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IMBRUVICA® (ibrutinib) Data in Chronic Lymphocytic Leukemia (CLL) Show up to Seven Years of Progression-free Survival (PFS) in 80 Percent of Previously Untreated Patients, the Longest Follow-up for a Bruton’s Tyrosine Kinase Inhibitor to Date

On December 2, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported the results of up to seven years of clinical trial follow-up for IMBRUVICA (ibrutinib) monotherapy in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the longest follow-up for a Bruton’s tyrosine kinase (BTK) inhibitor to date (Press release, AbbVie, DEC 2, 2018, View Source [SID1234531819]). The updated Phase 1b/2 data demonstrated durable responses in CLL/SLL patients with an overall response rate (ORR) of 89 percent. Evaluated patients included those with high-risk genomic factors such as complex karyotype and unmutated IGHV, and more than 70 patients with three to 12 prior lines of therapy. Progression-free survival (PFS) rates were also sustained (estimated seven-year rates of 80% for previously untreated patients; 32% in the highly pre-treated relapsed/refractory [R/R] groups). The analysis also found that PFS trended better for R/R patients when treated with ibrutinib in earlier lines of therapy (after one or two prior lines of therapy versus three or more lines of prior therapy).

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These data were presented today at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA (Abstract #3133). IMBRUVICA is a once-daily, first-in-class BTK inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"With up to seven years of follow up, IMBRUVICA monotherapy continues to show long-lasting responses and survival benefits in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "These results help demonstrate that the benefits of IMBRUVICA can be sustained for many years, which were seen in patients with CLL and SLL that are typically more difficult to treat due to high-risk genomic factors."

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

"The long-term follow-up data with ibrutinib continues to look promising, with remissions that suggest patients are able to live many years beyond what was previously expected," said John C. Byrd, M.D., Warren Brown Chair of Leukemia Research, Professor of Medicine at the Ohio State University and the lead investigator of the seven-year follow-up study. "These data also suggest that starting treatment with ibrutinib as early as possible for CLL and SLL provides the best efficacy over the long-term – an important factor that treating physicians should consider."

About Abstract #3133: Up to 7 Years of Follow-up of Single-Agent Ibrutinib in the Phase 1b/II PCYC-1102 Trial of First Line and Relapsed/Refractory Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Poster presentation: Sunday, December 2 at 6:00 p.m. PST

In the PCYC-1102 and PCYC-1103 studies, newly diagnosed and R/R CLL/SLL patients, including those with high-risk features, received IMBRUVICA with up to seven years of follow up (n=132).

ORR was 89 percent for all patients (complete response [CR], 15%), with similar rates in previously untreated (87%) and R/R patients (89%). CR rates were higher in previously untreated patients (32%) than in R/R patients (10%). Median duration of response (DOR) was not reached (95% confidence interval [CI]: 0+-85+) for newly diagnosed patients but was 57 months (95% CI: 0+-85+) for R/R patients. Median PFS was not reached (95% CI: NE-NE) for newly diagnosed patients and was 51 months (95% CI: 37-70) for R/R patients. Estimated seven-year PFS rates were 80 percent and 32 percent for newly diagnosed and R/R patients, respectively. Median overall survival (OS) was not reached in newly diagnosed (95% CI: 80-NE months) or R/R patients (95% CI: 63-NE months), with estimated seven-year OS rates of 75 percent and 52 percent, respectively.

High grade adverse events (AEs) were reported in 74 percent of newly diagnosed patients and 89 percent of R/R patients. Hypertension (newly diagnosed, 32%; R/R, 26%), diarrhea (newly diagnosed, 16%; R/R, 4%) and hyponatremia (newly diagnosed, 10%; R/R, 0%) were among the most common grade 3 or higher treatment-emergent AEs. Major hemorrhage and grade 3 or higher atrial fibrillation, thrombocytopenia, anemia and arthralgia were observed in 11 percent or less of newly diagnosed and R/R patients. In addition, infection (newly diagnosed, 23%; R/R, 55%) was more common in R/R patients. No new or unexpected AEs were observed, and the occurrence of most grade 3 or higher AEs and serious AEs decreased over time, with the exception of hypertension.

