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

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

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

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

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

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

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

Poster details

Abstract 2879

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

Authors: A. Kolstad, A et al.

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

Conference call/audio cast details:

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

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About ASH (Free ASH Whitepaper)

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

About Betalutin

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

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

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

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

About LYMRIT 37-01

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

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

On December 1, 2018 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported positive top-line results from the Phase 2b SADAL (Selinexor Against Diffuse Aggressive Lymphoma) study evaluating selinexor, the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue (Press release, Karyopharm, DEC 1, 2018, View Source [SID1234531776]). The data were highlighted in a poster presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting in San Diego. For the SADAL study’s primary endpoint, single-agent selinexor achieved a 29.6% overall response rate (ORR), which included a 9.6% complete response (CR) rate in patients with heavily pretreated relapsed or refractory DLBCL. Key secondary endpoints included a median duration of response (DOR, in the responding patients) of 9.2 months and median overall survival (OS, across the entire study) of 9.1 months.

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Selinexor recently received Fast Track designation from the FDA for the patient population evaluated in the SADAL study. Karyopharm plans to submit a New Drug Application (NDA) to the FDA during the first half of 2019, with a request for accelerated approval for oral single-agent selinexor as a new treatment for patients with relapsed or refractory DLBCL.

Top-Line Phase 2b SADAL Results

Based on the modified intention-to-treat analysis from the first 115 of 127 patients (median of 2 prior treatment regimens with a range 1-6), as adjudicated by an independent central radiological committee, 34 patients responded (11 patients with a CR and 23 patients with a PR) for an ORR of 29.6%. An additional 8 patients experienced stable disease (SD) for a disease control rate of 36.5%. The median DOR across responding patients was 9.2 months and responses tended to occur rapidly. Patients with a CR had a median DOR of 23.0 months and patients with a PR had a median DOR of 7.8 months. As of the data cutoff date of November 15, 2018, 7 patients who achieved a CR remained on treatment. In addition, 12 patients remain on treatment, but as of November 15th, had not reached their first response assessment and are not included in the top-line efficacy analyses.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related adverse events (AEs) were gastrointestinal and constitutional symptoms, along with cytopenias; most manageable with dose modifications and/or supportive care. The most common non-hematologic AEs were nausea (50.0%), fatigue (35.9%), and anorexia (32.0%) and mostly Grade 1 and 2 events. As expected, the most common Grade 3 and 4 AEs were thrombocytopenia (35.2%), neutropenia (20.3%), and anemia (10.9%) and were generally not associated with clinical sequelae. No significant major organ toxicities were observed, and bleeding and infection rates were low.

The median OS was 9.1 months for all patients in the study. As of the data cutoff date, median survival for the patients with a CR or PR was 29.7 months. The median survival for patients with best response of progressive disease or who were not evaluable for response was 3.2 months.

Selinexor showed robust, single-agent activity in patients with either GCB or non-GCB subtypes of DLBCL: of the 53 patients with the GCB-subtype, 18 responded (5 patients with a CR and 13 patients with a PR) for an ORR of 34.0%. Of the 57 patients with the non-GCB subtype, 12 responded (6 patients with a CR and 6 patients with a PR) for an ORR of 21.1%. In addition, there were 5 patients enrolled whose subtype was unclassified and 4 of these patients achieved a PR.

"The SADAL data presented at ASH (Free ASH Whitepaper) this year demonstrate that oral selinexor, when administered as a single-agent, is clinically active and capable of producing durable responses associated with prolonged overall survival," said Marie Maerevoet, MD, Institute Jules Bordet, "The 60mg twice weekly oral dose continues to be well tolerated with a low incidence of Grade 3 or greater adverse events, which were often manageable with dose modifications and supportive care. We are highly encouraged by the results of this single agent study in patients with heavily pretreated DLBCL who have limited available treatment options."

Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm, said, "In addition to the compelling efficacy and safety data observed with single agent oral selinexor, we were especially pleased to see strong response rates in patients with both the GCB and non-GCB subtypes. This is especially important because the prognosis in patients with refractory disease and the GCB-subtype is particularly poor. We believe that if selinexor is ultimately approved for use in patients with DLBCL, it will provide a meaningful therapeutic option for patients battling refractory disease regardless of DLBCL subtype. We look forward to submitting these data to the FDA during the first half of 2019 as part of a New Drug Application, with a request for accelerated approval."

