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

On December 1, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company reported its updated data from the pivotal Phase 3 MURANO trial of venetoclax (VENCLEXTA or VENCLYXTO) in combination with rituximab (VenR) (Press release, AbbVie, DEC 1, 2018, https://news.abbvie.com/news/press-releases/abbvie-presents-new-data-from-phase-3-murano-trial-venclextavenclyxto-venetoclax-in-combination-with-rituximab-in-patients-with-relapsedrefractory-chronic-lymphocytic-leukemia-who-completed-fixed-treatment-course.htm [SID1234531765]). The results at median follow-up of 36 months demonstrated that the majority of patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL), treated with VenR, did not experience disease progression or death (PFS; the time on treatment without disease progression or death2) after all patients completed the fixed duration of therapy and stopped treatment, compared to patients treated with a standard of care regimen of bendamustine plus rituximab (BR).1 The estimated PFS rate at 36 months was 71.4 percent (95% confidence interval [CI]: 0.64, 0.78) for patients treated with VenR compared with 15.2 percent (95% CI: 0.09, 0.21) for patients who completed treatment with a standard of care combination of BR (hazard ratio [HR]: 0.16; 95% CI: 0.12, 0.23).1 The data were presented today during the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition.

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Of the 130 patients who completed the two-year treatment course of venetoclax and remained off therapy for a median of 9.9 months (range: 1.4 to 22.5), six- and 12-month PFS estimates were 92 percent (95% CI: 0.87, 0.96) and 87 percent (95% CI: 0.81, 0.93), respectively.1 At the time of analysis, the overall survival (OS) benefit estimated at three years was approximately 10 percent higher in the VenR arm (87.9 percent) than in the BR arm (79.5 percent) (HR: 0.50; 95% CI: 0.30, 0.85).1

"There is a need for a chemo-free option with a fixed treatment duration that can potentially provide prolonged progression-free survival, along with minimal residual disease negativity, in patients with relapsed or refractory chronic lymphocytic leukemia," said Prof. John Seymour, MBBS, Ph.D., lead investigator of the MURANO trial and Director of the Department of Hematology at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia. "The results of this analysis showed that a high proportion of patients with relapsed or refractory chronic lymphocytic leukemia who were treated with venetoclax in combination with rituximab maintained minimal residual disease negativity and progression-free survival well after completing the fixed treatment duration."

In the MURANO clinical trial, 78 percent of patients who completed the two-year treatment course of VenR without disease progression (N=114) also demonstrated minimal residual disease (MRD)-negativity in peripheral blood.1 MRD-negativity was a secondary endpoint assessed at the end of combination therapy (nine-month assessment1,3,4). MRD-negativity (also known as undetectable MRD) is an objective measure defined as the presence of less than one CLL cell in 10,000 white blood cells remaining in the blood or bone marrow following treatment.2 Earlier prospective clinical trials in CLL patients have provided evidence that achieving MRD-negativity is associated with improved clinical outcomes.2

"This analysis of the MURANO clinical trial showed that after patients had completed rituximab and a two-year course of venetoclax, and were off treatment for a median of 9.9 months, the disease did not progress in a substantial number of patients with relapsed or refractory chronic lymphatic leukemia, and in many of those patients the disease was undetectable in peripheral blood," said Neil Gallagher, M.D., Ph.D., Head of Global Oncology Development, AbbVie. "These findings continue to support the use of venetoclax plus rituximab as a treatment with a fixed duration for patients with relapsed or refractory chronic lymphocytic leukemia and are encouraging as we continue to advance the research and development of transformative medicines in blood cancers."

Safety data were consistent with the known safety profiles of each medicine alone. During the venetoclax single-agent treatment phase (N=171), 10 percent of patients had an adverse event (AE) leading to drug withdrawal, 4 percent had an AE leading to dose reduction, 26 percent had an AE leading to dose interruption, and 4 percent had a fatal AE (four other cancers, two cardiac, one pneumonia). Grade 3/4 AEs occurred in 35 percent of patients. The most common Grade 3/4 AEs were neutropenia (12 percent), anemia (3 percent) and thrombocytopenia (2 percent). Seven percent of patients had a Grade 3/4 infection during the single-agent phase.1

Venetoclax, a first-in-class oral B-cell lymphoma-2 (BCL-2) inhibitor, is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of Roche Group, in the U.S. and by AbbVie outside the U.S.

