On December 7, 2019 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported results from an extended follow-up analysis of the Phase 3 E1912 clinical study – designed and conducted by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI), which is part of the National Institutes of Health. Study results showed superior progression-free survival (PFS) and overall survival (OS) in patients with chronic lymphocytic leukemia (CLL) new to treatment (Press release, AbbVie, DEC 7, 2019, View Source [SID1234552036]).

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These results demonstrated the benefits of IMBRUVICA (ibrutinib) plus rituximab compared to a standard chemoimmunotherapy regimen of fludarabine, cyclophosphamide and rituximab (FCR) for previously untreated patients with CLL aged 70 years or younger. These results were featured today in the CLL Therapy Oral Presentation Session at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, and served as the basis of the recent supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) to expand further the IMBRUVICA prescribing label in CLL.

Additionally, a new integrated analysis of up to six years of long-term follow-up from the Phase 3 RESONATE and RESONATE-2 studies will be presented on December 8 at the ASH (Free ASH Whitepaper) Annual Meeting, evaluating the use of IMBRUVICA monotherapy in previously untreated patients. Results showed better PFS, OS and overall response rate (ORR), with good tolerability compared to use in the relapsed/refractory (R/R) setting.

"These latest findings add to the extensive clinical evidence supporting the use of IMBRUVICA, the most comprehensively studied BTK inhibitor in CLL, as both a single-agent and as a combination regimen to improve patient outcomes in early lines of treatment, which has previously been reserved for chemoimmunotherapy," said Danelle James, M.D., M.A.S., IMBRUVICA Clinical Development Lead, Pharmacyclics LLC, an AbbVie company. "We’re pleased to present extended follow-up results from the Phase 3 E1912 and RESONATE/RESONATE-2 studies at this year’s ASH (Free ASH Whitepaper) Annual Meeting – all of which are landmark clinical trials that have uniquely changed our understanding of CLL."

"Phase 3 RESONATE and RESONATE-2 trials have proven to be cornerstone studies that have significantly advanced the treatment of CLL among a variety of patients – and the latest data presented at this year’s ASH (Free ASH Whitepaper) Annual Meeting demonstrate using IMBRUVICA alone and earlier in CLL treatment results in improved patient outcomes," said Paul M. Barr, M.D., study investigator of the Phase 3 RESONATE and RESONATE-2 trials, and Associate Professor of Medicine, Hematology/Oncology at the Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York. "These results reaffirm the sustained disease control and safety profile of IMBRUVICA and further support its use as a chemotherapy-free option for previously untreated patients living with this common form of adult leukemia."

IMBRUVICA is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Abstract #33: E1912 extended follow-up of IMBRUVICA plus rituximab compared to FCR in patients with CLL/SLL aged 70 or younger

Oral Presentation: Saturday, December 7, 2019 at 7:30 a.m. EST

Longer-term outcomes data from the Phase 3 E1912 clinical trial – designed and conducted by ECOG-ACRIN and sponsored by the NCI – were presented today in an oral session. As previously reported in earlier data readouts, the study evaluated 354 previously untreated patients with CLL aged 70 years or younger who were randomly assigned to receive IMBRUVICA and rituximab or six courses of intravenous FCR chemoimmunotherapy every 28 days. The study met the primary endpoints of PFS and OS.

At a median follow-up of 48 months, 73 percent of patients in the IMBRUVICA plus rituximab treatment arm remained on IMBRUVICA with median time on treatment of 43 months (range of 0.2 to 61 months). The median time to progression or death after discontinuing IMBRUVICA was 23 months. Superior PFS benefits were sustained for the IMBRUVICA plus rituximab arm compared to the FCR treatment arm (hazard ratio [HR]: 0.39; 95 percent confidence interval [CI], 0.26-0.57; p<0.0001). OS also continued to favor the IMBRUVICA plus rituximab arm (HR=0.34, 95 percent CI, 0.15-0.79; p=0.009). Grade 3 and above treatment-related adverse events (AEs) were observed in 70 percent of patients in the IMBRUVICA plus rituximab arm versus 80 percent in the FCR arm (odds ratio [OR]: 0.56; 95 percent CI, 0.34 – 0.90; p=0.013).

The E1912 study served as the basis of the recent sNDA to the U.S. FDA to expand the IMBRUVICA label to include the combination with rituximab for the first-line treatment of patients with CLL or SLL. The submission is being reviewed by the FDA under the Real-Time Oncology Review pilot program.

Abstract #3054: New RESONATE/RESONATE-2 long-term analysis of ibrutinib monotherapy in earlier lines of CLL treatment

Poster Presentation: Sunday, December 8, 2019 at 6:00 p.m. EST

A new integrated analysis with up to six years of follow-up from the Phase 3 RESONATE (PCYC-1112) and RESONATE-2 (PCYC-1115/1116) studies evaluating IMBRUVICA monotherapy in previously untreated patients (n=136; median age of 73 years) and R/R patients (n=135; median age of 65 years for patients with 1-2 prior lines; median age of 67 years for patients with 3 or more lines) with CLL will be presented. Results reported IMBRUVICA monotherapy demonstrated improved PFS, OS and ORR, with sustained efficacy for the first-line patient group, including patients with high-risk prognostic features, compared to the R/R group.