Additional presentation on ibrutinib monotherapy in CLL at ASH (Free ASH Whitepaper) 2018

Additional data presented at ASH (Free ASH Whitepaper) include a sub-analysis derived from patients with R/R CLL enrolled in the RESONATE trial. The sub-analysis assessed the effects of ibrutinib versus ofatumumab on T-cell function (including degranulation and cytokine release) and proliferation. CLL is a B-cell malignancy that is also characterized by profound immune dysregulation, including dysfunctional T cells. These data will also be presented at ASH (Free ASH Whitepaper) on December 2 (abstract #3114).

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.

Unum Therapeutics Presents Preliminary Results from Ongoing Phase 1 Study ATTCK-20-03 at the 2018 ASH Annual Meeting

On December 2, 2018 Unum Therapeutics Inc. (NASDAQ: UMRX), reported preliminary results from the ongoing, multicenter Phase 1 ATTCK-20-03 study of ACTR707 in combination with rituximab in patients with relapsed/refractory CD20+ B cell non-Hodgkin lymphoma (r/r NHL) at the American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in San Diego, CA (Press release, Unum Therapeutics, DEC 2, 2018, View Source [SID1234531811]).

Unum presented updated data from all patients in the first two dose levels of ACTR707 in combination with rituximab. First-in-human dosing was well tolerated, with no dose-limiting toxicities observed and no serious or severe adverse events of cytokine release syndrome (CRS) or neurological events observed in any patients. Three of the six patients treated at dose level 1 achieved a complete response, two of which were ongoing with greater than 6 months follow up, as of the November 1, 2018 cutoff. One of the three patients in dose level 2 also achieved a complete response, which remained ongoing as of the November 1 cutoff. Based on these data, enrollment in dose level 3 is progressing as planned.

"These preliminary results demonstrate ACTR T cell activity with complete responses at both dose levels, dose-dependent ACTR707 expansion, and a well-tolerated safety profile, supporting further dose escalation," said Michael Vasconcelles, Chief Medical Officer of Unum. "We are encouraged by these data and the potential of ACTR707 plus rituximab to have a best-in-class profile relative to CD19-directed CAR-T therapies in this heavily pretreated patient population with aggressive non-Hodgkin lymphoma."

Pharmacodynamic evidence of activity of ACTR707 in combination with rituximab supporting the proof of mechanism includes dose-dependent peak ACTR707 expansion and ACTR707 persistence, detectable > 200 days in the peripheral blood post ACTR707 infusion. Additionally, no impact of ACTR707 on the pharmacokinetics of rituximab has been observed. ACTR707-related serious adverse events were febrile neutropenia in 2 patients and 1 case of pancytopenia.

About the ATTCK-20-03 Trial

ATTCK-20-03 is a Phase I, multi-center, open label, single arm clinical trial evaluating ACTR707 in combination with rituximab in patients with r/r NHL. Eligible patients for enrollment must have, among other criteria, received adequate prior anti-lymphoma therapy, including anti-CD20 monoclonal antibody and chemotherapy, for their CD20+ r/r NHL. Key eligibility criteria include: pre-specified eligible NHL subtypes, including DLBCL, disease progression following immediate prior therapy, adequate organ function and performance status, and measurable disease. The trial design includes a dose escalation phase using an adaptive design, followed by a cohort expansion phase. Primary study objectives are to characterize the safety of ACTR707 in combination with rituximab and to determine the maximum tolerated dose and proposed recommended Phase 2 dose. Secondary study objectives include: assessment of the anti-lymphoma activity of the combination, ACTR707 persistence, rituximab pharmacokinetics, and inflammatory markers and cytokine levels. Following leukapheresis, each patient receives lymphodepletion followed by the first infusion of rituximab and then a single infusion of ACTR707. Rituximab infusions continue on a regular, pre-specified schedule.

About ACTR707
ACTR707 is an investigational drug that is being evaluated in adult patients with CD20+ r/r NHL in combination with rituximab as well as in adult patients with other cancer types in combination with other antibodies. ACTR707 was identified through a comprehensive high-throughput screening effort aimed at identifying receptors with improved functional characteristics across several dimensions. In preclinical testing, ACTR707 demonstrated potent activity against a wide range of hematologic and solid tumor cancers. Given the challenges of the immunosuppressive solid tumor microenvironment, Unum believes that ACTR707’s increased activity may be particularly important in addressing solid tumor cancers. ACTR707 is currently being tested in combination with rituximab in patients with r/r NHL in a Phase I multi-center open label clinical trial, ATTCK-20-03. Testing is expected to be initiated later in 2018 in ATTCK-34-01, a Phase I multi-center open label clinical trial exploring the combination of ACTR707 with trastuzumab in patients with HER2+ advanced cancers.

