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 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 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported that initial clinical data for its FT516 and FT500 off-the-shelf, iPSC-derived natural killer (NK) cell product candidates (Press release, Fate Therapeutics, DEC 7, 2019, View Source [SID1234552027]).

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"The safety, tolerability, and immunogenicity data from the Phase 1 dose-escalation stage of FT500, the first-ever cell therapy derived from a clonal master induced pluripotent stem cell line to undergo clinical investigation in the U.S., provide compelling evidence that multiple doses of iPSC-derived NK cells can be delivered off-the-shelf and administered without patient matching," said Wayne Chu, M.D., Vice President of Clinical Development of Fate Therapeutics. "Additionally, initial clinical observations with FT516 are very encouraging, as an assessment of the first AML patient’s bone marrow at Day 42 following three once-weekly doses of FT516 demonstrated anti-leukemia activity and hematopoietic recovery."

FT516 Universal, Off-the-shelf, Engineered iPSC-derived NK Cell Product Candidate
The FT516 study is an open-label, multi-dose Phase 1 clinical trial as a monotherapy for the treatment of acute myeloid leukemia (AML) and in combination with CD20-directed monoclonal antibodies for the treatment of advanced B-cell lymphoma, and is the first-ever clinical investigation of a cell product derived from a clonal master engineered induced pluripotent stem cell (iPSC) line. Two patients, both heavily pretreated, have been treated with FT516 to date, and the first clinical findings include:

FT516 First AML Patient. The first patient enrolled for the treatment of AML was refractory to initial 7+3 induction therapy, multiple subsequent re-induction attempts with chemotherapy, and a combination therapy of venetoclax plus decitabine. Following outpatient lympho-conditioning, the patient received a first cycle of three once-weekly doses of FT516 (90 million cells per dose) as a monotherapy and IL-2 cytokine support. A bone marrow biopsy obtained at Day 42 following the completion of the first FT516 treatment cycle showed no morphologic evidence of leukemia and evidence of hematopoietic recovery. Concurrently, no circulating leukemia cells were observed in the peripheral blood, and the patient showed neutrophil recovery without growth factor support (>1,000 per µL). In addition, no dose-limiting toxicities (DLTs), Grade ≥3 adverse events (AEs) or serious adverse events (SAEs) related to FT516 were reported. The patient is expected to receive a second FT516 treatment cycle of three once-weekly doses of FT516. A formal response assessment will be performed following completion of this second FT516 treatment cycle.
FT516 First Lymphoma Patient. Prior to treatment with FT516, the first patient enrolled with high-risk diffuse large B-cell lymphoma (DLBCL) having relapsed after multiple rituximab combination regimens, autologous hematopoietic stem cell transplant, and chimeric antigen receptor (CAR) T-cell therapy. Following outpatient lympho-conditioning, the patient received a first cycle of three once-weekly doses of FT516 (30 million cells per dose) in combination with rituximab and IL-2 cytokine support. A second treatment cycle of three once-weekly doses of FT516 in combination with rituximab has been initiated. A formal response assessment will be performed following completion of this second FT516 treatment cycle.
FT500 Universal, Off-the-shelf, iPSC-derived NK Cell Product Candidate
FT500 is the first iPSC-derived cell product candidate to emerge from the Company’s iPSC product platform. The FT500 study is an open-label, multi-dose Phase 1 clinical trial for the treatment of advanced solid tumors. The dose-escalation stage of the study is designed to assess the safety and tolerability of three once-weekly doses of FT500, without IL-2 cytokine support, as a monotherapy and in combination with one of three FDA-approved immune checkpoint inhibitor (ICI) therapies in patients that have failed prior ICI therapy.

As of a November 28, 2019 data cutoff, 12 patients (n=8 monotherapy; n=4 in combination with ICI) have been treated with FT500, and the key clinical findings include:

Safety. No DLTs, FT500-related SAEs or FT500-related Grade ≥3 AEs, and no incidents of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, have been reported in 12 patients.
Tolerability. All 12 patients completed the first FT500 treatment cycle of three once-weekly doses. Nine of 11 patients initiated a second FT500 treatment cycle, with eight of nine patients having completed the second FT500 treatment cycle. One patient is currently pending initiation of a second FT500 treatment cycle. The multi-dose, two-cycle treatment schedule was well-tolerated, and no treatment discontinuations were due to AEs.
Anti-FT500 T-cell Mediated Immunogenicity. The T-cell compartment of nine patients was evaluated for T-cell mediated host-versus-product allo-reactivity. A TCR repertoire analysis conducted at multiple time points following treatment with FT500 demonstrated that a maximum of up to 6% of the T-cell clones in the patients’ reconstituted T-cell compartment were comprised of pre-existing low-frequency T-cell clones, suggesting that a robust T-cell response against FT500 was not evident. As a point of contrast, in subjects undergoing immunization for infectious disease, it is observed that almost 90% of the T-cell clones that emerge existed in low frequency prior to immunization.
Anti-FT500 B-cell Mediated Immunogenicity. The antibody repertoire of 11 patients was analyzed for targeting of the six HLA class I types expressed by FT500 to assess B-cell mediated host-versus-product allo-reactivity. Among the 11 patients, a single FT500 anti-HLA antibody with a mean fluorescence intensity (MFI) level of ≥ 5,000 was detected in a single patient, suggesting that a robust anti-FT500 B-cell response was not evident. As a point of reference, in patients undergoing haplo-identical hematopoietic stem cell transplant, an MFI level ≥ 5,000 has been correlated with a 5-fold increase in risk of graft rejection.
FT500 Anti-tumor Activity. In the monotherapy arm, two of three patients in the 100 million cells per dose cohort and two of five patients in the 300 million cells per dose cohort achieved a best overall response of stable disease per iRECIST. In the ICI combination arm, two of three patients in the 100 million cells per dose cohort achieved a best overall response of stable disease per iRECIST. A fourth patient in the ICI combination arm is currently undergoing treatment in the 300 million cells per dose cohort.
Upon successful completion of the 300 million cells per dose cohort in the ICI combination arm, the Company plans to amend the current FT500 clinical protocol to include IL-2 cytokine support with each dose of FT500 and enrich for cancers that are expected to be amenable to NK cell anti-tumor activity. In the dose-expansion stage of the FT500 Phase 1 study, FT500 will be administered at 300 million cells per dose in combination with ICI therapy under this revised clinical protocol.

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 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), an oncology-focused pharmaceutical company, reported that two presentations highlighting new and updated data relating to XPOVIO (selinexor), the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, will be given at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 Annual Meeting taking place December 7-10, 2019 in Orlando (Press release, Karyopharm, DEC 7, 2019, View Source [SID1234552028]). The first study, which will be featured in an oral presentation, describes updated data from the Phase 1b/2 STOMP study evaluating the all oral regimen of selinexor in combination with Pomalyst (pomalidomide) and low-dose dexamethasone (dex) (SPd) in patients with relapsed or refractory multiple myeloma. The second abstract, which will be featured in a poster presentation, describes new data on the use of selinexor and dexamethasone, either alone or in combination with standard approved therapies, in patients with multiple myeloma whose disease has progressed following experimental chimeric antigen receptor T-cell (CAR-T) therapy.

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"We continue to be pleased with the efficacy and safety observed in the all oral selinexor plus Pomalyst arm of the Phase 1b/2 STOMP study, where patients with Pomalyst-naïve and Revlimid (lenalidomide)-relapsed or -refractory myeloma achieved a 56% overall response rate (ORR) and a 12-month progression free survival (PFS)," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "Another key study this year is the presentation of new data from patients treated with selinexor-based regimens after their myeloma had progressed following experimental CAR-T therapy. Although these data are early, six of seven patients whose disease relapsed after CAR-T achieved a response when treated with selinexor and dexamethasone alone or in combination with either Velcade (bortezomib) or Kyprolis (carfilzomib). There is currently very limited data regarding treatment options for patients whose disease has progressed following experimental CAR-T therapy, and we believe these encouraging results further reinforce the therapeutic activity of selinexor in patients with relapsed or refractory disease."

Updated Data from Phase 1b/2 STOMP Study Evaluating Selinexor in Combination with Pomalyst and Low-dose Dexamethasone (SPd)

In this arm of the Phase 1b/2 STOMP study, oral selinexor is being evaluated in combination with Pomalyst (3 or 4mg orally, once daily) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly) in patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or patients with myeloma refractory to both a PI and an IMiD. The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SPd Patients as of 1-Oct-20192
Prior Therapy Status N3 ORR VGPR4 PR Median PFS
Pomalyst-naïve and Revlimid refractory or relapsed 32 18 (56%) 6 (19%) 12 (38%) 12.2 months
Pomalyst Treated and Revlimid refractory 14 5 (36%) 1 (7%) 4 (29%) 5.6 months
Key: ORR=Overall Response Rate (VGPR+PR); VGPR=Very Good Partial Response; PR=Partial Response
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data
3 Five patients not evaluable for response: one death unrelated to myeloma, one non-compliance with study procedures, one withdrawal of consent before disease follow up, one death related to progressive disease (PD), one PD before C2D1
4 One unconfirmed VGPR

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related adverse events (AEs) were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (52%), fatigue (52%) and weight loss (39%). As expected, the most common treatment-related Grade 3 and 4 AEs were neutropenia (58%), thrombocytopenia (27%) and anemia (27%).