At up to six years of follow-up (first-line group: median of 59.8 months; 1-2 prior lines: 66.2 months; 3 or more prior lines: 65.1 months), the median PFS was not reached for the first-line or the 1-2 prior lines groups, and median PFS was 40.1 months for the 3 or more prior lines group. A greater portion of patients treated with IMBRUVICA in earlier lines remained progression-free or alive at 60 months (first-line: 70 percent; 1-2 prior lines: 60 percent; 3 or more prior lines: 33 percent), and first-line treatment resulted in a 34 percent reduction in risk of disease progression or death compared to patients who had 1-2 prior lines of therapy (HR: 0.66; 95 percent CI, 0.40 – 1.09). PFS was significantly prolonged for patients receiving first-line treatment compared to those who have received 3 or more prior therapy (HR: 0.32; 95 percent CI, 0.21 – 0.49). Furthermore, median OS for the first-line or 1-2 prior lines group was not reached and was 67.4 months for the 3 or more prior lines group. At 60 months, the ORR was 92 percent (first-line), 96 percent (1-2 prior lines) and 88 percent (3 or more prior lines).

At the time of analysis, 58 percent of patients remain on IMBRUVICA in the first-line group. Overall, 6 percent of patients in the first-line group discontinued due to progressive disease, while it was the most common reason for discontinuation for patients who received 1-2 prior lines of therapy (22 percent) and for those who received 3 or more prior lines (37 percent). Across all three groups, 19 percent of patients discontinued due to AEs (first-line: 21 percent; 1-2 prior: 19 percent; 3 or more prior: 15 percent).

About IMBRUVICA

IMBRUVICA (ibrutinib) is an oral, once-daily medicine that works differently than chemotherapy as it blocks a protein called Bruton’s tyrosine kinase (BTK). The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.1,2 By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.3

Since its launch in 2013, IMBRUVICA has received 10 FDA approvals across six disease areas:
chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; Waldenström’s macroglobulinemia (WM); previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy* – and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.4

IMBRUVICA is now approved in 95 countries and has been used to treat more than 170,000 patients worldwide across its approved indications. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. 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. IMBRUVICA was one of the first medicines to receive FDA approval via the Breakthrough Therapy Designation pathway.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL and it is the only Category 1 single-agent regimen for treatment-naïve patients without deletion 17p.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA is the most comprehensively studied BTK inhibitor, with more than 150 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. For more information, visit www.IMBRUVICA.com.

*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.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients exposed to IMBRUVICA in 27 clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 39% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. In IMBRUVICA clinical trials, 3.1% of patients taking IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms 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 24% of 1,124 patients exposed to IMBRUVICA in clinical trials. 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 (23%), thrombocytopenia (8%), and anemia (3%) 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 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA in clinical trials. 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 of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate.

Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

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 (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia (14%).

Approximately 7% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] 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%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (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.

DRUG INTERACTIONS

CYP3A Inhibitors: Co-administration of IMBRUVICA with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Dose modifications of IMBRUVICA may be recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if strong inhibitors are used short-term (e.g., for ≤ 7 days). See dose modification guidelines in USPI sections 2.4 and 7.1.

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 December 7, 2019 AstraZeneca reported that it results from the interim analysis of the Phase III ELEVATE TN trial, showing that Calquence (acalabrutinib) combined with obinutuzumab or as monotherapy significantly improved progression-free survival (PFS) compared to chlorambucil plus obinutuzumab, a standard chemo-immunotherapy treatment, in patients with previously untreated chronic lymphocytic leukaemia (CLL) (Press release, AstraZeneca, DEC 7, 2019, View Source [SID1234552037]).1

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The Independent Review Committee (IRC)-assessed results were presented at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exhibition in Orlando, US. At a median follow-up of 28.3 months, Calquence in combination with obinutuzumab or as a monotherapy significantly reduced the risk of disease progression or death by 90% and 80%, respectively, vs. chlorambucil plus obinutuzumab.1

In an exploratory analysis, Calquence in combination or alone demonstrated consistent PFS improvements across most pre-specified subgroups of patients with high-risk disease characteristics, including the unmutated immunoglobulin heavy-chain variable gene (IGHV), del(11q) and complex karyotype. Overall, the safety and tolerability profile of Calquence observed in the ELEVATE TN trial was consistent with its known profile.1

José Baselga, Executive Vice President, Oncology R&D said: "On the heels of approvals in the US, Australia and Canada, these full results provide further evidence that Calquence, as a new treatment option for patients with chronic lymphocytic leukaemia, demonstrates remarkable efficacy and a favourable tolerability profile. These results also provide, for the first time, post-hoc analysis data exploring the potential progression-free survival benefit of adding obinutuzumab to a BTK inhibitor such as Calquence versus BTK inhibitor monotherapy in a randomised trial."

Dr. Jeff Sharman, Director of Research at Willamette Valley Cancer Institute, Medical Director of Hematology Research for The US Oncology Network, and a lead author of the ELEVATE TN trial, said: "In the detailed results from the ELEVATE TN trial comparing Calquence to a commonly used chemo-immunotherapy treatment regimen, Calquence demonstrated a clinically meaningful improvement in progression-free survival, while maintaining its known tolerability and safety profile. These are encouraging results for a patient population that is known to face multiple comorbidities, and where tolerability is a critical factor in their treatment."

