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.

On December 7, 2019 Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) reported that results of the TOURMALINE-AL1 trial will be presented during an oral session at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting on Saturday, December 7, 2019 in Orlando, Florida (Press release, Takeda, DEC 7, 2019, View Source [SID1234552055]). TOURMALINE-AL1 is a Phase 3, randomized clinical trial evaluating the effect of NINLAROTM (ixazomib) in combination with dexamethasone in patients with relapsed or refractory systemic light-chain (AL) amyloidosis.

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"There are serious unmet needs for people living with amyloidosis. AL amyloidosis is a progressive and fatal disease; many patients are diagnosed late, significantly impacting life expectancy. The challenges associated with developing drugs for this disease make continued research and development for treatment critical"

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The TOURMALINE-AL1 trial did not meet the first of the two primary endpoints of significant improvement in overall hematologic response, as reported in June 2019. Hematologic responses were seen in 53% versus 51% of patients receiving NINLARO plus dexamethasone versus physician’s choice (odds ratio 1.10 [95% CI 0.60-2.01], p=0.762) as assessed by an Adjudication Committee (AC). The second primary endpoint of two-year vital organ deterioration or death was not mature at the time of analysis. Other endpoints studied including vital organ progression free survival (PFS), hematologic PFS, time to treatment failure and time to subsequent therapy were numerically higher in the NINLARO plus dexamethasone arm compared to the physician’s choice arm. Takeda is committed to making data available to researchers to continue investigation of this disease. NINLARO is not approved as a treatment for AL amyloidosis.

"AL amyloidosis is a rare condition, for which prognosis and patient outcomes are poor. Current treatments are often retrofitted from therapies used for multiple myeloma," said Angela Dispenzieri, MD, Mayo Clinic, and the trial’s principal investigator and lead author. "For a Phase 3 study that did not meet its primary endpoint, this trial provides interesting information for this community and for future studies. Ongoing research and development to investigate potential treatment options for this underserved patient population is critical."

"We look forward to the opportunity to share the data from the TOURMALINE-AL1 trial," said Phil Rowlands, Head of Oncology Clinical Research and Development, Takeda. "We are confident that sharing our findings with the community will help encourage conversations around the need for continued research to address the needs that remain in this patient population."

"There are serious unmet needs for people living with amyloidosis. AL amyloidosis is a progressive and fatal disease; many patients are diagnosed late, significantly impacting life expectancy. The challenges associated with developing drugs for this disease make continued research and development for treatment critical," said Isabelle Lousada, Founder and CEO of the Amyloidosis Research Consortium. "The data from TOURMALINE-AL1 provide valuable insights to researchers as they select endpoints for future amyloidosis studies, and knowledge that will provide context in future drug reviews and approvals, ultimately aiding in providing treatment options for patients."

Primary Results from the Phase 3 TOURMALINE-AL1 Trial of Ixazomib-Dexamethasone Versus Physician’s Choice of Therapy in Patients (Pts) with Relapsed/Refractory Primary Systemic AL Amyloidosis (RRAL). Saturday, December 7, 9:30 a.m., Orange County Convention Center, Hall E1.

Key findings, to be presented by Dr. Angela Dispenzieri, include:

