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.

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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 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]).

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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.

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.

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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 Takeda Pharmaceutical Company Limited (TSE:4502) reported that data from the Phase 3 randomized, TOURMALINE-MM3 study evaluating the effect of single-agent oral NINLARO (ixazomib) as a maintenance therapy in adult patients diagnosed with multiple myeloma who previously responded to high-dose therapy (HDT) and autologous stem cell transplant (ASCT) will be presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting on Sunday, December 2, 2018 in San Diego, California (Press release, Takeda, DEC 2, 2018, View Source [SID1234531792]). NINLARO is currently not approved as a maintenance therapy for multiple myeloma following ASCT.

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The trial achieved its primary endpoint with NINLARO resulting in a statistically significant improvement in progression-free survival (PFS) versus placebo in adult patients diagnosed with multiple myeloma who responded to HDT and ASCT as assessed by an Independent Review Committee (IRC) (HR 0.72; p-value=0.002). This corresponds to a 28 percent reduction in risk of progression or death and a 39 percent improvement in PFS with NINLARO compared with placebo. The safety profile of NINLARO in the maintenance setting is consistent with previously reported results of single-agent NINLARO use.

"A growing body of evidence has shown that maintenance therapy in multiple myeloma may prolong the duration of disease control," said Meletios Dimopoulos, MD, Professor and Chairman of the Department of Clinical Therapeutics at the University Athens School of Medicine, Athens, Greece. "As currently approved options are limited and do not include a proteasome inhibitor, there is a need for additional maintenance treatments that can sustain response and have a tolerable safety profile. Data from the TOURMALINE-MM3 clinical trial supports single-agent NINLARO as a potential oral proteasome inhibitor maintenance therapy option post-ASCT."

"The positive results from this pivotal study – the first and only Phase 3 placebo controlled study evaluating a proteasome inhibitor in this setting – support NINLARO as a potential maintenance therapy for patients who have undergone a stem cell transplant," said Jesús Gómez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. "It is crucial that we continue to support patients by developing treatment options aimed to maintain or deepen response and delay disease progression. According to the findings, patients treated with NINLARO had improved progression-free survival over those in the control arm, which corresponds to a reduced risk of progression or death of nearly one-third."

"As a result of continued research, the multiple myeloma treatment landscape is constantly evolving. While this is encouraging news for the multiple myeloma community, there is still work to be done to further our goal of addressing the unmet needs of patients," said Brian GM Durie, M.D., Chairman of the Board, International Myeloma Foundation. "To that end, the development of additional safe and effective maintenance therapies is essential."

Maintenance Therapy With the Oral Proteasome Inhibitor (PI) Ixazomib Significantly Prolongs Progression-Free Survival (PFS) Following Autologous Stem Cell Transplantation (ASCT) in Patients With Newly Diagnosed Multiple Myeloma (NDMM): Phase 3 TOURMALINE-MM3 Trial Sunday, December 2, 2018, 7:30 – 9:00 a.m., Marriott Marquis San Diego Marina, Grand Ballroom 7

Key findings, which will be presented by Dr. Meletios Dimopoulos, include:

The trial achieved its primary endpoint with NINLARO resulting in a statistically significant improvement in PFS versus placebo in adult patients diagnosed with multiple myeloma who responded to HDT and ASCT as assessed by an Independent Review Committee (IRC) (HR 0.72; 95% CI: 0.582, 0.890; p-value=0.002). This corresponds to a 28 percent reduction in risk of progression or death and a 39 percent improvement in PFS with NINLARO.
Per IRC assessment, median PFS for patients in the NINLARO arm was 26.5 months compared to 21.3 months in the placebo arm.
Conversion from documented minimal residual disease (MRD) positivity at study entry to MRD negativity occurred at a higher rate among patients treated with NINLARO compared with placebo (12 percent versus 7 percent, respectively).
NINLARO maintenance led to higher rates of deepened response compared with placebo (relative risk 1.41; 95 percent CI: 1.10, 1.80; p=0.0042).
PFS benefit was seen broadly across subgroups, including ISS III (HR 0.661), PI-exposed (HR 0.750), PI-naïve (HR 0.497), and patients with high-risk cytogenetics (HR 0.625).
Secondary endpoints including median PFS2 and OS have not yet been reached in either arm. Median follow-up was 31 months.
Global Quality of Life scores (EORTC QLQ-C30) for patients on NINLARO were similar to those on placebo.
The safety profile of NINLARO in the maintenance setting is consistent with previously reported results of single-agent NINLARO use.
Discontinuation of treatment due to adverse events (AE) was low, at 7 percent in the NINLARO arm compared to 5 percent in the placebo arm.
Grade ≥3 AEs were experienced by 42 percent of patients receiving NINLARO versus 26 percent receiving placebo.
Patients in the NINLARO arm experienced serious AEs at a rate of 27 percent versus 20 percent in the placebo arm.
Common grade ≥3 AEs in both the NINLARO and placebo arms included infections (15 and 8 percent, respectively) including pneumonia (6 and 4 percent, respectively), gastrointestinal disorders (6 and 1 percent, respectively), neutropenia (5 and 3 percent, respectively) and thrombocytopenia (5 and <1 percent, respectively).
On the NINLARO arm, peripheral neuropathy events were observed in 19 percent of patients versus 15 percent on the placebo arm. In the NINLARO arm, <1 percent of peripheral neuropathy events were Grade 3 compared with 0 in the placebo arm.
The rate of second primary malignancies was 3 percent in both arms.
One patient in the NINLARO arm died on study while no patients in the placebo arm did. The single study death was considered to be treatment-related and was due to pneumonia.
About the TOURMALINE-MM3 Trial

TOURMALINE-MM3 is a randomized, placebo-controlled, double-blind Phase 3 study of 656 patients, designed to determine the effect of NINLARO (ixazomib) maintenance therapy on progression-free survival (PFS), compared to placebo, in participants with multiple myeloma who have had a response (complete response [CR], very good partial response [VGPR], or partial response [PR]) to induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplant (ASCT). The primary endpoint is progression-free survival (PFS). A key secondary endpoint includes overall survival (OS). For additional information: View Source

About NINLARO (ixazomib) capsules

NINLARO (ixazomib) is an oral proteasome inhibitor which is also being studied across the continuum of multiple myeloma treatment settings as well as systemic light-chain (AL) amyloidosis. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval. NINLARO was approved by the U.S. Food and Drug Administration (FDA) in November 2015 following a priority review and by the European Commission in November 2016. In the U.S. and Europe, NINLARO is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO has received marketing authorization by regulatory authorities in more than 60 countries.

Ixazomib was granted orphan drug designation in multiple myeloma in both the U.S. and Europe in 2011 and for AL amyloidosis in both the U.S. and Europe in 2012. Ixazomib received Breakthrough Therapy status by the U.S. FDA for relapsed or refractory systemic light-chain (AL) amyloidosis, a related ultra orphan disease, in 2014. The Japanese Ministry of Health, Labour and Welfare granted Orphan Drug designation to ixazomib in 2016.

The comprehensive ixazomib clinical development program, TOURMALINE, includes a total of six ongoing pivotal trials – five, which together are investigating every major multiple myeloma patient population, and one in light-chain amyloidosis:

TOURMALINE-MM1, investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
TOURMALINE-MM2, investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3, investigating ixazomib versus placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
TOURMALINE-MM4, investigating ixazomib versus placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT
TOURMALINE-AL1, investigating ixazomib plus dexamethasone versus physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis; this study is currently enrolling
TOURMALINE-MM5, investigating ixazomib plus dexamethasone versus pomalidomide plus dexamethasone in patients with relapsed and/or refractory multiple myeloma who have become resistant to lenalidomide; this study is currently enrolling
For more information about actively enrolling Phase 3 studies please visit: View Source

In addition to the TOURMALINE program, ixazomib is being evaluated in multiple therapeutic combinations for various patient populations in investigator initiated studies globally.

NINLARO (ixazomib) capsules: Global Important Safety Information

SPECIAL WARNINGS AND PRECAUTIONS

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

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

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

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

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

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

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

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

SPECIAL PATIENT POPULATIONS

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

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

DRUG INTERACTIONS

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

ADVERSE REACTIONS

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

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.

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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.