MEI Pharma Presents Clinical Data from Ongoing Phase 1b Study of ME-401 in Patients with Indolent B-Cell Malignancies at the 2018 American Society of Hematology Annual Meeting

On December 2, 2018 MEI Pharma, Inc. (NASDAQ: MEIP), a late-stage pharmaceutical company focused on advancing new therapies for cancer, reported that results from an ongoing Phase 1b study support the complementary potential of intermittent and continuous dosing schedules of ME-401, a selective phosphatidylinositol 3-kinase ("PI3K") delta inhibitor, to optimize the clinical risk-benefit ratio in patients with relapsed/refractory follicular lymphoma (Press release, MEI Pharma, DEC 2, 2018, View Source [SID1234531809]). The data demonstrate that ME-401, as both a single agent and in combination with rituximab, continues to be associated with overall high objective response rates. In addition, low rates of Grade 3 immune-related adverse events (irAEs) were observed in patients on the intermittent dosing schedule while maintaining a high level of clinical response. These data are being presented today at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

The data announced today continue to support the rationale for MEI’s planned Phase 2 study that evaluates both a continuous (CS) and intermittent (IS) dosing schedule of ME-401 as a means to enhance the drug candidate’s clinical profile and thus potentially deliver improved benefits to patients. The Phase 2 study is expected to start around year-end and is intended to support MEI’s accelerated approval registration strategy if successful.

Patients in the Phase 1b study received ME-401 as a single agent (dosed on the CS or IS) and in combination with rituximab (dosed on the IS only) to explore treatment options for patients with B-cell malignancies. The IS dosing regimen consists of 60 mg given continuously, once-daily, for the first 2 cycles followed by 60 mg given on days 1-7 of a 28-day cycle and results showed:

As a single agent, 76% objective response rate in patients with relapsed or refractory follicular lymphoma (FL), and 100% in all patients with chronic lymphocytic lymphoma (CLL) and small lymphocytic lymphoma (SLL).
In combination with rituximab, 78% objective response rate in patients with FL.
Median duration of response has not been reached. The lead patient has a duration of response of approximately 20 months and the median follow-up is 9.3 months.
Low rate of irAEs; 4 irAEs were reported in 36 patients administered the IS, with all cases occurring in the first 2 cycles following the switch to IS.
89% of patients switched to IS remain on therapy.
Disease control was maintained in 72% of these patients.
70% of patients who resumed on the continuous daily dosing schedule (CS) recaptured a response after progressing on IS.
The ME-401 ASH (Free ASH Whitepaper) 2018 poster can be accessed on the MEI Pharma website.

"The data presented today are very supportive of our rationale to investigate both a continuous and intermittent dosing regimen as part of our Phase 2 study evaluating ME-401 in follicular lymphoma and may also help advance its complementary potential to deliver improved benefits to patients in combination with other modalities," said Daniel P. Gold, Ph.D., president and chief executive officer of MEI Pharma. "While advances have been made in the treatment of B-cell malignancies, there remains a significant need for innovative therapies across a range of indications and patient populations not addressed by current therapeutic options; we believe the emerging clinical profile of ME-401, as both a single agent or in combination, holds the potential to deliver improved clinical benefit to patients with B-cell diseases."

ME-401 Phase 1b ASH (Free ASH Whitepaper) 2018 Data
ME-401 is being evaluated in an ongoing Phase 1b dose escalation study in patients with relapsed or refractory B-cell malignancies. Through October 2018, 60 patients were enrolled across three groups:

Group 1 included 31 patients with relapsed FL (n = 22) or CLL/SLL (n = 9) who received ME-401 CS at doses ≥60 mg per day in the dose escalation phase of the study. Beginning in December 2017 a total of 17 patients from Group 1 (FL=9, CLL/SLL=8) advanced to the IS after in cycle 4 or later cycles.
Group 2 included 16 patients with relapsed FL (n = 9), diffuse large B-cell lymphoma (n = 5), marginal zone lymphoma (MZL, n = 1), and CLL (n = 1) who received rituximab 375 mg/m2 x 8 doses over 6 months and ME-401 dosed under the IS regimen after receiving ME-401 60 mg daily for the first two cycles.
Group 3 may enroll up to 30 patients with relapsed FL/CLL/SLL in an expansion cohort of ME-401 using the IS regimen after receiving ME-401 60 mg daily for the first two cycles. In this group, 13 patients were enrolled to date with one FL patient reaching the Cycle 6 disease assessment as data cut off.
The median number of prior therapies of patients in the study is two and 50% of patients enrolled were ≥ 3rd line of therapy. Responses are assessed after 2 cycles (58 days) and 6 cycles, and then every 6 cycles. Ninety-two percent of all patients were previously treated with an anti-CD20 antibody.

