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).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"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.

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).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.

On December 2, 2018 Kite, a Gilead Company (Nasdaq: GILD), reported two-year efficacy and safety data from the pivotal ZUMA-1 trial of Yescarta (axicabtagene ciloleucel) in patients with refractory large B-cell lymphoma (Press release, Kite Pharma, DEC 2, 2018, View Source;p=irol-newsArticle&ID=2378930 [SID1234531786]). With a minimum follow-up of two years after a single infusion of Yescarta (median follow up of 27.1 months), 39 percent of patients were in an ongoing response. This updated analysis with at least 24 months of follow-up was presented at the Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (ASH; Abstract #2967) and simultaneously published in The Lancet Oncology.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

This press release features multimedia. View the full release here: View Source

In October 2017, Yescarta became the first chimeric antigen receptor T (CAR T) cell therapy to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma. The U.S. Prescribing Information for Yescarta contains a Boxed Warning regarding the risk of cytokine release syndrome (CRS) and neurologic toxicities; see below for Important Safety Information.

At two years, the best objective response via investigator assessment (n=101) showed an overall response rate of 83 percent, with 58 percent of patients having achieved a complete response. With a median follow-up of 27.1 months, 39 percent of patients remained in response. Of the patients with an ongoing response at 12 months, 93 percent remained in response at 24 months. The median duration of response was 11.1 months; the median duration of complete response was not reached. Median overall survival was not reached.

"With aggressive cancers such as refractory large B-cell lymphoma, our primary goal is to extend the lives of patients," said Sattva S. Neelapu, MD, ZUMA-1 Co-Lead Investigator and Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "Outcomes with traditional standard of care for this highly refractory patient population have been extremely poor. Nearly 40 percent of patients in ZUMA-1 remain in response and half of the patients are still alive after at least two years of treatment with Yescarta."

In the two-year analysis (n=108), Grade 3 or higher CRS and neurologic events were seen in 11 percent and 32 percent of patients, respectively, and were generally reversible. Four patients developed new serious adverse events (occurring since the previous August 11, 2017 data cutoff), none of which were related to Yescarta. No new Yescarta-related CRS or neurologic events or deaths have occurred since the one-year analysis.

"The two-year point is a another major milestone for Yescarta, which has extended the lives of a significant number of patients in ZUMA-1 and has yielded important learnings that inform further research and development of CAR T therapies," said Alessandro Riva, MD, Executive Vice President, Oncology Therapeutics and Head, Cell Therapy, Gilead Sciences. "These data are not only significant for the lymphoma community, but also reinforce our leadership in cell therapy as we aim to transform the treatment of a variety of cancers with other investigational therapies in our pipeline."

Full study results are available in The Lancet Oncology:

Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30864-7/fulltext

U.S. Important Safety Information for Yescarta

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS.
CYTOKINE RELEASE SYNDROME (CRS): CRS occurred in 94% of patients, including 13% with ≥ Grade 3. Among patients who died after receiving Yescarta, 4 had ongoing CRS at death. The median time to onset was 2 days (range: 1-12 days) and median duration was 7 days (range: 2-58 days). Key manifestations include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Ensure that 2 doses of tocilizumab are available prior to infusion of Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES: Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks, with a median time to onset of 4 days (range: 1-43 days) and a median duration of 17 days. Grade 3 or higher occurred in 31% of patients. The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with Yescarta. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.

YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. The required components of the Yescarta REMS are: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Yescarta are trained about the management of CRS and neurologic toxicities. Further information is available at www.YESCARTAREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions may occur. Serious hypersensitivity reactions including anaphylaxis may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients, and in 23% with ≥ Grade 3. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Yescarta infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 36% of patients and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade 3 or higher cytopenias not resolved by Day 30 following Yescarta infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after Yescarta infusion.

HYPOGAMMAGLOBULINEMIA: B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The most common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

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.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.

On December 2, 2018 Nordic Nanovector ASA (OSE: NANO) reported that updated results from its LYMRIT 37-01 Phase 1/2 clinical study of Betalutin (177Lu-lilotomab-satetraxetan) in patients with relapsed/refractory indolent non-Hodgkin’s lymphoma (R/R iNHL) have been presented in a poster at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (1-4 December 2018 in San Diego, CA, USA) (Press release, Nordic Nanovector, DEC 2, 2018, View Source [SID1234553486]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The published dataset (as of 2 November 2018) includes 74 evaluable patients; all patients received Betalutin as a single administration and have six or more months of follow-up.

Lisa Rojkjaer, MD, Chief Medical Officer of Nordic Nanovector, commented: "We are very pleased with the clinical data, which continue to support our decision to compare two promising dose regimens in the pivotal Phase 2b PARADIGME trial. The efficacy and safety profile of Betalutin, the duration of response and the convenience of a single administration underscore the potential of Betalutin for the treatment of patients with advanced-stage follicular lymphoma."