Design and Results of MURANO Phase 3 Trial
A total of 389 patients with R/R CLL who had received at least one prior therapy were enrolled in the international, multicenter, open-label, randomized, Phase 3 MURANO trial. The trial was designed to evaluate the efficacy and safety of venetoclax in combination with rituximab (N=194) compared with bendamustine in combination with rituximab (N=195). The median age of patients in the trial was 65 years (range: 22 to 85).5

The primary efficacy endpoint was investigator (INV)-assessed PFS. Median PFS with venetoclax in combination with rituximab was not reached compared with 17.0 months for bendamustine in combination with rituximab (HR: 0.17; 95% CI: 0.11, 0.25; P<0.0001). In the primary efficacy analysis, the median follow-up for PFS was 23.8 months (range: 0.0 to 37.4). Additional efficacy endpoints included independent review committee (IRC)-assessed PFS, INV- and IRC-assessed overall response rate (defined as complete response + complete response with incomplete marrow recovery + partial response + nodular partial response), OS and rates of MRD-negativity.5

About VENCLEXTA/VENCLYXTO (venetoclax)
VENCLEXTA/VENCLYXTO (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other cancerous tumors, BCL-2 builds up and prevents cancer cells from undergoing their natural death or self-destruction process, which is called apoptosis. VENCLEXTA/VENCLYXTO targets the BCL-2 protein and works to restore the process of apoptosis.

VENCLEXTA/VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers.

VENCLEXTA/VENCLYXTO is approved in more than 50 countries, including the U.S. AbbVie and Roche are currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

Important VENCLEXTA (venetoclax) US Safety Information3

What is the most important information I should know about VENCLEXTA?

VENCLEXTA can cause serious side effects, including:
Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your health care provider will do tests to check your risk of getting TLS before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your health care provider will do blood tests in your first 5 weeks of treatment to check you for TLS during treatment with VENCLEXTA. It is important to keep your appointments for blood tests. Tell your health care provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water when taking VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased tumor lysis syndrome.

Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other, causing serious side effects.
Do not start new medicines during treatment with VENCLEXTA without first talking with your health care provider.
Before taking VENCLEXTA, tell your health care provider about all of your medical conditions, including if you:Have kidney or liver problems.

Have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
Have a history of high uric acid levels in your blood or gout.
Are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during or after treatment with VENCLEXTA until your health care provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your health care provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
Are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your health care provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your health care provider right away.
Are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.
What should I avoid while taking VENCLEXTA?
You should not drink grapefruit juice, eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?
VENCLEXTA can cause serious side effects, including:

Low white blood cell count (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your health care provider will do blood tests to check your blood counts during treatment with VENCLEXTA. Tell your health care provider right away if you have a fever or any signs of an infection while taking VENCLEXTA.
The most common side effects of VENCLEXTA when used in combination with rituximab include low white blood cell count, diarrhea, upper respiratory tract infection, cough, tiredness, and nausea.

The most common side effects of VENCLEXTA when used alone include low white blood cell count, diarrhea, nausea, upper respiratory tract infection, low red blood cell count, tiredness, low platelet count, muscle and joint pain, swelling of your arms, legs, hands, and feet, and cough.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your health care provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. Tell your health care provider if you have any side effect that bothers you or that does not go away.

People are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

The full U.S. prescribing information, including Medication Guide, for VENCLEXTA can be found here. Globally, prescribing information varies; refer to the individual country product label for complete information.

Important VENCLYXTO (venetoclax) EU Safety Information4

Contraindications
Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumor lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as VENCLYXTO efficacy may be reduced.

Special Warnings & Precautions for Use
Tumor lysis syndrome (TLS), including fatal events, has occurred in patients with previously treated CLL with high tumor burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLYXTO and at each dose increase. Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period. Serious infections including events of sepsis with fatal outcome have been reported. Supportive measures including antimicrobials for any signs of infection should be considered.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions
CYP3A inhibitors may increase VENCLYXTO plasma concentrations. At initiation and dose-titration phase: Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose: If moderate or strong CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease VENCLYXTO plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions
The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination study with rituximab were neutropenia, diarrhea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhea, nausea, anemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with rituximab or as monotherapy were pneumonia, febrile neutropenia and TLS.

Discontinuation due to adverse reactions occurred in 16% of patients receiving venetoclax plus rituximab and 9% receiving venetoclax monotherapy. Dosage adjustments due to adverse reactions occurred in 15% of patients receiving venetoclax plus rituximab and 2% receiving venetoclax monotherapy. Dose interruptions occurred in 71% of patients treated with the combination of venetoclax and rituximab.

