On December 3, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported results from the Phase 3 iLLUMINATE (PCYC-1130) trial, evaluating the chemotherapy-free, anti-CD20 combination of IMBRUVICA (ibrutinib) plus obinutuzumab (Gazyva) in patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (Press release, AbbVie, DEC 3, 2018, View Source [SID1234531878]). At a median follow-up of 31 months, study results showed IMBRUVICA plus obinutuzumab significantly prolonged progression-free survival (PFS) (median not reached [NR] vs. 19 months) with a 77 percent reduction in risk of progression or death versus chlorambucil plus obinutuzumab, the current National Comprehensive Cancer Network guidelines Category 1 treatment regimen (hazard ratio [HR] 0.23; 95% confidence interval [CI]: 0.15-0.37; P<0.0001).

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The data were presented today in an oral session at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (abstract #691) and were simultaneously published in The Lancet Oncology. Based on these data, a supplemental New Drug Application (sNDA) was recently accepted for Priority Review by the U.S. Food and Drug Administration (FDA) to expand the use of IMBRUVICA in combination with obinutuzumab in previously untreated CLL/SLL. 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.

"iLLUMINATE represents one of three IMBRUVICA Phase 3 studies in chronic lymphocytic leukemia being presented at this year’s ASH (Free ASH Whitepaper). Results from the iLLUMINATE study support the use of IMBRUVICA as a chemotherapy-free, anti-CD20 combination treatment option versus the current National Comprehensive Cancer Network guidelines Category 1 treatment of chlorambucil plus obinutuzumab," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "These latest findings, in addition to seven-year long-term data and a Late-Breaker at this year’s ASH (Free ASH Whitepaper), add to the robust amount of data supporting the use of IMBRUVICA as backbone therapy in CLL and SLL."

CLL is one of the two most common forms of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes).1 While these cancer cells start in the bone marrow, they then later spread into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 20,000 newly diagnosed patients every year.2,3 SLL is a slow-growing lymphoma biologically similar to CLL in which too many immature white blood cells cause lymph nodes to become larger than normal.4 Both CLL and SLL are predominately diseases of the elderly, with a median age at diagnosis ranging from 65-70 years.5

"For years, we had to rely on chemotherapy as the only treatment option for patients with previously untreated chronic lymphocytic leukemia and small lymphocytic lymphoma," said Carol Moreno, M.D., Ph.D., Consultant Hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Barcelona, Spain, and lead study investigator of iLLUMINATE. "We’re pleased to share results from iLLUMINATE that help show that it is possible to provide efficacious treatment for patients with CLL and SLL without the use of chemotherapy."

About Abstract #691: Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab as First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results from Phase 3 iLLUMINATE

Oral presentation: Monday, December 3 at 10:30 a.m. PST

In the Phase 3 iLLUMINATE (PCYC-1130) study, newly diagnosed CLL patients were randomized to receive IMBRUVICA 420 milligrams (mg) once daily continuously in combination with obinutuzumab 1000 mg intravenously over six cycles (n=113); or chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle plus obinutuzumab 1000 mg intravenously over six cycles (n=116). The primary endpoint was PFS, as assessed by an Independent Review Committee (IRC). The study also evaluated: PFS for patients with high-risk features (unmutated IGHV, del11q, del17p or TP53 mutation); rate of undetectable minimal residual disease (MRD); overall response rate (ORR); overall survival (OS); and safety.

At a median follow-up of 31.3 months, ibrutinib plus obinutuzumab significantly prolonged the IRC-assessed PFS compared to chlorambucil plus obinutuzumab, with a 77 percent reduction in risk of progression or death (median NR vs. 19 months; hazard ratio [HR] 0.23; 95% CI: 0.15-0.37; P<0.0001). At 30 months, the IRC-assessed PFS rates were 79 percent and 31 percent with ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab, respectively. The investigator-assessed PFS was also significantly improved with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab (median NR vs. 21.9 months; HR 0.26; 95% CI: 0.16-0.42; P<0.0001).