Summary of key efficacy results as assessed by IRC from the ELEVATE TN trial at a median follow-up of 28.3 months:1

CI, confidence interval; NR, not reached; NE, not estimable; HR, hazard ratio; ORR, overall response rate;
OS, overall survival

Adverse events (AEs) led to treatment discontinuation in 11.2% of patients treated with Calquence in combination with obinutuzumab and 8.9% of patients treated with Calquence monotherapy versus 14.1% of patients treated with chlorambucil plus obinutuzumab.1

With over two years of follow-up, 79% of patients in both the Calquence-containing arms remain on Calquence as a monotherapy. In the Calquence combination arm (n=178), the most common AEs of any grade (≥30%) included headache (39.9%), diarrhoea (38.8%) and neutropenia (31.5%). In the Calquence monotherapy arm (n=179), the most common AEs of any grade (≥30%) included headache (36.9%) and diarrhoea (34.6%). In the chlorambucil plus obinutuzumab arm (n=169), the most common AEs of any grade (≥30%) included neutropenia (45.0%), infusion-related reaction (39.6%) and nausea (31.4%).1

SPM, secondary primary malignancy; NMSC, non-melanoma skin cancer

These findings, along with previously reported data from the Phase III ASCEND trial in relapsed or refractory CLL, support the recent approvals of Calquence by the US FDA and the Australian Therapeutic Goods Administration for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) and by Health Canada for CLL.2

About Calquence

In the US and Australia, Calquence (acalabrutinib) is approved for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) and in Canada for CLL. In the US, Canada, Australia, Brazil, Qatar, the United Arab Emirates, Mexico, Argentina, Singapore, Chile, and recently India, Calquence is also approved for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Calquence was approved for MCL under accelerated review in the US; continued approval for previously treated MCL is contingent upon verification and confirmation of clinical benefit in confirmatory trials.

Calquence is a next-generation selective inhibitor of Bruton’s tyrosine kinase (BTK). It binds covalently to BTK, thereby inhibiting its activity.2,3,4,5 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.2

As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluating Calquence in 23 company-sponsored clinical trials. Calquence is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström macroglobulinaemia, follicular lymphoma and other haematologic malignancies. Several Phase III clinical trials in CLL are ongoing, including ASCEND, ELEVATE TN, ELEVATE-RR (ACE-CL-006) evaluating Calquence versus ibrutinib in patients with previously treated high-risk CLL, and ACE-CL-311 evaluating Calquence in combination with venetoclax and with/without obinutuzumab versus chemoimmunotherapy in patients with previously untreated CLL without 17p deletion or TP53 mutation.

About ELEVATE TN

ELEVATE TN (ACE-CL-007) is a randomised, multicentre, open-label Phase III trial evaluating the safety and efficacy of Calquence in combination with obinutuzumab, a CD20 monoclonal antibody, or Calquence alone versus chlorambucil, a chemotherapy, in combination with obinutuzumab in previously untreated patients with CLL. Patients 65 years of age or older, or between 18 and 65 years of age with a total Cumulative Illness Rating Scale (CIRS) >6 or creatinine clearance of 30 to 69 mL/min, were enrolled. In the trial, 535 patients were randomised (1:1:1) into three arms. Patients in the first arm received chlorambucil in combination with obinutuzumab. Patients in the second arm received Calquence (100mg approximately every 12 hours until disease progression or unacceptable toxicity) in combination with obinutuzumab. Patients in the third arm received Calquence monotherapy (100mg approximately every 12 hours until disease progression or unacceptable toxicity).1,6

The primary endpoint is PFS in the Calquence and obinutuzumab arm compared to the chlorambucil and obinutuzumab arm, assessed by an independent review committee (IRC), and a key secondary endpoint is IRC-assessed PFS in the Calquence monotherapy arm compared to the chlorambucil and obinutuzumab arm. Other secondary endpoints include objective response rate, time to next treatment and overall survival.1,6

About CLL

Chronic lymphocytic leukaemia (CLL) is one of the most common types of leukaemia in adults, with an estimated 105,000 new cases globally in 2016 and 20,720 new cases in the US in 2019, and the number of people living with CLL is expected to grow with improved treatment as patients live longer with the disease.7,8,9,10 In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections.7 As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells and platelets.7 This could result in anaemia, infection and bleeding.7 B-cell receptor signalling through BTK is one of the essential growth pathways for CLL.

About AstraZeneca in haematology

Leveraging its strength in oncology, AstraZeneca has established haematology as one of four key oncology disease areas of focus. The Company’s haematology franchise includes two US FDA-approved medicines and a robust global development programme for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca’s haematology research and development arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

About AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On December 7, 2019 ALX Oncology, a clinical-stage immuno-oncology company developing therapies to block the CD47 checkpoint mechanism, reported new results from the hematological portion of the ALX148 Phase 1 program at the 2019 ASH (Free ASH Whitepaper) Annual Meeting [publication number #1953] (Press release, ALX Oncology, DEC 7, 2019, View Source [SID1234552053]). As of November 01, 2019, twenty-nine patients with relapsed or refractory non-Hodgkin lymphoma (NHL) were administered ALX148 in combination with a standard rituximab regimen. Objective responses were observed at all dose levels administered.

