On December 7, 2019 Cellular Biomedicine Group Inc. (NASDAQ: CBMG) ("CBMG" or the "Company"), a biopharmaceutical firm engaged in the drug development of immunotherapies for cancer and stem cell therapies, reported early data from its ongoing investigator initiated trial ("IIT") at an oral presentation titled "Novel Anti-BCMA CAR-T for Relapsed or Refractory Multiple Myeloma" at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) ("ASH") annual meeting on December 7, 2019 in Orlando, Florida (Press release, Cellular Biomedicine Group, DEC 7, 2019, View Source [SID1234552068]).

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ABSTRACT DETAILS
C-CAR088 is a novel anti-B-cell maturation antigen ("BCMA") chimeric antigen receptor T-cell ("CAR-T") product designed to improve efficacy through increasing the specificity and reducing immunogenicity by fusing a single-chain variable fragment ("scFv") from high-affinity human monoclonal antibody to a CD3ζ/4-1BB signaling domain. It can effectively eradicate BCMA positive tumor cells both in vitro and in vivo.

A Phase 1, dose escalation trial is being conducted in patients with relapsed or refractory Multiple Myeloma ("r/r MM") to assess the safety and efficacy of C-CAR088. As of the end of November the Company has enrolled eleven patients, of which eight were infused with C-CAR088, and five patients were evaluable for clinical response. Three of the five patients were treated with C-CAR088 at the dose of 1.0 x 106 CAR-T cells/kg, and the other two patients treated at 3.0×106 CAR-T cells/kg. All five patients showed clinical improvement as early as two weeks post treatment. By 4 weeks, one patient achieved a complete response ("CR"), three patients reached a very good partial response ("VGPR"), and one patient reached a partial response ("PR") post C-CAR088 infusion. Furthermore, the Company observed that C-CAR088 proliferation & expansion in the peripheral blood correlated with the decrease of tumor burden in all patients. C-CAR088 treatment showed to be well tolerated. There were no dose-limiting toxicities ("DLTs"). Reversible Grade 1 and Grade 2 Cytokine release syndrome ("CRS") were observed in four and one patient respectively.

"The early IIT clinical trial results in patients with relapsed and refractory multiple myeloma for C-CAR088 support preclinical findings that C-CAR088 shows promising efficacy and has a manageable safety profile," stated Dr. Yihong Yao, Chief Scientific Officer of CBMG. Dr. Yao added, "The very early clinical efficacy signal at low and suboptimal dosing is encouraging and needs to be confirmed by the ongoing clinical trial. We will continue to monitor and evaluate the duration of response ("DOR") and to further pursue DOR improvement alternatives."

The complete text of the abstract can be found at View Source
The full presentation can be found on the company’s website.

About Multiple Myeloma
Multiple Myeloma, a cancer derived from plasma cells, accounts for 1% of all cancers and approximately 10% of all hematological malignancies[1]. It is estimated that there are 27,800 new cases of MM diagnosed in China each year. With the acceleration of the aging process in China, it is predicted that MM, with a rapid growth in incidence, will become one of the more significant diseases that affect people’s health in the country[2]. The American Cancer Society estimates that in the United States, approximately 32,110 new cases of MM (18,130 in men and 13,980 in women) will be diagnosed in 2019[3].
[1] Moreau P et al., Annals of Oncology 24 (Supplement 6): vi133–vi137, 2013
[2] Blood Cancer J. 2014 Aug 15;4:e239. doi: 10.1038/bcj.2014.55
[3] View Source

On December 7, 2019 Aleta Biotherapeutics, a privately held immunotherapy company focused on transforming cellular therapeutics to allow a broad spectrum of cancer indications to be targeted, reported in vitro and in vivo results demonstrating that Aleta’s novel CD19-anti-CD20 bridging protein prevents and reverses CD19-negative relapse from CAR-CD19 T cell treatment (Press release, Aleta Biotherapeutics, DEC 7, 2019, View Source [SID1234552059]).