Objective Response Rates

The objective response rate of patients across all groups with FL is 76% (29/38) and for CLL/SLL is 100% (11/11).
As a single agent, 76% (22/29) objective response rate in patients with FL and 100% (10/10) in patients with CLL and SLL.
In combination with rituximab, 78% (7/9) objective response rate in patients with FL.
Duration of Response

In FL and CLL/SLL patients, the median follow-up is 9.3 months (range, approximately 2.1 to 19.5 months) with no median yet reached.
Across all groups, failure-free survival (i.e. no disease progression on the continuous dosing schedule) in FL and CLL/SLL has not reached a median yet; median follow-up is 6.9 months (range 0.4 to 21.1 months).
72% of patients across all groups on the IS regimen have not experienced disease progression with a median follow-up of 7.9 months (range, 0.8 to 10.5 months).
Of the 10 patients that progressed on the IS regimen, 70% of patients retreated with daily dosing recaptured disease response.
Rates of irAEs

Of the 36 patients who switched to IS, only 11% (4/36) experienced an irAE after the switch. All 4 reported cases of irAEs occurred in the first 2 cycles after the switch to the IS regimen.
About ME-401
ME-401 is an investigational oral phosphatidylinositol 3-kinase ("PI3K") delta inhibitor; PI3K delta is often overexpressed in cancer cells and plays a key role in the proliferation and survival of hematologic cancer cells. ME-401 displays high selectivity for the PI3K delta isoform and has distinct pharmaceutical properties from other PI3K delta inhibitors. It is being clinically evaluated in patients with various B-cell malignancies. MEI is initiating a Phase 2 study to evaluate the efficacy, safety, and tolerability of ME-401 as a single agent in patients with follicular lymphoma after failure of at least two prior systemic therapies including chemotherapy and an anti-CD20 antibody. The Phase 2 study is intended to support an accelerated approval marketing application with the U.S. Food and Drug Administration.

Aprea Therapeutics Presents Results From Phase Ib/II Clinical Study of APR-246 and Azacitidine (AZA) in Patients with TP53 Mutant Myelodysplastic Syndromes (MDS) at the 2018 American Society of Hematology (ASH) Annual Meeting in San Diego

On December 2, 2018 Aprea Therapeutics reported results at the 2018 ASH (Free ASH Whitepaper) Annual Meeting from its Phase Ib/II clinical study in MDS (Press release, Aprea, DEC 2, 2018, View Source [SID1234531805]). The ongoing study is evaluating the safety and efficacy of APR-246 in combination with azacitidine for the treatment of TP53 mutated MDS. The study is sponsored by the Moffitt Cancer Center with financial support from the MDS Foundation and the Aplastic Anemia and MDS International Foundation as administrator for the Evans MDS Clinical Research Consortium.

The overall response rate in 20 evaluable patients was 95%, with 14 (70%) patients achieving a complete remission (CR) at data cutoff. Relative to baseline, p53 immunohistochemistry positivity, mutant TP53 variant allele frequency (VAF) and TP53 minimal residual disease (MRD) were significantly decreased at time of disease assessment. No dose-limiting toxicities have been experienced to date and no exacerbation of the expected AZA-related safety profile has been observed.

"The expanding data set from this study is very encouraging," said David Sallman, M.D., lead principal investigator of the clinical study from the Moffitt Cancer Center. "As of this latest data cutoff, responses have been achieved in nearly all patients, including a 70% complete remission rate, and accompanied by deep molecular remission in the majority of patients as assessed by serial TP53 analysis. In addition, the overall safety experience indicates that the combination regimen of APR-246 and azacitidine is both safe and well-tolerated. Comparison of the current data set to historical AZA clinical experience suggests that combination of APR-246 with AZA may offer these patients a better potential treatment option than AZA alone."