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Key results:

ALX148 was well tolerated with no dose limiting toxicities, and no maximum tolerated dose reached with a maximum administered dose of 15 mg/kg once weekly (molar equivalent to 30 mg/kg once weekly of an antibody). The most common treatment-related adverse event was Grade 1/2 rash.
Response-evaluable patients with relapsed/refractory NHL (n=21) who were administered ALX148 (10 mg/kg once weekly) demonstrated an objective response rate (ORR) of 43% and median progression free survival (mPFS) of 7.3 months.
In patients with aggressive NHL (n=14) an ORR of 36% and mPFS of 3.1 months were observed.
In patients with indolent NHL (n=7) an ORR of 57% was observed and mPFS was not reached.
Two patients achieved complete response, one of whom was refractory to prior rituximab therapy.
In patients with rituximab refractory disease (n=9) an ORR of 44% was observed.
In initial response-evaluable patients with relapsed/refractory NHL (n=3) administered ALX148 (15 mg/kg once weekly) an ORR of 67% was reported, and mPFS was not reached.
ALX148 demonstrates antibody-like and linear pharmacokinetics at the two dose levels evaluated with complete CD47 target occupancy in combination with rituximab.
"The compelling anti-tumor activity seen in relapsed and refractory patients with non-Hodgkin lymphoma confirms the central role of the CD47/SIRPa myeloid checkpoint as a critical target in maximizing tumor control," said Sophia Randolph, M.D., Ph.D., Chief Medical Officer of ALX Oncology. "ALX148, a myeloid checkpoint inhibitor, has previously demonstrated emerging activity in head and neck squamous cell carcinoma, gastric and gastroesophageal junction cancer, and now, additionally, in non-Hodgkin lymphoma. The safety profile of ALX148 observed across the clinical program differentiates from all other CD47 targeted agents currently in the clinic, enabling broad development of ALX148 in multiple cancer indications. We believe ALX148 has the potential to become a cornerstone of treatment for patients with cancer.

Conference Call on December 12th at 8:00 a.m. EST
ALX Oncology will host a conference call on Thursday, December 12, 2019 at 8:00 a.m. EST to discuss the Company’s lead development candidate, ALX148, a next generation CD47 myeloid checkpoint inhibitor and its clinical data in hematologic and solid cancers. In addition to ALX Oncology’s executive management team, three distinguished physicians will be featured on the call:

Justin Gainor, MD – Director of Targeted Immunotherapy, Henri and Belinda Termeer Center for Targeted Therapies, Center for Thoracic Cancers, Assistant Professor of Medicine, Harvard Medical School in Boston, Massachusetts on ALX148 in patients with head and neck squamous cell carcinoma
Tae Min Kim, MD, PhD – Professor, Department of Internal Medicine, Division of Hematology and Medical Oncology at Seoul National University Hospital in Seoul, South Korea on ALX148 in patients with non-Hodgkin lymphoma
Jeeyun Lee, MD – Associate Professor of Hematology/Oncology at the Samsung Medical Center, Sungkyunkwan University School of Medicine in Seoul, South Korea on ALX148 in patients with gastric and gastroesophageal junction cancer
To access the conference call, please dial (844) 467-7655 or (409) 983-9840 (international) at least 10 minutes prior to the start time and refer to conference ID 9162888. Presentation slides will be available to download from the Company’s website www.alxoncology.com.

On December 7, 2019 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported new data on two investigational CD20-CD3 T-cell engaging bispecific antibodies, mosunetuzumab and CD20-TCB, in people with relapsed or refractory (R/R) B-cell non-Hodgkin’s lymphoma (NHL) (Press release, Genentech, DEC 7, 2019, View Source [SID1234552054]). Results from the Phase I/Ib GO29781 study of mosunetuzumab, including data from people previously treated with chimeric antigen receptor (CAR) T-cell therapy, will be presented at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 Annual Meeting during the Plenary Scientific Session. The Plenary Scientific Session highlights the top six abstracts submitted to the meeting, as determined by the ASH (Free ASH Whitepaper) Program Committee. Additionally, results from the Phase I/Ib NP30179 study evaluating CD20-TCB as a combination therapy with Gazyva (obinutuzumab) for people with R/R NHL, will be presented.

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"We’re encouraged by these early results, which suggest that our novel bispecific cancer immunotherapies may help people with relapsed or treatment-refractory disease who need more options."

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"Despite recent treatment advancements, slow-growing and aggressive non-Hodgkin’s lymphomas present increasingly difficult management challenges with each subsequent relapse," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "We’re encouraged by these early results, which suggest that our novel bispecific cancer immunotherapies may help people with relapsed or treatment-refractory disease who need more options."

The GO29781 study evaluated mosunetuzumab in patients with R/R NHL, including patients who have relapsed following, or are resistant to, CAR T-cell therapy – a patient population with limited treatment options. Results from this dose-escalation study showed encouraging efficacy with an objective response rate (ORR) of 62.7 percent (n=42/67) in slow-growing NHL and 37.1 percent (n=46/124) in aggressive NHL. Additionally, data demonstrated a complete response (CR) rate of 43.3 percent (n=29/67) in slow-growing NHL and 19.4 percent (n=24/124) in aggressive NHL. CRs showed durability, with 82.8 percent (n=24/29) of patients with slow-growing NHL remaining in remission up to 26 months off initial treatment and 70.8 percent (n=17/24) of patients with aggressive NHL, remaining in remission up to 16 months off initial treatment. Of the participants who received prior CAR T-cell therapy, the ORR was 38.9 percent (n=7/18), and 22.2 percent (n=4/18) achieved a CR. Adverse reactions included cytokine release syndrome (CRS) in 28.9 percent of patients with 20.0 percent at Grade 1 and 1.1 percent at Grade 3. Grade 3 neurological adverse events occurred in 3.7 percent of patients.