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"FDA-approved CAR-CD19 T cell therapies such as tisagenlecleucel and axicabtagene ciloleucel have demonstrated remarkable success in treating B cell cancers including refractory and relapsed acute lymphoblastic leukemia and non-Hodgkin lymphoma. However, relapse rates of up to 50% have been reported, most occurring within 6 months of CAR-CD19 T cell therapy. Some patients relapse due to the loss of expression of CD19 on tumor cells and other patients relapse because the cell therapy has failed to fully control tumor cell proliferation," said Paul Rennert, Ph.D., President and Chief Scientific Officer, Aleta Biotherapeutics. "The studies we presented today demonstrate that Aleta’s CD19-anti-CD20 bridging protein can reactivate CAR-CD19 T cells to prevent and to reverse relapses by redirecting CAR-CD19 T cells to the novel antigen CD20, present on the majority of B cell malignancy tumor cells. Aleta has identified a development candidate for the treatment of B cell malignancy patients relapsing from CAR-CD19 treatment and based on these and other studies, we are advancing this program into development and then into Phase 1 clinical trials."

Results Presented at ASH (Free ASH Whitepaper) 2019
A stabilized form of the CD19 extracellular domain (ECD) was cloned in frame with an anti-CD20 antibody fragment and an anti-albumin antibody fragment, to create a monomeric CD19-ECD-anti-CD20 bridging protein with extended circulating half-life characteristics. The protein was purified from a mammalian cell expression system. Protein stability, binding affinities, and cytotoxic activity were analyzed in vitro.

The Aleta CD19-anti-CD20 bridging protein was shown to be expressed at high levels, readily purified and highly stable. The purified bridging protein directed CAR19 cytotoxicity against CD19-negative/CD20-positive cells with superb potency (IC50 = 0.7 pM = 0.04 ng/ml). CAR-CD19 T cells that were previously activated by a CD19-positive tumor cell could subsequently be activated by a CD19-negative tumor cell in the presence of the Aleta CD19-anti-CD20 bridging protein.

In vitro, CAR19 T cells found and eliminated CD19-negative cells that escaped from CAR-CD19 T cell treatment. In vivo, CAR-CD19 T cells, plus the injected Aleta bridging protein, controlled tumor cell growth, preventing escape from therapy, while CAR-CD19 T cells alone did not prevent tumor relapse. The growth of an aggressive mantle-cell-derived tumor cell line was only delayed by therapy with CAR-CD19 T cells alone but was fully eradicated when CAR-CD19 cells were given along with Aleta’s CD19-anti-CD20 bridging protein injected systemically. In a parallel set of studies, it was shown that CAR-CD19 T cells modified to secrete the CD19-anti-CD20 bridging protein were as effective as CAR-CD19 T cells given in the presence of the purified bridging protein.

On December 7, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported initial results from the Phase 1b/2 CARTITUDE-1 study (NCT03548207) evaluating the efficacy and safety of JNJ-68284528 (JNJ-4528), an investigational B cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (CAR-T) therapy being evaluated in the treatment of patients with relapsed or refractory multiple myeloma (Press release, Janssen Pharmaceuticals, DEC 7, 2019, View Source [SID1234552058]). The study enrolled patients who had received at least three prior lines of therapy or were double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD); had received a PI, IMiD and an anti-CD38 antibody. The CARTITUDE-1 study results, premiered at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, were featured as an oral presentation and highlighted in the official ASH (Free ASH Whitepaper) press programme (Abstract #577).1

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Results from the Phase 1b portion of the CARTITUDE-1 study showed early and deep responses among patients (n=29) with a median of five prior multiple myeloma treatment regimens (range, 3–18) treated with JNJ-4528 (median administered dose 0.73×106 CAR+ viable T cells/kg).1 One hundred percent of patients achieved a response at a median follow-up of six months.1 Eighty-six percent of patients were triple-refractory to a PI, IMiD, and anti-CD38 antibody, 72 percent were penta-exposed, and 31 percent were penta-refractory).1 The overall response rate (ORR) included 69 percent of patients achieving a complete response (CR) or better (66 percent achieved a stringent CR); 86 percent of patients achieved a very good partial response (VGPR) or better; and 14 percent of patients achieved a partial response (PR). In addition, all 15 out of a total of 29 patients (100 percent evaluable) at the 10-5 sensitivity level were MRD negative at the latest sample available.1 At the median follow-up of six months, 27 of 29 patients were progression-free. Based on the Phase 1b results, a recommended Phase 2 dose of 0.75×106 CAR+ viable T cells/kg was confirmed.1