Details for the Poster Presentation at ASH (Free ASH Whitepaper) 2018:

Title: Single Agent Oral Selinexor Demonstrates Deep and Durable Responses in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) in Both GCB and Non-GCB Subtypes: The Phase 2b SADAL Study
Presenter: Marie Maerevoet, Institute Jules Bordet, Brussels, Belgium
Abstract Number/Publication ID: 1677
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster I
Date and Time:Saturday, December 1, 2018; 6:15-8:15 PM PT
Location: San Diego Convention Center, Hall GH

About Selinexor

Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,800 patients have been treated with selinexor. In April and September 2018, Karyopharm reported positive data from the Phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with penta-refractory multiple myeloma. Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm’s New Drug Application (NDA) has been accepted for filing and granted Priority Review by the FDA, and oral selinexor is currently under review by the FDA as a possible new treatment for patients with penta-refractory multiple myeloma. The Company also plans to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in early 2019 with a request for conditional approval. 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 diffuse large B-cell lymphoma (SADAL), liposarcoma (SEAL), and an investigator-sponsored study 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.

On December 1, 2018 Unum Therapeutics Inc. (NASDAQ: UMRX), reported preliminary results from the ongoing Phase 1 ATTCK-17-01 study, testing ACTR087 in combination with SEA-BCMA in patients with relapsed/refractory multiple myeloma (r/r MM) at the American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in San Diego, CA (Press release, Unum Therapeutics, DEC 1, 2018, View Source [SID1234531761]).

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First-in-human dosing of single agent SEA-BCMA, and of ACTR087 in combination with SEA-BCMA, in the ATTCK-17-01 multi-center, open-label Phase 1 dose-escalation study was well-tolerated, with no dose-limiting toxicities (DLTs) in the first three cohorts. Following infusion, ACTR+ T cells were detectable in these patients and demonstrated expansion post infusion. Furthermore, early disease assessments suggest combination activity of SEA-BCMA with ACTR087. These data support continued dose escalation of ACTR087 and SEA-BCMA in the trial.

"We are pleased with the early data we have observed showing biomarker evidence of antibody-dependent ACTR T cell activation at the lowest doses of SEA-BCMA," said Michael Vasconcelles, Chief Medical Officer of Unum. "Combining ACTR087 with a novel antibody like SEA-BCMA brings together multiple anti-myeloma mechanisms of action that are unique to this combination. Furthermore, this approach provides us the ability to adjust the doses of both the antibody and ACTR087, to optimize the therapeutic index of the combination. We are excited about the potential to develop a meaningful combination for patients with relapsed or refractory myeloma. We look forward to continued dose escalation of the combination in ATTCK-17-01 to further assess its safety and anti-myeloma activity."

The majority of subjects, including at the lowest SEA-BCMA dose levels, demonstrated increasing serum and urine M protein levels during SEA-BCMA single-agent dosing that stabilized or decreased following ACTR087 administration, suggesting combination activity of ACTR087+SEA-BCMA. Subjects exhibited early increases in interferon gamma following ACTR087 administration, and additional elevations following subsequent SEA-BCMA administrations, suggestive of antibody-dependent T cell activation. SEA-BCMA was well-tolerated with no serious adverse events related to SEA-BCMA reported. No DLTs after the SEA-BCMA single-agent dosing period or after the ACTR087 + SEA-BCMA combination were reported across all three cohorts. No severe events of cytokine release syndrome (CRS) or severe neurological events were reported.

About the ATTCK-17-01 Trial
ACTR087 used in combination with SEA-BCMA is being tested in ATTCK-17-01, a Phase I, multi-center, open-label clinical trial designed to test the safety, tolerability, and anti-myeloma activity in patients with r/r MM, currently in the dose escalation phase. Primary study objectives are to characterize the safety of ACTR087 in combination with SEA-BCMA and to determine the recommended Phase 2 dose. Secondary study objectives include assessment of the anti-myeloma activity of the combination, ACTR T cell expansion and persistence, cytokine and SEA-BCMA pharmacokinetics. Immediately following leukapheresis, patients may begin to receive SEA-BCMA as a single agent. Following lymphodepleting chemotherapy, a single ACTR087 infusion is administered. This is the first clinical trial conducted under the Company’s strategic collaboration with Seattle Genetics.