Results from the Phase I/Ib dose-escalation NP30179 study, evaluating CD20-TCB at doses ranging from 0.6 mg to 16 mg plus Gazyva in people with R/R B-cell NHL, showed an ORR of 54 percent (n=15/28) and a CR rate of 46 percent (n=13/28). This included an ORR and CR of 66.7 percent (n=4/6) in people with follicular lymphoma and an ORR of 50.0 percent (n=11/22) and a CR of 40.9 percent (n=9/22) in aggressive NHL. The most frequently observed adverse event across all treatment doses was CRS, occurring in 67.9 percent of patients (n=19/28), with the majority of events being low grade (Grade 1-2).

Both mosunetuzumab and CD20-TCB continue to be evaluated in a robust clinical development program, investigating the treatments as monotherapies and in combination with other therapies, in people with slow-growing and aggressive forms of NHL.

About Genentech’s Investigational Bispecifics

Genentech is currently developing two T-cell engaging bispecific antibodies, mosunetuzumab and CD20-TCB, designed to target CD20 on the surface of B-cells and CD3 on the surface of T-cells. This dual targeting activates and redirects a patient’s existing T-cells to engage and eliminate target B-cells by releasing cytotoxic proteins into the B-cells. Mosunetuzumab and CD20-TCB differ in their structures, and both are being developed by Genentech as part of our ongoing strategy to explore multiple bispecific formats, to identify those that maximize potential clinical benefits for patients. The clinical development programs for mosunetuzumab and CD20-TCB include ongoing investigations of these molecules as monotherapies and in combination with other medicines, for the treatment of people with CD20-positive B-cell non-Hodgkin’s lymphomas, including diffuse large B-cell lymphoma and follicular lymphoma.

About the GO29781 study

The GO29781 study [NCT02500407] is a Phase I/Ib, multicenter, open-label, dose-escalation study evaluating the safety and pharmacokinetics of mosunetuzumab in people with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Outcome measures include best objective response rate by revised International Working Group criteria, maximum tolerated dose, and tolerability.

About the NP30179 study

The NP30179 study [NCT03075696] is a Phase I/Ib, multicenter, open-label, dose-escalation study, evaluating the efficacy, safety, tolerability and pharmacokinetics of CD20-TCB. In this study, CD20-TCB is assessed as a single agent and in combination with Gazyva, following pre-treatment with a one-time, fixed dose of Gazyva, in people with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Outcome measures include overall response rate, complete response rate per Lugano 2014 criteria, maximum tolerated dose, and tolerability.

About Non-Hodgkin’s Lymphoma

There are two main types of lymphoma: Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (NHL). NHL has two subsets, aggressive and indolent (slow-growing).

NHL represents approximately 85 percent of all lymphomas diagnosed. According to the American Cancer Society, it is expected that nearly 74,000 people will be diagnosed with NHL in the United States in 2019, and nearly 20,000 will die from the disease.

Most cases of NHL start in B-lymphocytes, cells that are part of the body’s immune system and help to defend the body against infections. B-cell lymphoma develops when these cells become cancerous and begin to multiply and collect in the lymph nodes or lymphatic tissues such as the spleen.

Gazyva Indications

Gazyva (obinutuzumab) is a prescription medicine used:

With the chemotherapy drug, chlorambucil, to treat chronic lymphocytic leukemia (CLL) in adults who have not had previous CLL treatment.
With the chemotherapy drug, bendamustine, followed by Gazyva alone for follicular lymphoma (FL) in adults who did not respond to a rituximab-containing regimen, or whose FL returned after such treatment.
With chemotherapy, followed by Gazyva alone in those who responded, to treat stage II bulky, III, or IV FL in adults who have not had previous FL treatment.
Important Safety Information

The most important safety information patients should know about Gazyva

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that can become serious or life threatening, including:

Hepatitis B Virus (HBV): Hepatitis B can cause liver failure and death. If the patient has a history of hepatitis B infection, Gazyva could cause it to return. Patients should not receive Gazyva if they have active hepatitis B liver disease. The patient’s doctor or healthcare team will need to screen them for hepatitis B before, and monitor the patient for hepatitis during and after, their treatment with Gazyva. Sometimes this will require treatment for hepatitis B. Symptoms of hepatitis include: worsening of fatigue and yellow discoloration of skin or eyes.
Progressive Multifocal Leukoencephalopathy (PML): PML is a rare and serious brain infection caused by a virus. PML can be fatal. The patient’s weakened immune system could put them at risk. The patient’s doctor will watch for symptoms. Symptoms of PML include: confusion, difficulty talking or walking, dizziness or loss of balance, and vision problems.
Who should not receive Gazyva:

Patients should NOT receive Gazyva if they have had an allergic reaction (e.g., anaphylaxis or serum sickness) to Gazyva. Patients must tell their healthcare provider if they have had an allergic reaction to obinutuzumab or any other ingredients in Gazyva in the past.