The PFS in the IMBRUVICA plus obinutuzumab arm in the high-risk population, including those with unmutated IGHV, del11q, del17p, or TP53 mutation was assessed, with an 85 percent reduction in risk of progression or death (median not reached vs. 14.7 months; HR 0.15; 95% CI: 0.09-0.27; P<0.0001). In addition, IRC-assessed ORR was higher in the ibrutinib plus obinutuzumab arm versus the chlorambucil plus obinutuzumab arm (88% vs. 73%); complete response (CR)/complete response with incomplete blood recovery (CRi) rates were also higher with 19 percent versus eight percent, respectively. The investigator-assessed ORR was also higher in the ibrutinib plus obinutuzumab arm versus the chlorambucil plus obinutuzumab arm (91% vs. 81%); CR/CRi rates were also higher with 41 percent versus 16 percent, respectively. Depth of remission as reflected by undetectable MRD in blood and/or bone marrow was greater in patients with ibrutinib plus obinutuzumab, with 35 percent of patients showing undetectable MRD compared to 25 percent of patients with chlorambucil plus obinutuzumab. OS rates at 31 months were 86 percent for the ibrutinib arm compared to 85 percent for the chlorambucil arm.

Most common Grade 3 or higher adverse events (AEs) in the ibrutinib plus obinutuzumab arm versus chlorambucil plus obinutuzumab arm were neutropenia (43% vs. 63%), thrombocytopenia (35% vs. 25%), diarrhea (34% vs. 10%), cough (27% vs. 12%), infusion-related reactions (25% vs. 58%), arthralgia (22% vs. 10%), pyrexia (19% vs. 26%), anemia (17% vs. 25%), and nausea (12% vs. 30%). Ibrutinib plus obinutuzumab also seemed to decrease the risk of infusion reactions related to the use of obinutuzumab.

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2018, please visit: View Source

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by inhibiting 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.6 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).7

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was 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 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.
In August 2018, IMBRUVICA plus rituximab was approved for adult patients with WM.
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.8 IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, more than 135,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to IMBRUVICA in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% 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 24% of 1,011 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 1,011 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 has occurred in 12% of 1,011 patients treated with IMBRUVICA in clinical trials with a median time to onset of 5 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 (9%) including non-skin carcinomas (2%) have occurred in 1,011 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%)*, neutropenia (58%)*, diarrhea (42%), anemia (39%)*, rash (31%), musculoskeletal pain (31%), bruising (31%), nausea (28%), fatigue (27%), hemorrhage (23%), 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 (36%)*, thrombocytopenia (15%)*, and pneumonia (10%).

Approximately 6% (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%)*, 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 adjustments 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 December 3, 2018 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported its updated efficacy and safety data from the untreated acute myeloid leukemia (AML) arm from the ongoing Phase 1 dose-escalation and expansion study evaluating single agent ivosidenib in patients with hematologic malignancies and an isocitrate dehydrogenase-1 (IDH1) mutation (Press release, Agios Pharmaceuticals, DEC 3, 2018, View Source [SID1234531872]). The data were featured in an oral presentation at the 60thAmerican Society of Hematology Annual Meeting in San Diego.

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"Ivosidenib induced deep, durable remissions in newly diagnosed AML patients who are older, have high rates of secondary AML and prior hypomethylating agent exposure," said Gail Roboz, M.D., Weill Cornell Medical College and an investigator in the study. "Ivosidenib had a favorable safety profile characterized by a low rate of febrile neutropenia and infections. In addition, transfusion independence was observed across response categories, including in patients who did not achieve complete remission."

"We believe these data are encouraging and represent compelling evidence for the potential of single agent ivosidenib as a new treatment option for newly diagnosed AML patients who are ineligible for standard therapies," said Chris Bowden, M.D., chief medical officer at Agios. "There is tremendous need for targeted treatment options for these patients who are typically older and have comorbid conditions, and we are on track to submit a supplemental new drug application for ivosidenib for this patient population under the FDA Real Time Oncology Review pilot program by the end of January 2019."

Untreated AML Data Presentation
As of the May 11, 2018 data cutoff, a total of 258 patients with advanced hematologic malignances and an IDH1 mutation were treated in the Phase 1 study, including 34 patients with untreated AML (nine from dose-escalation and 25 from expansion) who received 500 mg of ivosidenib daily. Enrollment to the study is closed.