"The continued positive data from this clinical study has created the potential for a new treatment paradigm for patients with few therapeutic options," said Christian S. Schade, President and Chief Executive Officer of Aprea. "As a result of this exciting progress, Aprea expects to soon begin enrolling a randomized, controlled Phase III clinical study of APR-246 in combination with AZA for the treatment of TP53 mutated MDS."

About the Clinical Study

Eligible patients in the Phase Ib/II clinical study include HMA naïve, TP53 mutated MDS and oligoblastic acute myeloid leukemia (AML, ≤ 30% blasts). In the Phase Ib part of the clincal study, patients received APR-246 in a 3+3 dose escalation design (50, 75, 100 mg/kg lean body weight) IV daily over 4 days in a lead-in phase (days -14 to -10), followed by the same dose of APR-246 (days 1-4) and AZA 75 mg/m2 SC/IV over 7 days (days 4-10 or 4-5 and 8-12) in 28-day cycles. In the Phase II part of the clinical study, patients receive APR-246 as a 4,500 mg fixed dose IV daily (days 1-4) and AZA over 7 days (days 4-10 or 4-5 and 8-12) in 28-day cycles. Primary objective in Phase Ib part of the clinical study was safety, with AEs graded by CTCAE v4.03 and DLT assessment over 6 weeks. Secondary endpoints included response rate by IWG 2006 criteria, PFS, OS, as well as serial next generation sequencing and p53 immunohistochemistry for evaluation of clonal suppression and depth of remission. In the Phase II part of the clinical study the primary endpoint is response rate.

About Myelodysplastic Syndrome

Myelodysplastic syndromes (MDS) represents a spectrum of hematopoietic stem cell malignancies in which bone marrow fails to produce sufficient numbers of healthy blood cells. Approximately 30-40% of MDS patients progress to acute myeloid leukemia (AML) and mutation of the p53 tumor suppressor protein is thought to contribute to disease progression. Mutations in p53 are found in up to 20% of MDS and AML patients and are associated with poor overall prognosis.

About p53 and APR-246

The p53 tumor suppressor gene is the most frequently mutated gene in human cancer, occurring in approximately 50% of all human tumors. These mutations are often associated with resistance to anti-cancer drugs and poor overall survival, representing a major unmet medical need in the treatment of cancer.

APR-246 has been shown to reactivate mutant and inactivated p53 protein – by restoring wild-type p53 conformation and function – and thereby induce programmed cell death in human cancer cells. APR-246 has demonstrated pre-clinical anti-tumor activity in a wide variety of solid and hematological (blood) tumors, including MDS, AML, and ovarian cancer, among others. Additionally, strong synergy has been seen with both traditional anti-cancer agents, such as chemotherapy, as well as newer mechanism-based anti-cancer drugs and immuno-oncology checkpoint inhibitors. In addition to pre-clinical testing, a Phase I/II clinical program with APR-246 has been completed, demonstrating a favorable safety profile and both biological and confirmed clinical responses in hematological malignancies and solid tumors with mutations in the TP53 gene.

Celgene Corporation and Acceleron Pharma Announce Results of the Phase 3 MEDALIST Trial Evaluating Luspatercept in Patients with Myelodysplastic Syndromes at the ASH 2018 Plenary Session

On December 2, 2018 Celgene Corporation (NASDAQ: CELG) and Acceleron Pharma Inc. (NASDAQ: XLRN) reported results from the pivotal, phase 3 MEDALIST trial evaluating the efficacy and safety of investigational luspatercept to treat patients with ring sideroblast (RS+) myelodysplastic syndromes (MDS)-associated anemia who require red blood cell transfusions and who had failed, were intolerant to, or ineligible for erythropoietin therapy (Press release, Celgene, DEC 2, 2018, View Source [SID1234531801]). Results were presented by Alan F. List, M.D. during the Plenary Scientific Session at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, C.A. (Abstract #1).

"Severe anemia resulting in red blood cell transfusion dependence is a significant challenge for patients with low- and intermediate-risk MDS. Those who become resistant or refractory to currently available treatments have limited alternatives," said Dr. List, President and CEO of Moffitt Cancer Center. "The findings from MEDALIST are very exciting as they support the hypothesis that targeting red blood cell precursor maturation could help to address patients’ anemia and allow them to achieve transfusion independence."