Additional possible serious side effects of Gazyva:

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that may become severe or life threatening, including:

Infusion Reactions: These side effects may occur during or within 24 hours of any Gazyva infusion. Some infusion reactions can be serious, including, but not limited to, severe allergic reactions (anaphylaxis), acute life-threatening breathing problems, or other life-threatening infusion reactions. If the patient has a reaction, the infusion is either slowed or stopped until their symptoms are resolved. Most patients are able to complete infusions and receive medication again. However, if the infusion reaction is life threatening, the infusion of Gazyva will be permanently stopped. The patient’s healthcare team will take steps to help lessen any side effects the patient may have to the infusion process. The patient may be given medicines to take before each Gazyva treatment. Symptoms of infusion reactions may include: fast heartbeat, tiredness, dizziness, headache, redness of the face, nausea, chills, fever, vomiting, diarrhea, rash, high blood pressure, low blood pressure, difficulty breathing, and chest discomfort.
Hypersensitivity Reactions Including Serum Sickness: Some patients receiving Gazyva may have severe or life-threatening allergic reactions. This reaction may be severe, may happen during or after an infusion, and may affect many areas of the body. If an allergic reaction occurs, the patient’s doctor will stop the infusion and permanently discontinue Gazyva.
Tumor Lysis Syndrome (TLS): Tumor lysis syndrome, including fatal cases, has been reported in patients receiving Gazyva. Gazyva works to break down cancer cells quickly. As cancer cells break apart, their contents are released into the blood. These contents may cause damage to organs and the heart, and may lead to kidney failure requiring the need for dialysis treatment. The patient’s doctor may prescribe medication to help prevent TLS. The patient’s doctor will also conduct regular blood tests to check for TLS. Symptoms of TLS may include nausea, vomiting, diarrhea, and tiredness.
Infections: While the patient is taking Gazyva, they may develop infections. Some of these infections may be fatal and severe, so the patient should be sure to talk to their doctor if they think they have an infection. Patients administered Gazyva in combination with chemotherapy, followed by Gazyva alone are at a high risk of infections during and after treatment. Patients with a history of recurring or chronic infections may be at an increased risk of infection. Patients with an active infection should not be treated with Gazyva. Patients taking Gazyva plus bendamustine may be at higher risk for fatal or severe infections compared to patients taking Gazyva plus CHOP or CVP.
Low White Blood Cell Count: When the patient has an abnormally low count of infection-fighting white blood cells, it is called neutropenia. While the patient is taking Gazyva, their doctor will do blood work to check their white blood cell count. Severe and life-threatening neutropenia can develop during or after treatment with Gazyva. Some cases of neutropenia can last for more than one month. If the patient’s white blood cell count is low, their doctor may prescribe medication to help prevent infections.
Low Platelet Count: Platelets help stop bleeding or blood loss. Gazyva may reduce the number of platelets the patient has in their blood; having low platelet count is called thrombocytopenia. This may affect the clotting process. While the patient is taking Gazyva, their doctor will do blood work to check their platelet count. Severe and life-threatening thrombocytopenia can develop during treatment with Gazyva. Fatal bleeding events have occurred in patients treated with Gazyva. If the patient’s platelet count gets too low, their treatment may be delayed or reduced.
The most common side effects of Gazyva in CLL were infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.

The safety of Gazyva was evaluated based on 392 patients with relapsed or refractory NHL, including FL (81 percent), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) (a disease for which Gazyva is not indicated), who did not respond to or progressed within 6 months of treatment with rituximab product or a rituximab product-containing regimen. In patients with follicular lymphoma, the profile of side effects that were seen were consistent with the overall population who had NHL. The most common side effects of Gazyva were infusion reactions, low white blood cell counts, nausea, fatigue, cough, diarrhea, constipation, fever, low platelet counts, vomiting, upper respiratory tract infection, decreased appetite, joint or muscle pain, sinusitis, low red blood cell counts, general weakness, and urinary tract infection.

A randomized, open-label multicenter trial (GALLIUM) evaluated the safety of Gazyva as compared to rituximab product in 1,385 patients with previously untreated follicular lymphoma (86 percent) or marginal zone lymphoma (14 percent).The most common side effects of Gazyva were infusion reactions, low white blood cell count, upper respiratory tract infection, cough, constipation and diarrhea.

Before receiving Gazyva, patients should talk to their doctor about:

Immunizations: Before receiving Gazyva therapy, the patient should tell their healthcare provider if they have recently received or are scheduled to receive a vaccine. Patients who are treated with Gazyva should not receive live vaccines.
Pregnancy: The patient should tell their doctor if they are pregnant, think that they might be pregnant, plan to become pregnant, or are breastfeeding. Gazyva may harm their unborn baby. The patient should speak to their doctor about using Gazyva while they are pregnant. The patient should talk to their doctor or their child’s doctor about the safety and timing of live virus vaccinations to their infant if they received Gazyva during pregnancy. It is not known if Gazyva may pass into the patient’s breast milk. The patient should speak to their doctor about using Gazyva if they are breastfeeding.
Patients should tell their doctor about any side effects.

These are not all of the possible side effects of Gazyva. For more information, patients should ask their doctor or pharmacist.

Gazyva is available by prescription only.

Report side effects to the FDA at (800) FDA-1088, or View Source Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the Gazyva full Prescribing Information, including BOXED WARNINGS, for additional Important Safety Information.

About Genentech in Hematology

For more than 20 years, Genentech has been developing medicines with the goal to redefine treatment in hematology. Today, we’re investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. For more information visit View Source

On December 7, 2019 Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) reported that results of the TOURMALINE-AL1 trial will be presented during an oral session at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting on Saturday, December 7, 2019 in Orlando, Florida (Press release, Takeda, DEC 7, 2019, View Source [SID1234552055]). TOURMALINE-AL1 is a Phase 3, randomized clinical trial evaluating the effect of NINLAROTM (ixazomib) in combination with dexamethasone in patients with relapsed or refractory systemic light-chain (AL) amyloidosis.