Among the untreated AML patients, 20.6% had de novo AML and 79.4% had secondary AML (sAML).
The median age for these patients was 76.5 years (64-87) and 41.2% had received a prior hypomethylating agent.
The median treatment duration for the untreated AML patients was 4.3 months (0.3-35.1).
Safety Data
As of the data cut-off, a safety analysis conducted for the 34 untreated AML patients showed that ivosidenib demonstrates a safety profile that is consistent with previously reported data for all 258 patients. The most common adverse events (AEs) of any grade >25% regardless of causality were diarrhea (52.9%), fatigue (44.1%), nausea (38.2%), decreased appetite (32.4%), leukocytosis (26.5%), anemia (26.5%) and edema peripheral (26.5%). Adverse events of interest were the following:

8.8% reported Grade ≥3 ECG QT prolongation. Ivosidenib was dose reduced in two patients and held in four patients (for any grade of ECG QT prolongation).
17.6% reported IDH-differentiation syndrome (IDH-DS) of any grade, which was managed with corticosteroids and diuretics. Three patients had their dose temporarily held, and no patients required dose reductions.
3% reported Grade ≥3 leukocytosis.
No AEs of interest lead to any permanent treatment discontinuations or deaths.
Efficacy Data
Data from 33 untreated AML patients with an IDH1 mutation confirmed by the Abbott RealTime IDH1 assay demonstrated an overall response rate (ORR) of 57.6% (19 of 33 patients) [95% CI 39.2, 74.5] and a combined complete remission (CR) and CR with partial hematologic recovery (CRh) rate of 42.4% [95% CI 25.5, 60.8] which is the primary endpoint of the study.

The CR rate was 30.3% (10 of 33 patients) [95% CI 15.6, 48.7] and the CRh rate was 12.1% (4 of 33 patients) [95% CI 3.4, 28.2]. CRh is defined as <5% of blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts (ANC >500/microliter and platelets >50,000/microliter).
Median time to first response was 1.9 months (range 0.9, 3.6) for all patients who responded and median time to CR/CRh was 2.8 months (range 1.9, 12.9).
Median durations of CR, CR+CRh, and ORR were not estimable (lower bound of 95% CI 4.2, 6.5 and 6.5 months, respectively); the estimated 12-month durations of response were 77.8%, 66.7% and 59.5%, respectively.
Transfusion independence, defined as an absence of transfusions for at least 56 consecutive days on treatment, was observed across all response categories.
Of the patients who achieved a CR or CRh and were transfusion dependent at baseline, all became independent of platelet and RBC transfusions during any 56-day post baseline period.
Achievement of transfusion independence was also seen among some non-CR/CRh responders and non-responders.
IDH1 mutation clearance, defined as a reduction in mIDH1 variant allele frequency to below the limit of detection of 0.02–0.04% (2-4 x10-4), was observed in 64% (9/14) of patients with untreated AML who achieved CR or CRh, including 50% (5/10) of patients with CR and 100% (4/4) of patients with CRh.
MDS Data Presentation
Updated safety and efficacy data based on May 11, 2018 data cutoff were also presented on December 1, 2018 for 12 myelodysplastic syndrome (MDS) patients from the dose-escalation (n=3) and expansion (n=9) portions of the Phase 1 study whose starting dose was 500 mg daily. The median age was 72.5 years (52-78).

The most common AEs of any grade occurring in ≥20% of patients were back pain and fatigue (n=4, 33.3% each) and anemia, decreased appetite, diarrhea, dyspnea, hypokalemia, pruritus, and rash (n=3, 25% each). Most AEs were grade 1–2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment.
Grade 2 IDH differentiation syndrome (IDH-DS) was observed in 1 of 12 patients.
Of the 12 patients with MDS, five achieved CR (41.7%) [95% CI (15.2%, 72.3%)], one achieved a partial response (PR) (8.3%) and five achieved marrow CR (mCR) (41.7%), resulting in an ORR of 91.7% [95% CI (61.5%, 99.8%)].
The median durations of CR was not estimable at the time of the data cutoff; the median duration of response was 21.4 months with 95% CI [2.3, NE]. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively.
Among the five patients who were transfusion dependent at baseline, four became transfusion independent for at least 56 days on treatment.
TIBSOVO (ivosidenib) is not approved for the treatment of patients with newly diagnosed AML or MDS by any regulatory authority.