"These initial results from the Phase 1b portion of the CARTITUDE-1 study highlight a compelling clinical profile for JNJ-4528 in heavily pre-treated patients with relapsed or refractory multiple myeloma," said Deepu Madduri, M.D., Assistant Professor of Medicine, Hematology and Medical Oncology, Tisch Cancer Institute at Mount Sinai, New York, and principal study investigator. "With the CARTITUDE-1 expansion cohort fully enrolled and all patients dosed, we look forward to collecting additional efficacy and safety data to further define the profile of this BCMA-targeted CAR-T therapy."

Dr Patrick Laroche, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag, adds, "Janssen has a long-standing commitment to improving outcomes for patients with multiple myeloma and patients with relapsed or refractory disease remain in urgent need of new treatment options. We are excited to further explore the potential of JNJ-4528 and build on the early promising data seen in CARTITUDE-1."

The most common adverse events (AEs) observed in the CARTITUDE-1 study were cytokine release syndrome (CRS) (93 percent); neutropenia (93 percent); anaemia (86 percent); and thrombocytopenia (86 percent).1 In patients who experienced grade 3 and above AEs (25 percent); the most common were neutropenia (93 percent); thrombocytopenia (69 percent); and anaemia (55 percent).1 A majority of patients (86 percent) experienced grade 1-2 CRS. One patient experienced grade 3 CRS and one patient died of complications from CRS at day 99.1 The median onset of CRS was generally predictable at seven days (range, 2-12) post-infusion, with a median duration of four days (range, 1-60).1

"We are encouraged by the overall response reported in patients receiving JNJ-4528, results that build upon the LEGEND-2 study data as reported in Chinese patients and now show promise in U.S. patients," said Sen Zhuang, M.D., Ph.D., Vice President, Oncology Clinical Development, Janssen Research & Development, LLC. "We are committed to advancing this novel BCMA-targeted CAR-T therapy through clinical development and bringing this immunotherapy to patients who are still in need of effective therapies to rapidly control their disease."

JNJ-4528 is a structurally differentiated CAR-T with two BCMA targeting single domain antibodies.2 LCAR-B38M identifies the investigational product in China, sponsored by Janssen development partner, Legend Biotech. JNJ-4528 identifies the investigational product with the same CAR construct being studied in the U.S. and Europe.

Safety and efficacy results observed in the CARTITUDE-1 study were consistent with the LEGEND-2 study of LCAR-B38M, sponsored by Legend Biotech. In follow-up data from the LEGEND-2 study presented at ASH (Free ASH Whitepaper) (Abstract #579), investigators reported the long-term response and safety profile for LCAR-B38M.3 Overall response rates of 88 percent were observed, with 46 percent of all-treated patients and 64 percent of the MRD-negative patients with CR remaining progression-free.3 The median progression-free survival (PFS) for all-treated patients was 20 months (range, 10–28); median PFS for MRD-negative patients with CR was 28 months (range, 20–31).3

In a separate oral presentation (Abstract #928), data highlighting post-infusion CAR+ T cell expansion in the bone marrow and blood of patients enrolled in the CARTITUDE-1 study will be reported. While both CD4+ and CD8+ CAR+ T cells expanded in vivo, a preferential expansion of memory CD8+ CAR+ T cells was observed at peak expansion.4 These and other correlative studies are being conducted to better understand the immune mechanisms associated with response to JNJ-4528, and suggest that the high anti-myeloma activity of JNJ-4528 seen at a relatively low T cell dose is potentially related to its preferential and consistent in vivo expansion of CD8+ CAR+ T cells.4