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"There are serious unmet needs for people living with amyloidosis. AL amyloidosis is a progressive and fatal disease; many patients are diagnosed late, significantly impacting life expectancy. The challenges associated with developing drugs for this disease make continued research and development for treatment critical"

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The TOURMALINE-AL1 trial did not meet the first of the two primary endpoints of significant improvement in overall hematologic response, as reported in June 2019. Hematologic responses were seen in 53% versus 51% of patients receiving NINLARO plus dexamethasone versus physician’s choice (odds ratio 1.10 [95% CI 0.60-2.01], p=0.762) as assessed by an Adjudication Committee (AC). The second primary endpoint of two-year vital organ deterioration or death was not mature at the time of analysis. Other endpoints studied including vital organ progression free survival (PFS), hematologic PFS, time to treatment failure and time to subsequent therapy were numerically higher in the NINLARO plus dexamethasone arm compared to the physician’s choice arm. Takeda is committed to making data available to researchers to continue investigation of this disease. NINLARO is not approved as a treatment for AL amyloidosis.

"AL amyloidosis is a rare condition, for which prognosis and patient outcomes are poor. Current treatments are often retrofitted from therapies used for multiple myeloma," said Angela Dispenzieri, MD, Mayo Clinic, and the trial’s principal investigator and lead author. "For a Phase 3 study that did not meet its primary endpoint, this trial provides interesting information for this community and for future studies. Ongoing research and development to investigate potential treatment options for this underserved patient population is critical."

"We look forward to the opportunity to share the data from the TOURMALINE-AL1 trial," said Phil Rowlands, Head of Oncology Clinical Research and Development, Takeda. "We are confident that sharing our findings with the community will help encourage conversations around the need for continued research to address the needs that remain in this patient population."

"There are serious unmet needs for people living with amyloidosis. AL amyloidosis is a progressive and fatal disease; many patients are diagnosed late, significantly impacting life expectancy. The challenges associated with developing drugs for this disease make continued research and development for treatment critical," said Isabelle Lousada, Founder and CEO of the Amyloidosis Research Consortium. "The data from TOURMALINE-AL1 provide valuable insights to researchers as they select endpoints for future amyloidosis studies, and knowledge that will provide context in future drug reviews and approvals, ultimately aiding in providing treatment options for patients."

Primary Results from the Phase 3 TOURMALINE-AL1 Trial of Ixazomib-Dexamethasone Versus Physician’s Choice of Therapy in Patients (Pts) with Relapsed/Refractory Primary Systemic AL Amyloidosis (RRAL). Saturday, December 7, 9:30 a.m., Orange County Convention Center, Hall E1.

Key findings, to be presented by Dr. Angela Dispenzieri, include:

The first of two primary endpoints was not met in TOURMALINE-AL1. Hematologic responses were seen in 53% versus 51% of patients receiving NINLARO plus dexamethasone versus physician’s choice (odds ratio 1.10 [95% CI 0.60-2.01], p=0.762).
Complete response (CR) rate was 26% in the NINLARO plus dexamethasone arm versus 18% in the physician’s choice arm.
The second primary endpoint, two-year vital organ deterioration or death, was not mature at the time of analysis.
Other endpoint data as assessed by investigators includes:
Median duration of hematologic response was 46.5 months in the NINLARO plus dexamethasone arm and 20.2 months in the physician’s choice arm as assessed by investigators.
Vital organ PFS was 18.0 months in the NINLARO plus dexamethasone arm and 11.0 months in the physician’s choice arm.
Hematologic PFS was 20.1 months in the NINLARO plus dexamethasone arm and 16.7 months in the physician’s choice arm.
Time to treatment failure was 10.1 months in the NINLARO plus dexamethasone arm and 5.2 months in the physician’s choice arm.
Time to subsequent therapy was 26.5 months in the NINLARO plus dexamethasone arm and 12.5 months in the physician’s choice arm.
At data cut-off, patients had received a median treatment duration of 11.7 versus 5.0 months on the NINLARO plus dexamethasone versus physician’s choice arms.
Safety data includes:
Drug-related adverse events (AE) were experienced by 82% of patients receiving NINLARO plus dexamethasone compared to 81% of patients receiving physician’s choice.
Serious adverse events (SAE) were experienced by 47% of patients in the NINLARO plus dexamethasone arm compared to 33% in the physician’s choice arm.
Discontinuation of treatment due to AEs was 26% in the NINLARO plus dexamethasone arm compared to 20% in the physician’s choice arm.
Common any grade AEs in both the NINLARO plus dexamethasone arm and physician’s choice arm included fatigue (45% and 43%), peripheral edema (46% and 32%), diarrhea (34% and 30%), insomnia (38% and 17%), rash (33% and 20%), constipation (21% and 26%), dyspnea (24% and 19%), upper respiratory tract infection (24% versus 16%), nausea (24% versus 14%) and peripheral neuropathy (19% versus 15%).
Common (≥5% overall) grade ≥3 AEs were fatigue (9% versus 9%), peripheral edema (5% versus 5%), rash (4% versus 5%) and dyspnea (6% versus 4%).
6% of patients in the NINLARO plus dexamethasone arm and 5% of patients in the physician’s choice arm died on study. All deaths were considered to be related to AL amyloidosis or complications thereof.
About the TOURMALINE-AL1 Trial