About TIBSOVO (ivosidenib)

TIBSOVO (ivosidenib) is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. For more information, visit TIBSOVO.com.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.
WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 34 patients who experienced differentiation syndrome, 27 (79%) recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) of any grade were fatigue (39%), leukocytosis (38%), arthralgia (36%), diarrhea (34%), dyspnea (33%), edema (32%), nausea (31%), mucositis (28%), electrocardiogram QT prolonged (26%), rash (26%), pyrexia (23%), cough (22%), and constipation (20%).
The most frequently reported ≥Grade 3 adverse reactions (≥5%) were electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), tumor lysis syndrome (6%), and differentiation syndrome (5%).
Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.

Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.

Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.

Please see full Prescribing Information, including Boxed WARNING.

About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and the median age of diagnosis is 68. The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 27 percent. IDH1 mutations are present in about 6 to 10 percent of AML cases.

About Myelodysplastic Syndrome (MDS)
MDS comprises a diverse group of bone marrow disorders in which immature blood cells in the bone marrow do not mature or become healthy blood cells. The National Cancer Institute estimates that more than 10,000 people are diagnosed with MDS in the U.S. each year. Failure of the bone marrow to produce mature healthy cells is a gradual process, and reduced blood cell and/or reduced platelet counts may be accompanied by the loss of the body’s ability to fight infections and control bleeding. For roughly 30 percent of the patients diagnosed with MDS, this bone marrow failure will progress to AML. Chemotherapy and supportive blood products are used to treat MDS.

On December 3, 2018 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported the presentation of clinical data from the pivotal Phase 2 trial of its investigational anti-PD-1 antibody, tislelizumab, in Chinese patients with relapsed/refractory (R/R) classical Hodgkin’s lymphoma (cHL) (Press release, BeiGene, DEC 3, 2018, View Source;p=RssLanding&cat=news&id=2379122 [SID1234531870]). These data were presented in an oral session at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), taking place December 1-4, 2018 in San Diego, CA, and are included in BeiGene’s new drug application (NDA) in China for tislelizumab for the treatment of patients with R/R cHL.

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"We set out to address the needs of patients with R/R cHL who have failed to achieve a response or progressed after autologous stem cell transplant (ASCT), or who are not candidates for ASCT, as these patients, unfortunately, have very poor outcomes," said Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene. "We are excited to report strong results including high complete response (CR) rates from the first registration study for this potentially differentiated anti-PD-1 agent."

Tislelizumab was discovered by BeiGene scientists, and is being developed globally and in China as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid and hematologic cancers with 11 Phase 3 or potentially registration-enabling studies ongoing or planned to initiate in the near term. The NDA for tislelizumab in China in patients with R/R cHL has been accepted by the China National Medical Products Administration (NMPA, formerly known as CFDA) and granted priority review status.

"In this study, tislelizumab demonstrated an overall response rate (ORR) of 86 percent, including a CR rate of 61 percent. Tislelizumab was also generally well-tolerated by patients with R/R cHL. We are excited by its clinical activity and believe that tislelizumab represents a potential new immunotherapy option for patients in China and elsewhere in the world," said Yuqin Song, M.D., Ph.D., Associate Professor of Medical Oncology, Deputy Director of the Lymphoma Department at Peking University Cancer Hospital in China, and the presenting author of the study.

Summary of Clinical Results

This single arm, open-label, multi-center, pivotal Phase 2 trial of tislelizumab as a monotherapy in Chinese patients with R/R cHL (ClinicalTrials.gov Identifier: NCT03209973) enrolled 70 patients who failed to achieve a response or progressed after ASCT, or received at least 2 prior lines of systemic therapy for cHL and were not an ASCT candidate. Patients were treated with tislelizumab, dosed at 200 mg intravenously every three weeks. The primary endpoint of the trial is ORR assessed by independent review committee (IRC) using PET-based imaging according to the Lugano Classification 2014.