#ENDS#

About CARTITUDE-1

CARTITUDE-1 (NCT03548207) is an ongoing Phase 1b/2, open-label, multicentre study evaluating the safety and efficacy of JNJ-68284528 (JNJ-4528) in adults with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy or are double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD); have received a PI, IMiD and an anti-CD38 antibody.1 The primary objective of the Phase 1b portion of the study is to characterise the safety and confirm the dose of JNJ-68284528 (JNJ-4528), which was informed by the first-in-human study with LCAR-B38M CAR-T cells (LEGEND-2). The primary objective for the Phase 2 portion of the study is to evaluate the efficacy of JNJ-68284528 (primary endpoint: overall response rate as defined by the International Myeloma Working Group response criteria).5

About LEGEND-2

LEGEND-2 (NCT03090659) is an ongoing Phase 1, single-arm, open-label study in China comprised of four independent institutional studies being conducted at participating hospitals evaluating the efficacy and safety of LCAR-B38M for the treatment of patients with relapsed or refractory multiple myeloma.6

About JNJ-68284528 (LCAR-B38M)

JNJ-68284528 (LCAR-B38M) is an investigational chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of patients with relapsed or refractory multiple myeloma. The design comprises a structurally differentiated CAR-T with two BCMA targeting single domain antibodies. In December 2017, Janssen entered into an exclusive worldwide license and collaboration agreement with Legend to develop and commercialise JNJ-68284528/LCAR-B38M. In May 2018, Janssen initiated a Phase 1b/2 trial (NCT03548207) to evaluate the efficacy and safety of JNJ-68284528 in adults with relapsed/refractory multiple myeloma, informed by the LEGEND-2 study results.5,7

In April 2019, JNJ-68284528 was granted PRIME (PRIority MEdicines) designation by the European Medicines Agency (EMA).8 PRIME offers enhanced interaction and early dialogue to optimise development plans and speed up evaluation of cutting-edge, scientific advances that target a high unmet medical need.9

About CAR-T and BCMA

CAR-T cells are an innovative approach to eradicating cancer cells by harnessing the power of a patient’s own immune system.10 BCMA is a protein that is highly expressed on myeloma cells.11 By targeting BCMA via a CAR-T approach, CAR-T therapies may have the potential to redefine the treatment paradigm for multiple myeloma and potentially advance towards cures for patients with the disease.

About Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.12 In Europe, more than 48,200 people were diagnosed with MM in 2018, and more than 30,800 patients died.13 Around 60 percent of newly diagnosed patients do not reach five-year survival,14 and almost 29 percent of patients with multiple myeloma will die within one year of diagnosis.15

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.16 Refractory MM is when a patient’s disease progresses within 60 days of their last therapy.17 Relapsed cancer is when the disease has returned after a period of initial, partial or complete remission.18 While some patients with MM have no symptoms at all, others are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.19 Patients who relapse after treatment with standard therapies, including protease inhibitors and immunomodulatory agents, have poor prognoses and require new therapies for continued disease control.20

On December 7, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported combination data from two studies and a long-term integrated analysis evaluating the use of Imbruvica (ibrutinib) for the treatment of previously untreated patients with CLL (Press release, Janssen Pharmaceuticals, DEC 7, 2019, View Source [SID1234552057]). Results from a 48-month follow-up analysis of the Phase 3 E1912 clinical study reported a statistically significant difference in PFS and OS for ibrutinib plus rituximab compared to a standard chemoimmunotherapy regimen of FCR.1 Further, the latest integrated analysis from the Phase 3 RESONATETM (PCYC-1112) and RESONATETM-2 (PCYC-1115/1116) studies investigating the use of single-agent ibrutinib in CLL, reported at up to six years of follow-up, PFS, OS and response rates improved when ibrutinib was used in earlier lines of therapy.2 During this extended follow-up, ibrutinib was tolerated across all lines of therapy with 19 percent of patients discontinuing due to adverse events.2

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"The data presented at ASH (Free ASH Whitepaper) adds to the robust body of evidence supporting the safety and efficacy of ibrutinib in the first-line, as a monotherapy or in combination with other treatments"