The first of two primary endpoints was not met in TOURMALINE-AL1. Hematologic responses were seen in 53% versus 51% of patients receiving NINLARO plus dexamethasone versus physician’s choice (odds ratio 1.10 [95% CI 0.60-2.01], p=0.762).
Complete response (CR) rate was 26% in the NINLARO plus dexamethasone arm versus 18% in the physician’s choice arm.
The second primary endpoint, two-year vital organ deterioration or death, was not mature at the time of analysis.
Other endpoint data as assessed by investigators includes:
Median duration of hematologic response was 46.5 months in the NINLARO plus dexamethasone arm and 20.2 months in the physician’s choice arm as assessed by investigators.
Vital organ PFS was 18.0 months in the NINLARO plus dexamethasone arm and 11.0 months in the physician’s choice arm.
Hematologic PFS was 20.1 months in the NINLARO plus dexamethasone arm and 16.7 months in the physician’s choice arm.
Time to treatment failure was 10.1 months in the NINLARO plus dexamethasone arm and 5.2 months in the physician’s choice arm.
Time to subsequent therapy was 26.5 months in the NINLARO plus dexamethasone arm and 12.5 months in the physician’s choice arm.
At data cut-off, patients had received a median treatment duration of 11.7 versus 5.0 months on the NINLARO plus dexamethasone versus physician’s choice arms.
Safety data includes:
Drug-related adverse events (AE) were experienced by 82% of patients receiving NINLARO plus dexamethasone compared to 81% of patients receiving physician’s choice.
Serious adverse events (SAE) were experienced by 47% of patients in the NINLARO plus dexamethasone arm compared to 33% in the physician’s choice arm.
Discontinuation of treatment due to AEs was 26% in the NINLARO plus dexamethasone arm compared to 20% in the physician’s choice arm.
Common any grade AEs in both the NINLARO plus dexamethasone arm and physician’s choice arm included fatigue (45% and 43%), peripheral edema (46% and 32%), diarrhea (34% and 30%), insomnia (38% and 17%), rash (33% and 20%), constipation (21% and 26%), dyspnea (24% and 19%), upper respiratory tract infection (24% versus 16%), nausea (24% versus 14%) and peripheral neuropathy (19% versus 15%).
Common (≥5% overall) grade ≥3 AEs were fatigue (9% versus 9%), peripheral edema (5% versus 5%), rash (4% versus 5%) and dyspnea (6% versus 4%).
6% of patients in the NINLARO plus dexamethasone arm and 5% of patients in the physician’s choice arm died on study. All deaths were considered to be related to AL amyloidosis or complications thereof.
About the TOURMALINE-AL1 Trial

TOURMALINE-AL1 (NCT01659658) is an international, randomized, controlled, open-label, multicenter, Phase 3 study, designed to determine whether NINLAROTM (ixazomib) in combination with dexamethasone improves hematologic response, two-year vital organ (heart or kidney) deterioration and mortality rate versus a physician’s choice of a chemotherapy regimen in participants diagnosed with relapsed or refractory systemic light chain (AL) amyloidosis. 168 patients were enrolled and randomly selected to receive either NINLARO plus dexamethasone, or physician’s choice of the following: dexamethasone plus melphalan; dexamethasone plus cyclophosphamide; dexamethasone plus thalidomide; dexamethasone plus lenalidomide; or dexamethasone alone. The discontinuation of the TOURMALINE-AL1 trial was announced in June 2019. For more information, please visit View Source

About AL Amyloidosis

Primary AL amyloidosis is a condition that falls under the umbrella of plasma cell dyscrasias. AL amyloidosis arises from a clonal plasma cell that produces abnormal immunoglobulin light-chain fragments. These misfolded light-chains form insoluble fibrils that aggregate as amyloid deposits in organs and tissues throughout the body, ultimately leading to organ dysfunction and death. The most common organs affected are the kidneys, heart, liver, and autonomic or peripheral nerves.

There are currently no treatments approved for the treatment of AL amyloidosis.

About NINLAROTM (ixazomib) capsules

NINLARO (ixazomib) is an oral proteasome inhibitor which is being studied across the continuum of multiple myeloma treatment settings. NINLARO was first approved by the U.S. Food and Drug Administration (FDA) in November 2015 and 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 is currently approved in more than 60 countries, including the United States, Japan and in the European Union, with more than 10 regulatory filings currently under review. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval.

The comprehensive ixazomib clinical development program, TOURMALINE, includes several ongoing pivotal trials, which together are investigating major multiple myeloma patient populations:

TOURMALINE-MM1, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
TOURMALINE-MM2, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT
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 percent vs. 14 percent 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 percent vs. 36 percent), constipation (34 percent vs. 25 percent), nausea (26 percent vs. 21 percent), and vomiting (22 percent vs. 11 percent), occasionally requiring use of antiemetic and anti-diarrheal medications, and supportive care.