TOURMALINE-AL1 (NCT01659658) is an international, randomized, controlled, open-label, multicenter, Phase 3 study, designed to determine whether NINLAROTM (ixazomib) in combination with dexamethasone improves hematologic response, two-year vital organ (heart or kidney) deterioration and mortality rate versus a physician’s choice of a chemotherapy regimen in participants diagnosed with relapsed or refractory systemic light chain (AL) amyloidosis. 168 patients were enrolled and randomly selected to receive either NINLARO plus dexamethasone, or physician’s choice of the following: dexamethasone plus melphalan; dexamethasone plus cyclophosphamide; dexamethasone plus thalidomide; dexamethasone plus lenalidomide; or dexamethasone alone. The discontinuation of the TOURMALINE-AL1 trial was announced in June 2019. For more information, please visit View Source

About AL Amyloidosis

Primary AL amyloidosis is a condition that falls under the umbrella of plasma cell dyscrasias. AL amyloidosis arises from a clonal plasma cell that produces abnormal immunoglobulin light-chain fragments. These misfolded light-chains form insoluble fibrils that aggregate as amyloid deposits in organs and tissues throughout the body, ultimately leading to organ dysfunction and death. The most common organs affected are the kidneys, heart, liver, and autonomic or peripheral nerves.

There are currently no treatments approved for the treatment of AL amyloidosis.

About NINLAROTM (ixazomib) capsules

NINLARO (ixazomib) is an oral proteasome inhibitor which is being studied across the continuum of multiple myeloma treatment settings. NINLARO was first approved by the U.S. Food and Drug Administration (FDA) in November 2015 and is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is currently approved in more than 60 countries, including the United States, Japan and in the European Union, with more than 10 regulatory filings currently under review. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval.

The comprehensive ixazomib clinical development program, TOURMALINE, includes several ongoing pivotal trials, which together are investigating major multiple myeloma patient populations:

TOURMALINE-MM1, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
TOURMALINE-MM2, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT
In addition to the TOURMALINE program, ixazomib is being evaluated in multiple therapeutic combinations for various patient populations in investigator initiated studies globally.

NINLARO (ixazomib) capsules: Global Important Safety Information

SPECIAL WARNINGS AND PRECAUTIONS
Thrombocytopenia has been reported with NINLARO (28 percent vs. 14 percent in the NINLARO and placebo regimens, respectively) with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. It did not result in an increase in hemorrhagic events or platelet transfusions. Monitor platelet counts at least monthly during treatment with NINLARO and consider more frequent monitoring during the first three cycles. Manage with dose modifications and platelet transfusions as per standard medical guidelines.

Gastrointestinal toxicities have been reported in the NINLARO and placebo regimens respectively, such as diarrhea (42 percent vs. 36 percent), constipation (34 percent vs. 25 percent), nausea (26 percent vs. 21 percent), and vomiting (22 percent vs. 11 percent), occasionally requiring use of antiemetic and anti-diarrheal medications, and supportive care.

Peripheral neuropathy was reported with NINLARO (28 percent vs. 21 percent in the NINLARO and placebo regimens, respectively). The most commonly reported reaction was peripheral sensory neuropathy (19 percent and 14 percent in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1 percent). Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.

Peripheral edema was reported with NINLARO (25 percent vs. 18 percent in the NINLARO and placebo regimens, respectively). Evaluate patients for underlying causes and provide supportive care, as necessary. Adjust the dose of dexamethasone per its prescribing information or the dose of NINLARO for severe symptoms.

Cutaneous reactions occurred in 19 percent of patients in the NINLARO regimen compared to 11 percent of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Manage rash with supportive care, dose modification or discontinuation.

Hepatotoxicity, drug-induced liver injury, hepatocellular injury, hepatic steatosis, and hepatitis cholestatic have been uncommonly reported with NINLARO. Monitor hepatic enzymes regularly and adjust dose for Grade 3 or 4 symptoms.

Pregnancy- NINLARO can cause fetal harm. Advise male and female patients of reproductive potential to use contraceptive measures during treatment and for an additional 90 days after the final dose of NINLARO. Women of childbearing potential should avoid becoming pregnant while taking NINLARO due to potential hazard to the fetus. Women using hormonal contraceptives should use an additional barrier method of contraception.

Lactation- It is not known whether NINLARO or its metabolites are excreted in human milk. There could be potential adverse events in nursing infants and therefore breastfeeding should be discontinued.

SPECIAL PATIENT POPULATIONS
Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialyzable and, therefore, can be administered without regard to the timing of dialysis.

DRUG INTERACTIONS
Co-administration of strong CYP3A inducers with NINLARO is not recommended.

ADVERSE REACTIONS
The most frequently reported adverse reactions (≥ 20 percent) in the NINLARO regimen, and greater than in the placebo regimen, were diarrhea (42 percent vs. 36 percent), constipation (34 percent vs. 25 percent), thrombocytopenia (28 percent vs. 14 percent), peripheral neuropathy (28 percent vs. 21 percent), nausea (26 percent vs. 21 percent), peripheral edema (25 percent vs. 18 percent), vomiting (22 percent vs. 11 percent), and back pain (21 percent vs. 16 percent). Serious adverse reactions reported in ≥ 2 percent of patients included thrombocytopenia (2 percent) and diarrhea (2 percent). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1percent of patients in the NINLARO regimen.

For European Union Summary of Product Characteristics: View Source
For US Prescribing Information: View Source
For Canada Product Monograph: View Source