MEDALIST met the primary endpoint of red blood cell transfusion independence (RBC-TI) for 8 or more weeks during the first 24 weeks of the study. Treatment with luspatercept resulted in a statistically significantly greater proportion of patients achieving RBC-TI ≥ 8 weeks compared to placebo. The study also found in secondary endpoints that treatment with luspatercept resulted in a statistically significant higher percentage of patients achieving RBC-TI of 12 or more weeks in the first 24 or 48 weeks of the study, as well as hematologic improvement-erythroid (HI-E) of 8 or more weeks.

Endpoints Luspatercept Placebo P-Value
RBC-TI ≥8 weeks (weeks 1-24) 37.9 % (58/153) 13.2 % (10/76) < 0.0001
RBC-TI ≥12 weeks (weeks 1-24) 28.1 % (43/153) 7.9 % (6/76) 0.0002
RBC-TI ≥12 weeks (weeks 1-48) 33.3 % (51/153) 11.8 % (9/76) 0.0003
HI-E ≥ 8 weeks (IWG 2006, weeks 1-24) 52.9 % (81/153) 11.8 % (9/76) < 0.0001

MEDALIST Safety Summary

Treatment-emergent adverse events (TEAEs) of Grade 3 or 4 were reported in 42.5% (65/153) of patients receiving luspatercept and 44.7% (34/76) of patients receiving placebo. Progression to acute myeloid leukemia (AML) occurred in four patients, three patients (2.0%) receiving luspatercept and one patient (1.3%) receiving placebo. Five patients receiving luspatercept (3.3%) and four patients receiving placebo (5.3%) experienced one or more TEAE that resulted in death.

Most common TEAEs of any Grade in Greater than 10% of Patients in Either Arm

Luspatercept
N=153

Placebo
N=76

Fatigue 26.8 % 13.2 %
Diarrhea 22.2 % 9.2 %
Asthenia 20.3 % 11.8 %
Nausea 20.3 % 7.9 %
Dizziness 19.6 % 5.3 %
Back pain 19.0 % 6.6 %

"The MEDALIST results demonstrate the potential clinical benefit of luspatercept in achieving red blood cell transfusion independence in patients with low-to-intermediate risk RS+ MDS, an area in need of new treatments," said Alise Reicin, MD, President, Global Clinical Development for Celgene. "Based on these results, we are encouraged that this first-in-class erythroid maturation agent may help these patients address the underlying cause of their disease-related chronic anemia."

"It’s truly an honor to showcase the results from the MEDALIST trial as the first presentation of the ASH (Free ASH Whitepaper) Plenary Session," said Habib Dable, President and Chief Executive Officer of Acceleron. "The results from the MEDALIST trial increase our confidence in the potential of luspatercept to provide a meaningful treatment option for patients suffering from lower-risk RS+ MDS worldwide. We’re excited to continue our clinical development program in MDS, beta-thalassemia, and myelofibrosis, while also exploring additional applications for luspatercept in a range of diseases associated with anemia."

Luspatercept is not approved in any region for any indication. The companies are planning regulatory application submissions of luspatercept in the United States and Europe in the first half of 2019.

About MEDALIST

MEDALIST is a phase 3, randomized, double blind, placebo-controlled, multi-center study evaluating the safety and efficacy of luspatercept in patients with very low-, low-, or intermediate-risk non-del(5q) myelodysplastic syndromes (MDS). All patients were RBC transfusion dependent and were either refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) therapy, or were ESA naïve with endogenous serum erythropoietin ≥ 200 U/L, and had no prior treatment with disease modifying agents. The median age of the patients enrolled in the trial was 71 years in the luspatercept treatment group and 72 years in the placebo group. Median transfusion burden in both treatment arms was 5 RBC units/8 weeks. 229 patients were randomized to receive either luspatercept 1.0 mg/kg (153 patients) or placebo (76 patients) via subcutaneous injection once every 21 days. The study was conducted at 65 sites in 11 countries.

About Luspatercept

Luspatercept is a first-in-class erythroid maturation agent (EMA) that is believed to regulate late-stage red blood cell maturation. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Phase 3 clinical trials continue to evaluate the safety and efficacy of luspatercept in patients with MDS (the MEDALIST trial) and in patients with beta-thalassemia (the BELIEVE trial). The COMMANDS phase 3 trial in first-line, lower-risk, MDS patients, the BEYOND phase 2 trial in non-transfusion-dependent beta-thalassemia, and a phase 2 trial in myelofibrosis are ongoing. For more information, please visit www.clinicaltrials.gov.