Based on these Phase 2 results, a Phase 3 study investigating the SPd combination is planned.

In parallel with the ongoing Phase 1b/2 STOMP study, Karyopharm is conducting the pivotal, randomized Phase 3 BOSTON study evaluating once-weekly selinexor in combination with the PI Velcade and dexamethasone (SVd) for the treatment of patients with multiple myeloma who have had one to three prior lines of therapy. Enrollment in the BOSTON study is complete and top-line data are expected in early 2020 contingent upon the occurrence of PFS events, the primary endpoint of the study. Data from the BOSTON study, if positive, are expected to be used to support regulatory submissions to the U.S. Food and Drug Administration and the European Medicines Agency requesting the use of selinexor in combination with Velcade and dexamethasone in patients with multiple myeloma who have received at least one prior therapy.

New Data from Study Evaluating Selinexor in Patients with Multiple Myeloma Following CAR-T Therapy

In this study, seven patients were identified from selinexor myeloma trials who had received an active dose of CAR-T cell therapy (>108 CAR-positive cells targeting B-cell maturation antigen) as treatment for their multiple myeloma prior to being enrolled in a trial using a selinexor-containing regimen. One patient was treated with selinexor (starting at 80 mg twice-weekly) and dexamethasone (20 mg twice weekly), one patient was treated with the regimen currently being investigated in the ongoing Phase 3 BOSTON study, a combination of selinexor (100 mg once-weekly), Velcade (1.3 mg/m2 once-weekly for 4 of 5 weeks) and dexamethasone (40 mg once-weekly), and five patients were treated with a combination of selinexor (100 mg once-weekly), Kyprolis (20/56 mg/m2 or 20/70 mg/m2) and dexamethasone (40 mg once weekly or 20 mg twice weekly). Patients had a median of ten prior therapeutic regimens (range: 5-15), all had high-risk cytogenetics, and six of the seven had rapidly progressing disease as indicated by the percent increase in paraprotein (17-91%) between screening and Cycle 1 Day 1 (range: 7-22 days).

The following table is a summary of the efficacy results:

Best Responses1 in Evaluable Patients2
N ORR sCR VGPR PR
All patients 7 6 (86%) 1 (14%) 3 (43%) 2 (29%)
Key: ORR=Overall Response Rate (CR+VGPR+PR); sCR=Stringent Complete Response
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data

Of the six patients who responded (≥PR), the duration of response ranged from 1.4 months to 7.4 months, with two patients still on therapy and responding. Adverse events were consistent with what has previously been reported with selinexor-containing regimens in heavily-pretreated patients with multiple myeloma and included nausea, fatigue, thrombocytopenia, neutropenia, and anemia.

These preliminary data suggest that selinexor-dexamethasone alone or in combination with Velcade or Kyprolis may offer a therapeutic option for patients who have exhausted other available treatments, have rapidly progressing disease, and who have progressed after CAR-T therapy.

Details for these two ASH (Free ASH Whitepaper) 2019 presentations are as follows:

Oral Presentation

Title: Selinexor, Pomalidomide, and Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma
Presenter: Christine Chen, Princess Margaret Cancer Centre
Abstract #: 141
Session: 653. Myeloma: Therapy, excluding Transplantation: New Approaches in the Treatment of Relapsed/Refractory Plasma Cell Discrasias
Date and Time: Saturday, December 7, 2019; 9:30-11:00 AM ET
Location: Orange County Convention Center, Hall E1
Poster Presentation – Company-Sponsored Studies

Title: Selinexor-Containing Regimens for the Treatment of Patients with Multiple Myeloma Refractory to Chimeric Antigen Receptor T-Cell (CAR-T) Therapy
Presenter: Ajai Chari, Icahn School of Medicine at Mount Sinai
Abstract #: 1854
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster I
Date and Time: Saturday, December 7, 2019; 5:30-7:30 PM ET
Location: Orange County Convention Center, Hall B

PDF copies of these presentations will be available here following conclusion of the presentations at the meeting.