About ACTR087 in combination with SEA-BCMA
ACTR087 is a 4-1BB-containing receptor that also has been evaluated in combination with rituximab in adult patients with relapsed or refractory non-Hodgkin lymphoma (r/r NHL). SEA-BCMA is a novel humanized non-fucosylated antibody that targets the antigen BCMA, developed by Seattle Genetics using the Company’s sugar-engineered antibody (SEA) technology. BCMA is expressed on normal plasma cells, some mature B cells, and at comparatively elevated levels on malignant multiple myeloma cells but is absent from other normal tissues. SEA-BCMA is engineered to enhance its binding to ACTR087, providing additional rationale for this novel-novel combination.

On December 1, 2018 Novartis reported longer-term analyses of both ELIANA and JULIET, the pivotal clinical trials of Kymriah (tisagenlecleucel) in children and young adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL), respectively (Press release, Novartis, DEC 1, 2018, View Source [SID1234531763]). In these analyses, Kymriah continued to demonstrate strong efficacy with durable responses and maintained a consistent and well-characterized safety profile. These data are being presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting. Additionally, today, the New England Journal of Medicine published online the 14-month results from JULIET, the study led by the Abramson Cancer Center at the University of Pennsylvania[3].

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"After bringing the first CAR-T cell therapy to patients, Novartis is committed to continue our pioneering efforts to reimagine the treatment paradigm for patients with aggressive blood cancer," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "These analyses underscore the longer-term durability of response with Kymriah and its consistent safety profile, reinforcing our belief in the potential for CAR-T cell therapy to extend the lives of patients with these advanced B-cell malignancies."

In the 24-month follow-up analysis of the ELIANA study in children and young adults with r/r B-cell ALL, Kymriah demonstrated deep and durable responses without subsequent therapy in a significant portion of patients in this population. Among 79 evaluable patients, who were followed for at least three months or discontinued earlier, 82% (95% confidence interval [CI], 72% – 90%) achieved complete response (CR) or CR with incomplete blood count recovery (CRi) within three months of infusion; and among these responding patients, 98% had negative minimal residual disease (MRD-). The relapse-free survival rate was 62% at 24 months; and the median duration of remission (mDOR) and median overall survival (mOS) remained unreached, signifying responses are deep and sustained, and further reinforcing the potential for Kymriah to be a definitive therapy for many patients. The probability of OS was 76% (95% CI, 65% – 85%) at 12 months and 66% (95% CI, 58% – 79%) at 24 months. The safety profile observed in this updated analysis was consistent with previously reported results, with no emergence of new safety signals. Grade 3/4 cytokine release syndrome (CRS) – as defined by the rigorous Penn Grading Scale – occurred in 49% of patients. Within eight weeks of infusion, 13% of patients experienced grade 3 neurological events, with no grade 4 events or cerebral edema[1]. These updated data will be presented in an oral session at the ASH (Free ASH Whitepaper) annual meeting (Abstract # 895; Monday, December 3, 4:30 PM PST).

"Our group has devoted a great deal of attention to advancing treatment options for children and young adults with B-cell ALL. This two-year analysis is an exciting milestone for the field, as it is the longest follow-up data for a multicenter CAR-T cell trial for those patients who have failed to respond to other treatment options," said Stephan A. Grupp, MD, PhD, Director of the Cancer Immunotherapy Program and Section Chief of Cell Therapy and Transplant at Children’s Hospital of Philadelphia, and a Professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania. "Seeing that the majority of responding patients from ELIANA are still in remission for this long after a one-time infusion further establishes Kymriah as a truly transformative treatment option."

The 19-month analysis from the JULIET study of Kymriah in adult patients with r/r DLBCL showed prolonged durability of response in patients (n=99) who had previously been through multiple rounds of chemotherapy and unsuccessful stem cell transplants. The overall response rate (ORR) after a median of 19 months of follow-up was 54% (95% CI, 43% – 64%; CR, 40%; partial response [PR], 13%) among patients who were followed for at least 3 months or discontinued earlier. The mDOR was not reached at the time of analysis indicating most responders were still experiencing a response at the time of analysis; and the relapse-free probability, which was 66% (95% CI, 51%-78%) at 6 months, remained consistent at 64% (95% CI, 48%-76%) between 12-month and 18-month analyses. Further, 54% (15/28) of patients who had achieved a PR converted to CR. Median OS for all infused patients was 11.1 months (95% CI, 6.6 months-NE) and not reached (95% CI, 21 months-NE) for patients in CR. The OS probability was 48% (95% CI, 38%-57%) at 12 months and 43% (95%CI, 33%-53%) at 18 months (max follow-up, 29 months). Analyses of ORR, DOR and OS data showed consistent results across all patient subgroups, regardless of relapsed/refractory status, age and high-risk cytogenetics.