The conclusions from the updated study results are that a single administration of Betalutin is well-tolerated and continues to demonstrate encouraging anti-tumour activity in recurrent iNHL, especially in follicular lymphoma (FL) patients, the primary NHL population for which Betalutin is being developed. Key results are:

Patients Number of patients (n) Overall Response Rate (ORR) Complete Responses (CR)
All iNHL patients 74 61 % 28 %
FL patients 57 65 % 28 %
3L FL patients (≥2 prior therapies) 37 70 % 32 %
FL patients in Arm 1
(40 mg lilotomab followed by 15 MBq/kg Betalutin) 25 64 % 32 %
FL patients in Arm 4
(100 mg/m2 lilotomab followed by 20 MBq/kg Betalutin) 16 69 % 25 %
RTX refractory FL, ≥2 prior therapies 21 62 % 19 %
The median follow-up time for all patients was 18.4 months (range 3.2-61.6 months). The median duration of response (mDoR) was 9.0 months for all patients and 20.7 months for those with a CR. Twenty-five patients (34%) have remained free of disease progression for 12 months or more. Follow-up for duration of response is on-going.

Betalutin therapy was well tolerated with no unexpected safety findings and most common adverse events were predictable and manageable.

Two recommended Phase 2 doses were identified from this study and are now being compared in the pivotal, randomised Phase 2b PARADIGME trial in relapsed, anti-CD20 refractory FL patients who have received two or more prior therapies.

Poster details

Abstract 2879

Abstract title: LYMRIT 37-01: A phase I/II study of 177Lu-lilotomab satetraxetan (Betalutin) antibody-radionuclide-conjugate (ARC) for the treatment of relapsed non-Hodgkin’s lymphoma (NHL) – Analysis with 6-month follow-up

Authors: A. Kolstad, A et al.

The abstract is available at View Source the poster has been published on the Nordic Nanovector website in the section: /what-we-do/scientific-publications/scientific-posters.

Conference call/audio cast details:

Nordic Nanovector will host a conference call, 3 December 2018, at 08:00 CET. A question and answering session will follow the presentation. The conference call presentation will be available at: View Source

To participate in the call either:

Press crtl+click on the link https://bit.ly/2AzfKlS or paste it into your browser

Please note that the link will become active 15 minutes prior to the event. You will be asked to type in your phone number and registration details. The Event Conferencing system will automatically call you back on the phone number you provide and place you into the event.

Or

Use the manual dial-in numbers and participant passcode: 332692 (note that this connection might take more time):

Norway Dial-in Tollfree/Freephone 800 51025

Norway, Oslo Dial-in Local +47 2100 2613

About ASH (Free ASH Whitepaper)

The ASH (Free ASH Whitepaper) annual meeting is the premier event for scientific exchange in the field of haematology, attracting more than 20,000 attendees from all over the world. Typically, more than 5,000 scientific abstracts are submitted each year, and more than 3,000 abstracts are accepted for oral and poster presentations through an extensive peer review process.

About Betalutin

Betalutin is a tumour-seeking anti-CD37 antibody (lilotomab) conjugated to a low-intensity radionuclide (lutetium-177). It has shown promising efficacy and safety in the first part of the Phase 1/2 LYMRIT 37-01 clinical study in relapsed/refractory follicular lymphoma (R/R FL). A global, randomised Phase 2b trial, PARADIGME, in third line (3L) FL patients who are refractory to anti-CD20 immunotherapy (including rituximab, RTX) is currently on-going.

Betalutin is also being investigated in the Phase 1b Archer-1 study in combination with RTX in second-line FL patients, and in the Phase 1 LYMRIT 37-05 study in patients with R/R diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin’s lymphoma (NHL).

Betalutin has been granted Fast Track designation in the US and Promising Innovative Medicine (PIM) Designation in the UK for the treatment of patients with R/R FL. Betalutin also received Orphan Drug designations for FL in both the USA and Europe in 2014.

Betalutin is selective for CD37, which is highly expressed on the surface of B-cell non-Hodgkin’s lymphoma (NHL) cells. When bound to CD37 on tumour cells, Betalutin is internalised, causing DNA damage and cell death.

About LYMRIT 37-01

LYMRIT 37-01 is a Phase 1/2 dose-escalation study to determine the safety, pharmacokinetics and preliminary efficacy of a single dose of Betalutin in patients with relapsed iNHL, and to establish a recommended Phase 2 dose for the global, randomised Phase 2b PARADIGME trial.

LYMRIT 37-01 recruited 74 pts [57 follicular (FL), 7 mantle cell (MCL), 9 marginal zone (MZL), 1 small lymphocytic (SLL)] at 13 sites between December 2012 and February 2018. Median age was 68 years (range 38-87; 69% ≥ 65); the median number of prior therapies was 3 (range 1-9); 48 pts (65%) received 2 or more prior therapies.