were randomized equally (1:1). The co-primary endpoints were progression-free survival (PFS) per investigator assessment (RECIST 1.1) and overall survival (OS). PFS and OS were assessed in all randomized participants [intention-to-treat (ITT)] and in those whose disease expressed the PD-L1 protein. Secondary endpoints included objective response rate, duration of response and time to deterioration in Global Health Status/Health-Related Quality of Life.

During the treatment duration, people in:

Arm A received TECENTRIQ at a fixed dose of 840 milligrams via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle and ABRAXANE at a dose of 100 milligrams per square meter via IV infusion on Days 1, 8, and 15 of each 28-day cycle. ABRAXANE was administered for a target of at least 6 cycles, with no maximum. Participants received both agents until unacceptable toxicity or disease progression.
Arm B received ABRAXANE at a dose of 100 milligrams per square meter via IV infusion on Days 1, 8, and 15 of each 28-day cycle. ABRAXANE was administered for a target of at least 6 cycles, with no maximum, and placebo was administered via IV infusion on Days 1 and 15 of each 28-day cycle. Participants received both agents until unacceptable toxicity or disease progression.
About Triple Negative Breast Cancer

Breast cancer is the second most common cancer among women in the United States. According to the American Cancer Society, it is estimated that about 266,000 American women will be diagnosed with invasive breast cancer in 2018, and nearly 41,000 will die from the disease. Approximately 10-20 percent of breast cancers are triple negative breast cancer (TNBC). TNBC is an aggressive form of the disease with a high unmet need. It can be more difficult to treat because it is not sensitive to hormone therapy or medicines that target HER2.

TECENTRIQ is a registered trademark of Genentech, a member of the Roche Group.

About ABRAXANE

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Important Safety Information for ABRAXANE

WARNING – NEUTROPENIA

Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

CONTRAINDICATIONS

Neutrophil Counts

ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1500 cells/mm3
Hypersensitivity

Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS

Hematologic Effects

Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC) and 47% of patients with non-small cell lung cancer (NSCLC)
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 for NSCLC
Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3
In the case of severe neutropenia ( < 500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC
In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level > 1500 cells/mm3 and platelets recover to a level > 100,000 cells/mm3
In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle
Nervous System

Sensory neuropathy is dose- and schedule-dependent
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC followed by a dose reduction for all subsequent courses of ABRAXANE
Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug
Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression
For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment
Albumin (Human)

ABRAXANE contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D

ABRAXANE can cause fetal harm when administered to a pregnant woman
If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE
Use in Men

Men should be advised not to father a child while receiving ABRAXANE
ADVERSE REACTIONS

Randomized Metastatic Breast Cancer (MBC) Study

The most common adverse reactions (≥20%) with single-agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, < 1%), nausea (any 30%, 22%; severe 3%, < 1%), diarrhea (any 27%, 15%; severe < 1%, 1%) and infections (24%, 20%), respectively
Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients
Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, < 1%), mucositis (any 7%, 6%; severe < 1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe < 1%, < 1%), neutropenic sepsis ( < 1%, < 1%), and injection site reactions ( < 1%, 1%), respectively. Dehydration and pyrexia were also reported
Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)
In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)
Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension
Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported
Non-Small Cell Lung Cancer (NSCLC) Study

The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue
The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)
The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)
The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)
The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%)
The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group
Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively
Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively
Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin
Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations

Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration
DRUG INTERACTIONS

Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS

Nursing Mothers

It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pediatric

The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated
Geriatric

A higher incidence of epistaxis, diarrhea, dehydration, fatigue, and peripheral edema was found in patients 65 years or older who received ABRAXANE for MBC in a pooled analysis of clinical studies
Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC
Renal Impairment

There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance < 30 mL/min)
DOSAGE AND ADMINISTRATION

Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN
For MBC and NSCLC, reduce starting dose in patients with moderate to severe hepatic impairment
Dose reductions or discontinuation may be needed based on severe hematologic or neurologic toxicity
Monitor patients closely