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In addition, results presented from the Phase 2 CAPTIVATE study suggested that patients who received ibrutinib plus venetoclax as a time-limited treatment achieved high rates of uMRD in peripheral blood (75 percent of patients) and bone marrow (72 percent of patients).3

These new findings from the E1912, RESONATE/RESONATETM-2 and CAPTIVATE studies were presented at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

"We’re pleased to see follow-up results from the Phase 3 E1912 trial, where the investigational use of ibrutinib plus rituximab is shown to extend OS for previously untreated patients with CLL. In addition, with the integrated analysis of the Phase 3 RESONATE and RESONATE-2 studies, ibrutinib demonstrated an OS benefit in untreated and relapsed patients, with improved outcomes in early lines of therapy," said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC. "We are also excited to see the first MRD data from the fixed-duration regimen of ibrutinib plus venetoclax in the Phase 2 CAPTIVATE trial, reporting a high rate of undetectable MRD at 15 months both in the peripheral blood and bone marrow."

"The data presented at ASH (Free ASH Whitepaper) adds to the robust body of evidence supporting the safety and efficacy of ibrutinib in the first-line, as a monotherapy or in combination with other treatments," said Dr Patrick Laroche, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag. "As chemotherapy is not suitable for all patients there remains a need for non-chemotherapy treatment options and we are committed to exploring various ibrutinib-based combination regimens."

E1912 extended follow-up of investigational use of ibrutinib plus rituximab compared to FCR in patients with CLL ages 70 or younger (Abstract #33)1

Longer-term outcomes data from the Phase 3 E1912 clinical trial – designed and conducted by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health – were also presented. As previously reported in earlier data readouts, the study evaluated 354 previously untreated patients with CLL ages 70 years or younger who were randomly assigned to receive ibrutinib and rituximab or six courses of intravenous FCR every 28 days.1

At a median follow-up of 48 months, 73 percent of patients in the ibrutinib plus rituximab treatment arm remained on ibrutinib with median time on treatment of 43 months.1 PFS benefits were observed for the ibrutinib plus rituximab arm as compared to the FCR treatment arm (hazard ratio [HR]=0.39; 95 percent confidence interval [CI], 0.26-0.57; p<0.0001).1 OS benefit also continued to favour the ibrutinib plus rituximab arm (HR=0.34; 95 percent CI, 0.15-0.79; p=0.009).1

Grade 3 and above treatment-related adverse events (AEs) were observed in 70 percent of patients in the ibrutinib plus rituximab arm versus 80 percent in the FCR arm (odds ratio [OR]=0.56; 95 percent CI, 0.34-0.90; p=0.013).1

MRD cohort of the Phase 2 CAPTIVATE study on ibrutinib plus venetoclax combination in patients with previously untreated CLL (Abstract #35)3

The Phase 2 CAPTIVATE (PCYC-1142) clinical trial evaluated 164 patients younger than 70 years (median age of 58 years) with previously untreated CLL.3 Patients received ibrutinib monotherapy as lead-in treatment for three cycles, followed by 12 cycles of ibrutinib plus venetoclax combination therapy.3 MRD status was evaluated in peripheral blood (PB) after six, nine, and 12 cycles and in bone marrow (BM) after 12 cycles of ibrutinib plus venetoclax.3

"The new results from the CAPTIVATE study demonstrated the all-oral regimen of ibrutinib monotherapy followed by combined ibrutinib and venetoclax achieved promising rates of undetectable minimal residual disease, an important indicator of deep response, in previously untreated patients with CLL," said Constantine Tam, M.D., Haematologist and Disease Group Lead, Low Grade Lymphoma and CLL, Peter MacCallum Cancer Centre, Victoria, Australia, and principal study investigator. "We look forward to continuing to explore the efficacy and safety profile of this regimen and its potential to provide a limited-duration option in first-line treatment of CLL."