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

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

For European Union Summary of Product Characteristics: View Source
For US Prescribing Information: View Source
For Canada Product Monograph: View Source

On December 7, 2019 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported new data on two investigational CD20-CD3 T-cell engaging bispecific antibodies, mosunetuzumab and CD20-TCB, in people with relapsed or refractory (R/R) B-cell non-Hodgkin’s lymphoma (NHL) (Press release, Genentech, DEC 7, 2019, View Source [SID1234552054]). Results from the Phase I/Ib GO29781 study of mosunetuzumab, including data from people previously treated with chimeric antigen receptor (CAR) T-cell therapy, will be presented at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 Annual Meeting during the Plenary Scientific Session. The Plenary Scientific Session highlights the top six abstracts submitted to the meeting, as determined by the ASH (Free ASH Whitepaper) Program Committee. Additionally, results from the Phase I/Ib NP30179 study evaluating CD20-TCB as a combination therapy with Gazyva (obinutuzumab) for people with R/R NHL, will be presented.

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"We’re encouraged by these early results, which suggest that our novel bispecific cancer immunotherapies may help people with relapsed or treatment-refractory disease who need more options."

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"Despite recent treatment advancements, slow-growing and aggressive non-Hodgkin’s lymphomas present increasingly difficult management challenges with each subsequent relapse," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "We’re encouraged by these early results, which suggest that our novel bispecific cancer immunotherapies may help people with relapsed or treatment-refractory disease who need more options."

The GO29781 study evaluated mosunetuzumab in patients with R/R NHL, including patients who have relapsed following, or are resistant to, CAR T-cell therapy – a patient population with limited treatment options. Results from this dose-escalation study showed encouraging efficacy with an objective response rate (ORR) of 62.7 percent (n=42/67) in slow-growing NHL and 37.1 percent (n=46/124) in aggressive NHL. Additionally, data demonstrated a complete response (CR) rate of 43.3 percent (n=29/67) in slow-growing NHL and 19.4 percent (n=24/124) in aggressive NHL. CRs showed durability, with 82.8 percent (n=24/29) of patients with slow-growing NHL remaining in remission up to 26 months off initial treatment and 70.8 percent (n=17/24) of patients with aggressive NHL, remaining in remission up to 16 months off initial treatment. Of the participants who received prior CAR T-cell therapy, the ORR was 38.9 percent (n=7/18), and 22.2 percent (n=4/18) achieved a CR. Adverse reactions included cytokine release syndrome (CRS) in 28.9 percent of patients with 20.0 percent at Grade 1 and 1.1 percent at Grade 3. Grade 3 neurological adverse events occurred in 3.7 percent of patients.

Results from the Phase I/Ib dose-escalation NP30179 study, evaluating CD20-TCB at doses ranging from 0.6 mg to 16 mg plus Gazyva in people with R/R B-cell NHL, showed an ORR of 54 percent (n=15/28) and a CR rate of 46 percent (n=13/28). This included an ORR and CR of 66.7 percent (n=4/6) in people with follicular lymphoma and an ORR of 50.0 percent (n=11/22) and a CR of 40.9 percent (n=9/22) in aggressive NHL. The most frequently observed adverse event across all treatment doses was CRS, occurring in 67.9 percent of patients (n=19/28), with the majority of events being low grade (Grade 1-2).

Both mosunetuzumab and CD20-TCB continue to be evaluated in a robust clinical development program, investigating the treatments as monotherapies and in combination with other therapies, in people with slow-growing and aggressive forms of NHL.

About Genentech’s Investigational Bispecifics

Genentech is currently developing two T-cell engaging bispecific antibodies, mosunetuzumab and CD20-TCB, designed to target CD20 on the surface of B-cells and CD3 on the surface of T-cells. This dual targeting activates and redirects a patient’s existing T-cells to engage and eliminate target B-cells by releasing cytotoxic proteins into the B-cells. Mosunetuzumab and CD20-TCB differ in their structures, and both are being developed by Genentech as part of our ongoing strategy to explore multiple bispecific formats, to identify those that maximize potential clinical benefits for patients. The clinical development programs for mosunetuzumab and CD20-TCB include ongoing investigations of these molecules as monotherapies and in combination with other medicines, for the treatment of people with CD20-positive B-cell non-Hodgkin’s lymphomas, including diffuse large B-cell lymphoma and follicular lymphoma.

About the GO29781 study

The GO29781 study [NCT02500407] is a Phase I/Ib, multicenter, open-label, dose-escalation study evaluating the safety and pharmacokinetics of mosunetuzumab in people with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Outcome measures include best objective response rate by revised International Working Group criteria, maximum tolerated dose, and tolerability.