The safety profile observed in the 19-month follow-up from JULIET continued to be consistent with previous reports and no deaths occurred due to causes other than disease progression in this longer-term follow up analysis. Within eight weeks of infusion with Kymriah, Grade 3/4 CRS, as defined by the Penn Grading Scale, was reported in 23% of patients. CRS management was conducted per the Penn CRS management algorithm, which is specific to Kymriah. Tocilizumab and steroids were used in 16% and 11% of patients, respectively, to treat CRS. Eleven percent of patients had Grade 3/4 neurologic adverse events, which were managed with supportive care[2].

The updated JULIET data will be presented today in a poster at the ASH (Free ASH Whitepaper) annual meeting (Abstract #1684; Saturday, December 1, 6:15 PM PST).

"Before CAR-T cell therapy, achieving and maintaining a prolonged complete response in adult patients with relapsed or refractory DLBCL was incredibly rare, but now we are seeing Kymriah result in durable complete responses more than a year and a half after infusion[4]," said lead author of the updated JULIET analysis, Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research in the University of Pennsylvania’s (Penn) Perelman School of Medicine and director of the Lymphoma Program at the Abramson Cancer Center. "For physicians treating this patient population, duration of response and a consistent safety profile are incredibly important data points, and the findings from this updated analysis further instill confidence in the continuing potential of Kymriah in the treatment of these patients."

Kymriah is approved in the US, the EU, Canada and Switzerland for children and young adults with relapsed or refractory ALL and in adult patients with relapsed or refractory DLBCL, making it the only CAR-T cell therapy approved for two distinct indications and delivering the transformative potential for durable responses for patients who relapse or don’t respond to initial therapies and for whom the outlook is poor. Patients do not need to be in complete remission to receive Kymriah and no donor is required.

About the ELIANA Trial
ELIANA is the first pediatric global CAR-T cell therapy registration trial, examining patients in 25 centers in 11 countries across the US, Canada, Australia, Japan and the EU, including: Austria, Belgium, France, Germany, Italy, Norway and Spain, demonstrating effective distribution of Kymriah across four continents using a global supply chain. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

About the JULIET Trial
JULIET is the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL. JULIET, led by researchers at the University of Pennsylvania, is the largest and only registration study examining a CAR-T cell therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and Europe, including Austria, France, Germany, Italy, Norway and the Netherlands.

Kymriah (tisagenlecleucel, formerly CTL019) US Important Safety information
Kymriah may cause side effects that are severe or life-threatening, such as Cytokine Release Syndrome (CRS) or Neurological Toxicities. Patients with CRS may experience symptoms including difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, or dizziness/lightheadedness. Patients may be admitted to the hospital for CRS and treated with other medications.

Patients with neurological toxicities may experience symptoms such as altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Patients should be advised to call their healthcare provider or get emergency help right away if they experience any of these signs and symptoms of CRS or neurological toxicities.

Because of the risk of CRS and neurological toxicities, Kymriah is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Kymriah REMS.

Serious allergic reactions, including anaphylaxis, may occur after Kymriah infusion. Kymriah can increase the risk of life-threatening infections that may lead to death. Patients should be advised to tell their healthcare provider right away if they develop fever, chills, or any signs or symptoms of an infection.

Patients may experience prolonged low blood cell counts (cytopenia), where one or more types of blood cells (red blood cells, white blood cells, or platelets) are decreased. The patient’s healthcare provider will do blood tests to check all of their blood cell counts after treatment with Kymriah. Patients should be advised to tell their healthcare provider right away if they get a fever, are feeling tired, or have bruising or bleeding.

Patients may experience hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with Kymriah, and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with Kymriah. Patients should tell their healthcare provider about their treatment with Kymriah before receiving a live virus vaccine.

After treatment with Kymriah, patients will be monitored lifelong by their healthcare provider, as they may develop secondary cancers or recurrence of their cancer.