About XPOVIO (selinexor)

XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. In addition to receiving accelerated FDA approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, Karyopharm has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval of selinexor. Selinexor is also being studied in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In 2018, Karyopharm reported positive top-line results from the Phase 2b SADAL study evaluating selinexor in patients with relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue. Selinexor has received Fast Track designation from the FDA for the patient population evaluated in the SADAL study. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL), in recurrent gliomas (KING) and in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION

Thrombocytopenia

XPOVIO can cause thrombocytopenia, leading to potentially fatal hemorrhage. Thrombocytopenia was reported as an adverse reaction in 74% of patients, and severe (Grade 3-4) thrombocytopenia occurred in 61% of patients treated with XPOVIO. The median time to onset of the first event was 22 days. Bleeding occurred in 23% of patients with thrombocytopenia, clinically significant bleeding occurred in 5% of patients with thrombocytopenia and fatal hemorrhage occurred in <1% of patients.

Monitor platelet counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Neutropenia

XPOVIO can cause neutropenia, potentially increasing the risk of infection. Neutropenia was reported as an adverse reaction in 34% of patients, and severe (Grade 3-4) neutropenia occurred in 21% of patients treated with XPOVIO. The median time to onset of the first event was 25 days. Febrile neutropenia was reported in 3% of patients.

Obtain neutrophil counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Gastrointestinal Toxicity

Gastrointestinal toxicities occurred in patients treated with XPOVIO.

Nausea/Vomiting

Nausea was reported as an adverse reaction in 72% of patients, and Grade 3 nausea occurred in 9% of patients treated with XPOVIO. The median time to onset of the first nausea event was 3 days.

Vomiting was reported in 41% of patients, and Grade 3 vomiting occurred in 4% of patients treated with XPOVIO. The median time to onset of the first vomiting event was 5 days.

Provide prophylactic 5-HT3 antagonists and/or other anti-nausea agents, prior to and during treatment with XPOVIO. Manage nausea/vomiting by dose interruption, reduction, and/or discontinuation. Administer intravenous fluids and replace electrolytes to prevent dehydration in patients at risk. Use additional anti-nausea medications as clinically indicated.

Diarrhea

Diarrhea was reported as an adverse reaction in 44% of patients, and Grade 3 diarrhea occurred in 6% of patients treated with XPOVIO. The median time to onset of diarrhea was 15 days.

Manage diarrhea by dose modifications and/or standard anti-diarrheal agents; administer intravenous fluids to prevent dehydration in patients at risk.

Anorexia/Weight Loss

Anorexia was reported as an adverse reaction in 53% of patients, and Grade 3 anorexia occurred in 5% of patients treated with XPOVIO. The median time to onset of anorexia was 8 days.

Weight loss was reported as an adverse reaction in 47% of patients, and Grade 3 weight loss occurred in 1% of patients treated with XPOVIO. The median time to onset of weight loss was 15 days.

Monitor patient weight at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Manage anorexia and weight loss with dose modifications, appetite stimulants, and nutritional support.

Hyponatremia

XPOVIO can cause hyponatremia; 39% of patients treated with XPOVIO experienced hyponatremia, 22% of patients experienced Grade 3 or 4 hyponatremia. The median time to onset of the first event was 8 days.

Monitor sodium level at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Treat hyponatremia per clinical guidelines (intravenous saline and/or salt tablets), including dietary review. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Infections

In patients receiving XPOVIO, 52% of patients experienced any grade of infection. Upper respiratory tract infection of any grade occurred in 21%, pneumonia in 13%, and sepsis in 6% of patients. Grade ≥3 infections were reported in 25% of patients, and deaths resulting from an infection occurred in 4% of patients. The most commonly reported Grade ≥3 infections were pneumonia in 9% of patients, followed by sepsis in 6%. The median time to onset was 54 days for pneumonia and 42 days for sepsis. Most infections were not associated with neutropenia and were caused by non-opportunistic organisms.

Neurological Toxicity

Neurological toxicities occurred in patients treated with XPOVIO.

Neurological adverse reactions including dizziness, syncope, depressed level of consciousness, and mental status changes (including delirium and confusional state) occurred in 30% of patients, and severe events (Grade 3-4) occurred in 9% of patients treated with XPOVIO. Median time to the first event was 15 days.

Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes.

Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, XPOVIO can cause fetal harm when administered to a pregnant woman. Selinexor administration to pregnant animals during organogenesis resulted in structural abnormalities and alterations to growth at exposures below those occurring clinically at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥20%) are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.

The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had a reduction in the XPOVIO dose, and 65.3% had the dose of XPOVIO interrupted. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received XPOVIO included fatigue, nausea, and thrombocytopenia. The rate of fatal adverse reactions was 8.9%.