As of May 25, 2018, 70 patients with R/R cHL were evaluable for efficacy and 53 patients (75.7%) remained on study treatment. Thirteen patients received prior ASCT, and the remaining 57 patients were ineligible for prior ASCT, including 53 for failure to achieve an objective response to salvage chemotherapy, two for inadequate stem cell collection or unable to collect stem cells, and two for co-morbidities. The patients had a median of three prior lines of systemic therapy with a range of 2 to 11. The median study follow-up was 7.85 months (3.4-12.7). Results included:

The ORR by IRC was 85.7 percent (60/70); the CR rate was 61.4 percent (43/70) and the partial response (PR) rate was 24.4 percent (17/70). Among patients who had received prior ASCT, 92.3 percent (12/13) achieved an objective response, with nine patients (69.2%) achieving a CR;

The median duration of response (DOR) had not yet been reached. The estimated event-free rates at 9 months were 84 percent;

Progression-free survival (PFS) data were preliminary and 6-month PFS was estimated at 80 percent. The median PFS had not yet been reached;

The majority of adverse events (AEs) were grade 1 or 2 in severity. The most frequently reported treatment emergent adverse events (TEAEs) of any grade were pyrexia (52.9%), hypothyroidism (30.0%), weight increased (28.6%), upper respiratory tract infection (27.1%), cough (17.1%), white blood cell count decreased (14.3%), and pruritus (14.3%);

Grade ≥3 TEAEs occurred in 21.4% of patients. The most frequently reported Grade 3 or higher TEAEs were upper respiratory tract infection (2.9%), pneumonitis (2.9%), and productive cough (2.9%);

Four patients (5.7%) discontinued study drug due to TEAEs, including pneumonitis (n=2), focal segmental glomerulosclerosis (n=1), and organizing pneumonia (n=1); there were no cases of TEAE leading to death; and

Immune-related AEs reported in more than five percent of patients included thyroid disorder (18.6%), pneumonitis (5.7%), and skin adverse reactions (5.7%).
Investor Webcast:
Date and Time: Monday, December 3, 2018 at 20:00 PST (Tuesday, December 4 at 12:00 China Standard Time)
Webcast: A live webcast and replay of the event will be available on BeiGene’s investor website, View Source

About Classical Hodgkin’s Lymphoma
Hodgkin’s lymphoma is one of the two major types of lymphoma that begin in the lymph nodes and tissues of the lymphatic system. All other lymphomas are classified as non-Hodgkin’s lymphomas. Classical Hodgkin’s lymphoma, the most common form representing about 95 percent of the patients with Hodgkin’s lymphoma, is characterized by the presence of very large cells called Reed-Sternberg cells. There were approximately 2,100 diagnosed cases of Hodgkin’s lymphoma in China in 2012.i Although the cancer can occur in both children and adults, it is most commonly diagnosed in young adults between the ages of 15 and 35 and in older adults over age 50.

About Tislelizumab
Tislelizumab (BGB-A317) is an investigational humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.

Discovered by BeiGene scientists, tislelizumab is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. The new drug application (NDA) for tislelizumab in China for patients with R/R cHL has been accepted by the China National Medical Products Administration (NMPA, formerly known as CFDA) and granted priority review status. BeiGene and Celgene Corporation have a global strategic collaboration for the development of tislelizumab in solid tumors in the United States, Europe, Japan and the rest of world outside Asia.

On December 3, 2018 Bio-Path Holdings, Inc., (NASDAQ: BPTH), a biotechnology company leveraging its proprietary DNAbilize antisense RNAi nanoparticle technology to develop a portfolio of targeted nucleic acid cancer drugs, reported that previously announced interim data from the Company’s Phase 2 study evaluating prexigebersen as a treatment for acute myeloid leukemia (AML) were presented in a poster at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place from December 1-4, 2018 in San Diego, CA (Press release, Bio-Path Holdings, DEC 3, 2018, View Source [SID1234531869]).