Results showed uMRD – defined as less than one CLL cell per 10,000 leukocytes (MRD<0.01 percent) by flow cytometry – was achieved at any time after baseline in PB for 75 percent of patients (122 of 163 patients) and in BM for 72 percent (111 of 155 patients).3 The high rates of uMRD in BM were consistent across high-risk subgroups, including in patients with del(17p); del(17p) or TP53 mutation; del(11q); complex karyotype; and unmutated IGHV status. In patients with uMRD in PB with matched BM samples, 93 percent of patients had uMRD in both PB and BM. With median follow-up of 14.7 months, three patients (2 percent) experienced disease progression.3,4

The most common AEs of any grade (in 20 percent of patients or greater) were diarrhoea (31 percent) and arthralgia (22 percent) during treatment with ibrutinib alone; and diarrhoea (60 percent), neutropenia (40 percent), nausea (34 percent), upper respiratory tract infection (24 percent), and fatigue (20 percent) during treatment with ibrutinib plus venetoclax. AEs leading to dose reductions occurred in 20 percent of patients overall. AEs leading to discontinuation were infrequent, occurring in 7 percent of patients overall (ibrutinib: 5 percent; venetoclax: 4 percent).3,4

Results from the MRD-guided, randomised treatment discontinuation cohort and fixed-duration cohort of the CAPTIVATE clinical trial are being further evaluated and will be presented at a future medical meeting.

Ibrutinib, a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, is jointly developed and commercialised by Janssen Biotech, Inc., and Pharmacyclics LLC, an AbbVie company.

#ENDS#

About ibrutinib

Ibrutinib is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally.5 Ibrutinib blocks the BTK protein; the BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.6 By blocking BTK, ibrutinib may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.7

Ibrutinib is currently approved in Europe for:5

Chronic lymphocytic leukaemia (CLL): As a single agent or in combination with obinutuzumab for the treatment of adult patients with previously untreated CLL, and as a single agent or in combination with bendamustine and rituximab (BR) for the treatment of adult patients with CLL who have received at least one prior therapy
Mantle cell lymphoma (MCL): As a single agent for the treatment of adult patients with relapsed or refractory MCL
Waldenström’s macroglobulinemia (WM): As a single agent for the treatment of adult patients who have received at least one prior therapy or in first-line treatment for patients unsuitable for chemo-immunotherapy, and in combination with rituximab for the treatment of adult patients
Ibrutinib is approved in more than 95 countries for at least one indication, and to date, has been used to treat more than 170,000 patients worldwide across its approved indications.8

The most common adverse reactions seen with ibrutinib include diarrhoea, neutropenia, haemorrhage (e.g., bruising), musculoskeletal pain, nausea, rash, and pyrexia.5

For a full list of side effects and information on dosage and administration, contraindications and other precautions when using ibrutinib please refer to the Summary of Product Characteristics for further information.

About chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is typically a slow-growing blood cancer of the white blood cells.9 The overall incidence of CLL in Europe is approximately 4.92 cases per 100,000 persons per year and is about 1.5 times more common in men than in women.10 CLL is predominantly a disease of the elderly, with a median age of 72 years at diagnosis.11

The disease eventually progresses in the majority of patients, and they are faced with fewer treatment options with each relapse. Patients are often prescribed multiple lines of therapy as they relapse or become resistant to treatments.

On December 7, 2019 Epizyme, Inc. (Nasdaq: EPZM), a late-stage biopharmaceutical company developing novel epigenetic therapies, reported positive, mature data at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting from its ongoing Phase 2 trial of tazemetostat, an oral EZH2 inhibitor, as a monotherapy for patients with follicular lymphoma (FL), both with or without EZH2 activating mutations, who have received at least two prior lines of systemic therapy (Press release, Epizyme, DEC 7, 2019, View Source [SID1234552056]).

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The data show that treatment with tazemetostat demonstrated meaningful clinical activity as assessed by both investigators and an Independent Review Committee (IRC), and was generally well tolerated in both FL patients with EZH2 activating mutations (n=45) and FL patients with wild-type EZH2 (n=54). The IRC assessment was conducted for inclusion in Epizyme’s planned NDA submission to the U.S. Food and Drug Administration (FDA) in December 2019.