About the NP30179 study

The NP30179 study [NCT03075696] is a Phase I/Ib, multicenter, open-label, dose-escalation study, evaluating the efficacy, safety, tolerability and pharmacokinetics of CD20-TCB. In this study, CD20-TCB is assessed as a single agent and in combination with Gazyva, following pre-treatment with a one-time, fixed dose of Gazyva, in people with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Outcome measures include overall response rate, complete response rate per Lugano 2014 criteria, maximum tolerated dose, and tolerability.

About Non-Hodgkin’s Lymphoma

There are two main types of lymphoma: Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (NHL). NHL has two subsets, aggressive and indolent (slow-growing).

NHL represents approximately 85 percent of all lymphomas diagnosed. According to the American Cancer Society, it is expected that nearly 74,000 people will be diagnosed with NHL in the United States in 2019, and nearly 20,000 will die from the disease.

Most cases of NHL start in B-lymphocytes, cells that are part of the body’s immune system and help to defend the body against infections. B-cell lymphoma develops when these cells become cancerous and begin to multiply and collect in the lymph nodes or lymphatic tissues such as the spleen.

Gazyva Indications

Gazyva (obinutuzumab) is a prescription medicine used:

With the chemotherapy drug, chlorambucil, to treat chronic lymphocytic leukemia (CLL) in adults who have not had previous CLL treatment.
With the chemotherapy drug, bendamustine, followed by Gazyva alone for follicular lymphoma (FL) in adults who did not respond to a rituximab-containing regimen, or whose FL returned after such treatment.
With chemotherapy, followed by Gazyva alone in those who responded, to treat stage II bulky, III, or IV FL in adults who have not had previous FL treatment.
Important Safety Information

The most important safety information patients should know about Gazyva

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that can become serious or life threatening, including:

Hepatitis B Virus (HBV): Hepatitis B can cause liver failure and death. If the patient has a history of hepatitis B infection, Gazyva could cause it to return. Patients should not receive Gazyva if they have active hepatitis B liver disease. The patient’s doctor or healthcare team will need to screen them for hepatitis B before, and monitor the patient for hepatitis during and after, their treatment with Gazyva. Sometimes this will require treatment for hepatitis B. Symptoms of hepatitis include: worsening of fatigue and yellow discoloration of skin or eyes.
Progressive Multifocal Leukoencephalopathy (PML): PML is a rare and serious brain infection caused by a virus. PML can be fatal. The patient’s weakened immune system could put them at risk. The patient’s doctor will watch for symptoms. Symptoms of PML include: confusion, difficulty talking or walking, dizziness or loss of balance, and vision problems.
Who should not receive Gazyva:

Patients should NOT receive Gazyva if they have had an allergic reaction (e.g., anaphylaxis or serum sickness) to Gazyva. Patients must tell their healthcare provider if they have had an allergic reaction to obinutuzumab or any other ingredients in Gazyva in the past.

Additional possible serious side effects of Gazyva:

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that may become severe or life threatening, including:

Infusion Reactions: These side effects may occur during or within 24 hours of any Gazyva infusion. Some infusion reactions can be serious, including, but not limited to, severe allergic reactions (anaphylaxis), acute life-threatening breathing problems, or other life-threatening infusion reactions. If the patient has a reaction, the infusion is either slowed or stopped until their symptoms are resolved. Most patients are able to complete infusions and receive medication again. However, if the infusion reaction is life threatening, the infusion of Gazyva will be permanently stopped. The patient’s healthcare team will take steps to help lessen any side effects the patient may have to the infusion process. The patient may be given medicines to take before each Gazyva treatment. Symptoms of infusion reactions may include: fast heartbeat, tiredness, dizziness, headache, redness of the face, nausea, chills, fever, vomiting, diarrhea, rash, high blood pressure, low blood pressure, difficulty breathing, and chest discomfort.
Hypersensitivity Reactions Including Serum Sickness: Some patients receiving Gazyva may have severe or life-threatening allergic reactions. This reaction may be severe, may happen during or after an infusion, and may affect many areas of the body. If an allergic reaction occurs, the patient’s doctor will stop the infusion and permanently discontinue Gazyva.
Tumor Lysis Syndrome (TLS): Tumor lysis syndrome, including fatal cases, has been reported in patients receiving Gazyva. Gazyva works to break down cancer cells quickly. As cancer cells break apart, their contents are released into the blood. These contents may cause damage to organs and the heart, and may lead to kidney failure requiring the need for dialysis treatment. The patient’s doctor may prescribe medication to help prevent TLS. The patient’s doctor will also conduct regular blood tests to check for TLS. Symptoms of TLS may include nausea, vomiting, diarrhea, and tiredness.
Infections: While the patient is taking Gazyva, they may develop infections. Some of these infections may be fatal and severe, so the patient should be sure to talk to their doctor if they think they have an infection. Patients administered Gazyva in combination with chemotherapy, followed by Gazyva alone are at a high risk of infections during and after treatment. Patients with a history of recurring or chronic infections may be at an increased risk of infection. Patients with an active infection should not be treated with Gazyva. Patients taking Gazyva plus bendamustine may be at higher risk for fatal or severe infections compared to patients taking Gazyva plus CHOP or CVP.
Low White Blood Cell Count: When the patient has an abnormally low count of infection-fighting white blood cells, it is called neutropenia. While the patient is taking Gazyva, their doctor will do blood work to check their white blood cell count. Severe and life-threatening neutropenia can develop during or after treatment with Gazyva. Some cases of neutropenia can last for more than one month. If the patient’s white blood cell count is low, their doctor may prescribe medication to help prevent infections.
Low Platelet Count: Platelets help stop bleeding or blood loss. Gazyva may reduce the number of platelets the patient has in their blood; having low platelet count is called thrombocytopenia. This may affect the clotting process. While the patient is taking Gazyva, their doctor will do blood work to check their platelet count. Severe and life-threatening thrombocytopenia can develop during treatment with Gazyva. Fatal bleeding events have occurred in patients treated with Gazyva. If the patient’s platelet count gets too low, their treatment may be delayed or reduced.
The most common side effects of Gazyva in CLL were infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.

The safety of Gazyva was evaluated based on 392 patients with relapsed or refractory NHL, including FL (81 percent), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) (a disease for which Gazyva is not indicated), who did not respond to or progressed within 6 months of treatment with rituximab product or a rituximab product-containing regimen. In patients with follicular lymphoma, the profile of side effects that were seen were consistent with the overall population who had NHL. The most common side effects of Gazyva were infusion reactions, low white blood cell counts, nausea, fatigue, cough, diarrhea, constipation, fever, low platelet counts, vomiting, upper respiratory tract infection, decreased appetite, joint or muscle pain, sinusitis, low red blood cell counts, general weakness, and urinary tract infection.

A randomized, open-label multicenter trial (GALLIUM) evaluated the safety of Gazyva as compared to rituximab product in 1,385 patients with previously untreated follicular lymphoma (86 percent) or marginal zone lymphoma (14 percent).The most common side effects of Gazyva were infusion reactions, low white blood cell count, upper respiratory tract infection, cough, constipation and diarrhea.

Before receiving Gazyva, patients should talk to their doctor about:

Immunizations: Before receiving Gazyva therapy, the patient should tell their healthcare provider if they have recently received or are scheduled to receive a vaccine. Patients who are treated with Gazyva should not receive live vaccines.
Pregnancy: The patient should tell their doctor if they are pregnant, think that they might be pregnant, plan to become pregnant, or are breastfeeding. Gazyva may harm their unborn baby. The patient should speak to their doctor about using Gazyva while they are pregnant. The patient should talk to their doctor or their child’s doctor about the safety and timing of live virus vaccinations to their infant if they received Gazyva during pregnancy. It is not known if Gazyva may pass into the patient’s breast milk. The patient should speak to their doctor about using Gazyva if they are breastfeeding.
Patients should tell their doctor about any side effects.

These are not all of the possible side effects of Gazyva. For more information, patients should ask their doctor or pharmacist.

Gazyva is available by prescription only.

Report side effects to the FDA at (800) FDA-1088, or View Source Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the Gazyva full Prescribing Information, including BOXED WARNINGS, for additional Important Safety Information.

About Genentech in Hematology

For more than 20 years, Genentech has been developing medicines with the goal to redefine treatment in hematology. Today, we’re investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. For more information visit View Source