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Maro Ohanian, M.D., Assistant Professor of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, presented the poster titled, "Interim Safety and Efficacy of Lower Intensity Induction Therapy with Intravenous Prexigebersen (BP1001) in Patients with Untreated Acute Myeloid Leukemia (AML)." The poster reviewed interim data from the Company’s open-label Phase 2 study evaluating the efficacy and safety of prexigebersen in conjunction with low-dose cytarabine (LDAC), a therapeutic regimen well established in treatment of AML patients who cannot or elect not to be treated with more intensive chemotherapy. The primary objective of the study is to determine whether the combination of prexigebersen and LDAC provides greater efficacy than what would be expected with LDAC alone in this de novo patient population.

Prexigebersen was safely administered to patients with untreated AML, who were considered unsuitable for standard chemotherapy. Of the 17 evaluable patients, there were four patients (24%) who achieved complete responses and four patients with stable disease including one patient who achieved a morphologic leukemia free state and two patients who had significantly reduced bone marrow blasts. In total, 47% of the evaluable patients showed some form of response, including stable disease, to the combination treatment. Efficacy data are encouraging in this challenging population in which the majority of patients had secondary AML or adverse-risk AML, and compares favorably to the reported CR (complete remission), CRp (complete remission with incomplete platelet recovery), and CRi (complete remission with incomplete hematologic recovery) rate with LDAC alone of 7-13%1.

"We are excited to be presenting these important data at ASH (Free ASH Whitepaper) before an audience of world-leading scientists and oncologists, as they demonstrate the potential for the combination of prexigerbesen and LDAC to safely and effectively treat these de novo AML patients, including doubling the complete response to treatment compared to LDAC treatment alone," noted Peter H. Nielsen, chief executive officer of Bio-Path. "We look forward to presenting final data from this study as we expect they will provide even better results for these patients suffering with AML."

1 Heiblig, Mediterr J Hematol 2016; Kantarjian, J Clin Oncol 2012; Dohner, Blood 2014

On December 3, 2018 Helsinn Group, a Swiss pharmaceutical group focused on building quality cancer care products, and MEI Pharma, Inc. (Nasdaq: MEIP), an oncology company focused on the clinical development of novel therapies for cancer, reported interim data from a Phase 2 study evaluating pracinostat, a histone deacetylase inhibitor, in combination with azacitidine for the treatment of patients with IPSS-R high/very high-risk of Myelodysplastic Syndrome (MDS) (Press release, MEI Pharma, DEC 3, 2018, View Source [SID1234531866]). The data demonstrate a 9% discontinuation rate due to adverse events, a substantially lower rate than observed in an earlier study, as well as an encouraging 36% complete response rate among patients receiving at least 6 cycles of treatment. These data are being presented today at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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The ongoing Phase 2 open-label study is evaluating a 45 mg dose of pracinostat in combination with azacitidine in order to improve safety/tolerability and retain patients in study longer than in an earlier Phase 2 study evaluating a 60 mg dose. Prolonged treatment is envisaged to result in a systemic exposure to pracinostat sufficient to achieve the desired treatment effect. The data reported today reinforce results from a planned May 2018 interim analysis meeting a predefined discontinuation threshold and suggest a reduced dose of pracinostat may allow MDS patients to remain on treatment longer and thereby increase the likelihood of a treatment response. If the current Phase 2 open-label study is successful, Helsinn intends to initiate a global registration study.

Ehab Atallah, M.D., Study Chair, Associate Professor of Medicine, Medical College of Wisconsin, said: "Treatment options for patients with a higher risk of MDS are still limited and following diagnosis the survival rate is less than 18 months with the current standard of care. At the time of the Phase 2 data announced this year in May, I was excited to see that this treatment demonstrated that it can be offered to patients as a combination therapy and potentially improve outcomes. We’re pleased that the threshold for expansion of this study has been met, and I look forward to continuing to observe the progress of this combination treatment."

Ruben Giorgino, M.D. Ph.D. Helsinn Group Head of Clinical Development at Helsinn, commented: "Helsinn bolsters its commitment in developing pracinostat in combination with hypomethylating agents in patients with AML and with high risk MDS. Moving forward to the second stage of this really important Phase 2 clinical trial in MDS patients represents an important next step in our efforts to understand the potential benefit of pracinostat in these patients with poor prognosis and modest response to hypomethylating monotherapy".