Patients should not drive, operate heavy machinery, or do other dangerous activities for eight weeks after receiving Kymriah because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.

Some of the most common side effects of Kymriah are difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, dizziness/lightheadedness, and headache. However, these are not all of the possible side effects of Kymriah. Patients should talk to their healthcare provider for medical advice about side effects.

Prior to a female patient starting treatment with Kymriah, their healthcare provider may do a pregnancy test. There is no information available for Kymriah use in pregnant or breast-feeding women. Therefore, Kymriah is not recommended for women who are pregnant or breast feeding. Patients should talk to their healthcare provider about birth control and pregnancy.

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

After receiving Kymriah, patients should be advised that some commercial HIV tests may cause a false-positive test result. Patients should also be advised not to donate blood, organs, or tissues and cells for transplantation after receiving Kymriah.

On December 1, 2018 ImmunoGen, Inc., (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that new data from the ongoing Phase 1 studies of IMGN632 and IMGN779, next-generation CD123- and CD33-targeting ADCs, respectively, in patients with relapsed or refractory adult acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) will be presented during an oral session at the 60thAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego (Press release, ImmunoGen, DEC 1, 2018, View Source [SID1234531781]). Preclinical data for IMGN632 as a monotherapy in BPDCN patient-derived xenografts, as well as in combination with a PARP inhibitor in AML models, will also be presented at the conference.

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The data presented at ASH (Free ASH Whitepaper) demonstrate the potential of ADCs generated from the company’s IGN platform to overcome the narrow therapeutic window seen with previous generations of DNA-targeted agents and offer new treatment options for AML and other hematological malignancies.

"We designed our IGN payloads to alkylate one strand of DNA to produce potent anti-leukemia activity, while reducing toxicity to normal cells caused by the double-stranded damage associated with earlier DNA-acting approaches," said Anna Berkenblit, MD, Vice President and Chief Medical Officer of ImmunoGen. "IMGN779 and IMGN632 each incorporate an IGN payload and we are pleased to share Phase I clinical results for both programs today at ASH (Free ASH Whitepaper)."

"With IMGN632, we are encouraged by both the tolerability and responses seen thus far, including repeat dosing and complete remissions in AML and BPDCN," said Naval Daver, MD, Associate Professor in the Department of Leukemia at MD Anderson Cancer Center. "We look forward to continuing to enroll patients at several dose levels to establish a recommended Phase 2 dose and schedule for both indications."

"With IMGN779, I am encouraged to see a significant decrease in blasts in many patients with some achieving CRi," said Jorge Cortes, MD, Deputy Chair and Professor of Medicine in the Department of Leukemia at MD Anderson Cancer Center. "The anti-leukemia activity and tolerability seen with both the weekly and the every two week schedule support continued enrollment to identify a dose and schedule to enable further development of IMGN779 as combination therapy in AML."

Phase 1 Data on IMGN632 in AML and BPDCN

Key initial findings from the Phase 1 study of IMGN632 (Abstract #27) include the following:

IMGN632 was administered to 33 patients over dose levels ranging from 0.015 to 0.45 mg/kg intravenously every three weeks. IMGN632 displays a tolerable safety profile and anti-leukemia activity at doses up to 0.3 mg/kg.
Pharmacokinetic (PK) exposures and pharmacodynamic (PD) CD123 saturation increase with dose.
Reported adverse events (AEs) were consistent with underlying disease, with no evidence of cumulative toxicity following multiple doses (up to 6 doses).
Single dose limiting toxicities (DLTs) were seen at the three highest dose levels tested: one prolonged neutropenia and two reversible cases of veno-occlusive disease.
Six of 23 evaluable AML patients (26%) across multiple dose levels achieved an objective response, including two complete remissions (CR) and four CRs with incomplete recovery (CRi) in heavily pretreated patients, including over 60% of patients with primary or relapsed refractory disease.
Two of three evaluable BPDCN patients achieved an objective response after a single dose of IMGN632, 1 CRi and 1 partial remission.
Enrollment in expansion cohorts continues to identify a recommended Phase 2 dose and schedule for both AML and BPDCN.
Phase 1 Data on IMGN779 in AML

Key findings presented from the Phase 1 study of IMGN779 (Abstract #26) include the following:

IMGN779 continues to display a tolerable safety profile with repeat dosing across a wide range of doses explored in 57 patients with relapsed AML. Patients across both schedules (weekly and every two weeks) received a median of four doses of IMGN779 (range, 1-40).
Plasma IMGN779 concentrations indicate consistent and sustained exposure through seven days at doses ≥0.39 mg/kg; the weekly schedule provides more consistent pharmacodynamic CD33 saturation.
Reported AEs were consistent with underlying disease, and with no evidence of cumulative toxicity following multiple doses (up to 40 doses).
One DLT of veno-occlusive disease was observed at the highest dose tested on the weekly schedule, 1.2 mg/kg.
Anti-leukemia activity was seen at doses ≥0.39 mg/kg in both schedules:
41% (12 of 29) of evaluable patients showed a >30% reduction in bone marrow blasts with eight patients (28%) having <8% residual blasts, and two having a CR or CRi.
Enrollment continues to identify the recommended Phase 2 dose and schedule.
Oral Presentation Details

Title: Maturing Clinical Profile of IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Acute Myeloid Leukemia
Presenter:Jorge Cortes, MD Anderson Cancer Center
Day/Time:Saturday, December 1, 2018, 7:45am PST (Oral session 613)
Location: Manchester Grand Hyatt San Diego, Seaport Ballroom F
Abstract: 26
Title: A Phase I, First-in-Human Study Evaluating the Safety and Preliminary Antileukemia Activity of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Other CD123-Positive Hematologic Malignancies
Presenter: Naval Daver, MD Anderson Cancer Center
Senior Author: Hagop Kantarjian, MD Anderson Cancer Center
Day/Time: Saturday, December 1, 2018, 8:00am PST (Oral session 613)
Location: Manchester Grand Hyatt San Diego, Seaport Ballroom F
Abstract: 27
Preclinical Poster Presentations on IMGN632 in AML and BPDCN

Preclinical data on anti-leukemia activity for IMGN632 in combination with a PARP inhibitor in AML, as well as a monotherapy in BPDCN will also be presented.

Poster Presentation Details

Title: Synergistic anti-leukemia activity of PARP inhibition combined with IMGN632, an anti-CD123 antibody-drug conjugate in acute myeloid leukemia models
Day/Time: Sunday, December 2, 2018, 6:00-8:00pm PST (Poster session 604)
Senior author: Eunice Wang, Roswell Park Cancer Institute
Abstract: 2647
Title: Pre-clinical efficacy of CD123-targeting antibody-drug conjugate IMGN632 in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) models
Day/Time: Monday, December 3, 2018, 6:00-8:00pm PST (Poster session 605)
Senior author:Marina Konopleva, MD Anderson Cancer Center
Abstract: 3956
Additional information can be found at www.hematology.org, including abstracts.

About IMGN779

IMGN779 is a novel ADC that combines a high-affinity, humanized anti-CD33 antibody, a cleavable disulfide linker, and one of ImmunoGen’s novel indolino-benzodiazepine payloads, called IGNs, which alkylate DNA without crosslinking, resulting in potent preclinical anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.1,2 IMGN779 is in Phase 1 clinical testing for the treatment of AML.

About IMGN632

IMGN632 is a novel, anti-CD123 antibody-drug conjugate that is a potential treatment for AML, BPDCN, and other CD123-positive malignancies. IMGN632 uses a novel humanized anti-CD123 antibody coupled via a peptide linker to a unique DNA-alkylating IGN payload. In preclinical models, IMGN632 has exhibited potent antitumor activity with a wide therapeutic index in AML, BPDCN, and acute lymphoblastic leukemia (ALL). IMGN632 is in Phase 1 clinical testing for the treatment of AML and BPDCN.

About IGNs

Indolino-benzodiazepine cancer-killing agents, or IGNs, are a new class of cancer-killing agent developed by ImmunoGen for use in ADCs. These ultra-potent, DNA-acting IGNs alkylate DNA without crosslinking, which preclinically has resulted in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.3.4 IMGN779, a CD33-targeting ADC in Phase 1 testing for AML, was the first IGN ADC to enter clinical testing. IMGN632, a CD123-targeting ADC entering Phase 1 testing for AML and BPDCN, deploys a novel IGN payload.

About Acute Myeloid Leukemia (AML)

AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems, and anemia.

It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients will die from the disease.5