As assessed by the IRC, as of an August 9, 2019 data cutoff date, tazemetostat treatment resulted in:

Objective response rate (ORR) of 69% for patients with an EZH2 mutation and 35% for patients with wild-type EZH2
Median duration of response of 11 months for patients with an EZH2 mutation and 13 months for patients with wild-type EZH2
Median progression-free survival of 14 months for patients with an EZH2 mutation and 11 months for patients with wild-type EZH2
Overall survival has not yet been reached for either FL patient population
"Follicular lymphoma remains an incurable disease today, and it’s essential that patients be able to receive treatment for an extended period of time," said Dr. Shefali Agarwal, chief medical officer of Epizyme. "We believe the clinically meaningful benefit of tazemetostat seen across both FL patient populations in this trial, along with its continued tolerability, are impressive findings. We are particularly pleased with the robust response rates, extended durability and consistency of data as assessed by investigators and independent reviewers. These data support tazemetostat’s potential to make a difference for FL patients, and we look forward to submitting our NDA for both patient populations later this month."

Follicular Lymphoma Phase 2 Cohort Design
Follicular lymphoma patients who had been previously treated with two or more systemic therapies were enrolled into two cohorts in the Phase 2 study. One cohort enrolled 45 patients with EZH2 activating mutations and a second enrolled 54 patients with wild-type EZH2. All patients were treated with 800 mg of tazemetostat, administered orally twice a day. The primary endpoint of the study is ORR, as assessed by the investigator, and defined as a complete response or partial response according to 2007 Cheson criteria. Secondary endpoints include duration of response, progression free survival, overall survival and safety.

Detailed Efficacy Results
The updated data were reported in an oral presentation entitled "Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients with Relapsed or Refractory Follicular Lymphoma" by Franck Morschhauser, M.D., Ph.D., Centre Hospitalier Régional Universitaire de Lille, France, an investigator in the Phase 2 trial. Efficacy data as assessed by both investigators and the IRC are summarized below:

1 Four patients not evaluable, or have missing or unknown data
2 Five patients not evaluable, or have missing or unknown data
3 Patient had stage 4 FL and received >2 prior lines of treatment

Safety Results
Favorable safety and tolerability have been observed with tazemetostat in these ongoing Phase 2 study cohorts. The most frequently reported treatment-related treatment-emergent adverse events (TEAEs) of Grade 3 or higher included thrombocytopenia (3%), anemia (2%), asthenia (1%) and fatigue (1%). TEAEs led to only 8% of patients discontinuing tazemetostat treatment and 9% of patients requiring a dose reduction. There were no treatment-related deaths while on study.

"We are thrilled to present these mature clinical data, which support our planned NDA submission for tazemetostat as a treatment for patients with follicular lymphoma," said Robert Bazemore, president and chief executive officer of Epizyme. "We have made tremendous progress in advancing our tazemetostat program, with multiple clinical and regulatory achievements this year. Our NDA for epithelioid sarcoma is under review, and we have finalized our commercial readiness plans in anticipation of an early 2020 launch. We have multiple clinical trials ongoing for tazemetostat in additional indications and combinations, and we are well underway with preparations to submit the FL NDA later this month. If approved, tazemetostat would be a first-in-class EZH2 inhibitor for patients with FL, representing an important new treatment with demonstrated efficacy, durability and safety."

About the Tazemetostat Clinical Trial Program
Tazemetostat, an oral, potent, first-in-class EZH2 inhibitor, is currently being studied as a monotherapy in ongoing clinical programs in patients with certain molecularly defined solid tumors, including epithelioid sarcoma and other INI1-negative tumors, and in patients with follicular lymphoma, both with and without EZH2 activating mutations. Multiple clinical studies are underway through collaborations assessing tazemetostat as a combination treatment for patients with diffuse large B-cell lymphoma. Epizyme is also conducting additional clinical trials designed to evaluate the potential benefit of tazemetostat in earlier lines of therapy for follicular lymphoma, as well as new combinations and cancer indications.