Richard Ghalie, M.D., Senior Vice President, Clinical Development at MEI Pharma, commented: "The interim data demonstrating a 9% discontinuation rate due to adverse events, a substantially lower rate than observed in the earlier study, as well as an encouraging complete response rate to date of 36% of patients reaching the first disease assessment at 6 months, represents an opportunity to advance a promising new treatment for patients with high/very high-risk disease that currently have limited options."

The Phase 2 Study
The ongoing Phase 2 study is open-label and is investigating a 45 mg dose of pracinostat in combination with the standard dose of azacitidine in up to 60 patients with high and very high-risk MDS previously untreated with hypomethylating agents. The primary endpoints of the study are 1) safety and tolerability and 2) overall response rate, defined as complete remission (CR), partial remission (PR) and marrow CR. Secondary endpoints include CR rate, overall hematologic improvement (HI) progression-free survival and overall survival, among others.

As of the end of October 2018, 55 patients have completed at least one cycle of therapy. The data demonstrate a 9% discontinuation rate due to adverse events, 4% of which were early discontinuations (within the first 3 treatment cycles). Of note, 15% of patients discontinued because they advanced to Stem Cell Transplantation. The discontinuation rate reported today continues to meet the pre-defined threshold from the planned interim analysis conducted in May 2018 and is consistent with the discontinuation rate for azacitidine administered as a single agent.

In the group patients receiving at least 6 cycles of treatment, the complete response rate is 36%. The median duration on therapy is 4.7 months (range 0.5-13 months).

The 45 mg dose of pracinostat being evaluated in the Phase 2 is better tolerated than the 60 mg dose evaluated in a prior Phase 2 study. Treatment in the current Phase 2 study was generally well-tolerated: adverse events ≥ Grade 3 reported in 20% or more of patients are febrile neutropenia, anemia, neutropenia and thrombocytopenia. It is notable that patients in the current study were diagnosed with higher-risk MDS than in the prior study.

The study was initially designed with two stages: the completed first stage that met the predefined discontinuation rate threshold, and a randomized and placebo-controlled second stage triggered upon meeting the pre-defined discontinuation threshold in the first stage. Based on the discontinuation rate meeting the pre-defined threshold in a planned interim analysis in May 2018, the study design was amended by substituting stage 2 with an expanded open-label portion to enroll up to 60 patients to obtain data to support the design of a registration study upon successful completion of the Phase 2 study.

About Higher Risk MDS
Higher risk MDS (high and very high risk in the IPSS-R classification) is a serious medical condition, with median survival of less than 18 months. The high and very high-risk groups represent the highest unmet need in MDS, with median survival estimates of only 1.6 years and 0.8 years, respectively.

The only curative therapy is allogeneic stem cell transplantation (SCT), however most patients with MDS are not candidates for SCT given their typically advanced age, comorbidities and lack of a suitable donor. Standard therapy with HMAs in higher risk MDS provides modest responses, though azacitidine has been shown to improve survival when compared to conventional care regimens. Patients who do not respond to HMAs or progress after therapy with HMAs have a very poor outcome, with a median survival of less than one year.

About Pracinostat
Pracinostat is an oral histone deacetylase ("HDAC") inhibitor that is in a pivotal Phase 3 study in combination with azacitidine for the treatment of adults with newly diagnosed acute myeloid leukemia ("AML") who are unfit for intensive chemotherapy. It is also being evaluated in a Phase 2 study in patients with high or very high-risk myelodysplastic syndrome ("MDS"). The U.S. Food and Drug Administration has granted Breakthrough Therapy Designation for pracinostat in combination with azacitidine for the treatment of patients with newly diagnosed AML who are ≥75 years of age or unfit for intensive chemotherapy.

In August 2016, Helsinn and MEI Pharma entered into an exclusive license, development and commercialization agreement for pracinostat in AML and other potential indications.

The agreement provides that Helsinn is primarily responsible for development and commercialization costs for pracinostat in AML and other indications, including MDS. Pracinostat is an investigational agent and is not approved for commercial use in the U.S. and any country worldwide