Specific Populations
Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined. VENCLYXTO should be administered to patients with severe renal impairment only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity due to increased risk of TLS.

VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment

On December 1, 2018 Seattle Genetics, Inc. (Nasdaq:SGEN) reported its highlighted data from three ongoing clinical trials evaluating the combination of ADCETRIS (brentuximab vedotin) and Opdivo (nivolumab) at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in San Diego, Calif., December 1-4, 2018 (Press release, Seattle Genetics, DEC 1, 2018, View Source [SID1234531782]). Initial data were presented from a phase 2 clinical trial evaluating the combination in relapsed or refractory primary mediastinal large B-cell lymphoma (PMBL). In addition, data were presented from the ongoing phase 1/2 clinical trial evaluating the combination in relapsed or refractory classical Hodgkin lymphoma (HL). Lastly, an oral presentation on Monday, December 3, 2018 will highlight initial data from a phase 2 study evaluating combination approaches with ADCETRIS, Opdivo and bendamustine in children, adolescents and young adults with relapsed or refractory classical HL. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL that plays a role in tumor growth and survival. Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to harness the body’s own immune system to help restore anti-tumor immune response. ADCETRIS and Opdivo are not approved in combination for the treatment of relapsed or refractory PMBL, HL or for other indications.

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"Our goal with ADCETRIS is to identify the most effective treatment strategies to improve the outcome of patients, and the combination of ADCETRIS and Opdivo has demonstrated enhanced activity with a tolerable safety profile in Hodgkin lymphoma and now a type of non-Hodgkin lymphoma called primary mediastinal large B-cell lymphoma, or PMBL," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. "In the Hodgkin lymphoma setting, ADCETRIS plus Opdivo data continue to support investigation of this combination regimen in multiple ongoing studies. The initial data reported from the phase 2 PMBL clinical trial demonstrate a high level of activity of the combination, with an objective response rate of 70 percent and a complete response rate of 27 percent. We and BMS are exploring specific settings where the combination of ADCETRIS and Opdivo has the potential to improve patient outcomes."

Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Preliminary Results from the Phase 2 Checkmate 436 Trial (Abstract #1691, poster presentation on Saturday, December 1, 2018)

Data from the Checkmate 436 phase 2 trial of 30 patients with relapsed or refractory PMBL who received a combination of ADCETRIS plus Opdivo treatment after failure of frontline therapy or autologous stem cell transplant (ASCT) will be presented for the first time. Patients were treated once every three weeks until disease progression or unacceptable toxicity. The median age of patients was 35.5 years. Key findings will be presented in a poster presentation by Alison Moskowitz, M.D., Clinical Director, Lymphoma Inpatient Unit, Memorial Sloan Kettering Cancer Center, New York, and include:

Of 30 response-evaluable patients, 21 patients (70 percent) had an objective response, including eight patients (27 percent) with a complete response and 13 patients (43 percent) with a partial response, three patients (10 percent) with stable disease, four patients (13 percent) with progressive disease and two patients (seven percent) unable to determine.
Median time to response was 1.3 months and time to complete response was 3 months. Median duration of response and duration of complete response were not reached.
The most common adverse events (AEs) of any grade in at least 20 percent of patients were neutropenia (27 percent) and peripheral neuropathy (20 percent). The most common Grade 3 or 4 AEs were neutropenia (27 percent); thrombocytopenia and decreased neutrophil count (seven percent each); and hypersensitivity, diarrhea and maculopapular rash (all three percent). Immune-mediated AEs included diarrhea, maculopapular rash and hyperthyroidism.
Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Classic Hodgkin Lymphoma: Part 3 (Concurrent Dosing) Results and Updated Progression-Free Survival Results from Parts 1 and 2 (Staggered Dosing) (Abstract #1635, poster presentation on Saturday, December 1, 2018)

Data will be reported from 30 patients with relapsed or refractory HL who received concurrent combination of ADCETRIS plus Opdivo treatment after failure of frontline therapy, representing Part 3 of the study. Patients were treated once every three weeks, with up to four cycles of combination therapy in the outpatient setting. After completion of the fourth cycle of treatment, patients were eligible to undergo an ASCT. The median age of patients was 31.5 years. Data from Parts 1 and 2 of the study were recently reported at the 11th International Symposium on Hodgkin Lymphoma (ISHL) and can be found here. Key findings will be presented in a poster presentation and include:

Of 30 response-evaluable patients, 28 patients (93 percent) had an objective response, including 24 patients (80 percent) with a complete response and four patients (13 percent) with a partial response, one patient each (three percent) with stable and progressive disease.
After a median follow-up time of 12.7 months, the estimated PFS at 12 months was 89 percent.
The most common AEs of any grade occurring prior to ASCT or subsequent salvage therapy in at least 15 percent of patients were nausea (57 percent), diarrhea and fatigue (37 percent each), vomiting (33 percent), infusion-related reaction (IRR; 30 percent), headache (27 percent), pruritus and pyrexia (23 percent each), and abdominal pain and chills (20 percent each). The majority of IRR AE symptoms were Grade 2 or less and included no treatment discontinuations.
An additional poster will be presented on Monday, December 3, 2018 from the phase 1/2 clinical trial evaluating ADCETRIS in combination with Opdivo in relapsed or refractory HL titled "Baseline Tumor Transcriptome Characteristics Associated with the Response of Relapsed/Refractory Hodgkin Lymphoma Patients to Brentuximab Vedotin in Combination with Nivolumab" (Abstract #2837).

Additional ADCETRIS and Opdivo ASH (Free ASH Whitepaper) Data Presentation

The first data will be reported in an oral presentation from the phase 2 CheckMate-744 study, the first risk-stratified, response-adapted study of ADCETRIS and Opdivo, followed by ADCETRIS and bendamustine for suboptimal response, in children, adolescents and young adults with relapsed/refractory classical HL, prior to ASCT. At time of analysis, all evaluable patients achieved complete metabolic remission after completing induction and, as needed, intensification therapy. The most common AEs were nausea (53 percent), diarrhea (31 percent) and pyrexia (28 percent). No AEs led to discontinuation and there were no deaths. Presentation information includes:

Response-Adapted Therapy with Nivolumab and Brentuximab Vedotin (BV), Followed by BV and Bendamustine for Suboptimal Response, in Children, Adolescents and Young Adults with Standard Risk Relapsed/Refractory Classical Hodgkin Lymphoma (Abstract #927, oral presentation on Monday, December 3, 2018 at 5:00 p.m. PT at the San Diego Convention Center, Room 6F)
About ADCETRIS (brentuximab vedotin)

ADCETRIS is being evaluated broadly in more than 70 clinical trials in CD30-expressing lymphomas. These include three recently completed phase 3 trials: ECHELON-2 in frontline peripheral T-cell lymphomas (also known as mature T-cell lymphoma), ECHELON-1 in previously untreated Hodgkin lymphoma, and ALCANZA in cutaneous T-cell lymphoma. The phase 3 CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma is ongoing.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (4) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (5) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (6) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, and (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

ADCETRIS has received marketing authorization by regulatory authorities in 72 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

On December 1, 2018 MEI Pharma, Inc. (NASDAQ: MEIP), a late-stage pharmaceutical company focused on advancing new therapies for cancer, reported preclinical data presented at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting demonstrating that voruciclib, MEI’s orally available CDK9 inhibitor, synergistically induced apoptosis at clinically relevant concentrations when combined with venetoclax (marketed as Venclexta) in human derived acute myeloid leukemia (AML) cells lines and patient samples (Press release, MEI Pharma, DEC 1, 2018, View Source [SID1234531766]). Voruciclib is currently being evaluated in a Phase 1b dose ranging study in patients with B-cell malignancies.

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The data presented today demonstrate the synergistic induction of apoptosis of voruciclib when combined with venetoclax via the transient downregulation of MCL1 in multiple AML cell lines and patient samples. Inhibition of CDK9 blocks the production of MCL1, which is an established resistance mechanism to the BCL-2 inhibitor venetoclax.

"This study evaluating the synergistic activity of voruciclib in AML cells builds on existing preclinical data demonstrating similar activity in other B-cell malignancies, including diffuse large B-cell lymphoma and chronic lymphocytic leukemia, and reinforces the significant clinical utility voruciclib may hold when combined with inhibitors of BCL-2 in B-cell disease," said Daniel P. Gold, Ph.D., president and chief executive officer of MEI Pharma. "As we progress in our ongoing Phase 1 study, we look forward to selecting the voruciclib clinical dose to evaluate in combination with venetoclax to clinically assess synergies and the opportunity for combination treatments across multiple indications."

The voruciclib ASH (Free ASH Whitepaper) 2018 poster can be accessed on the MEI Pharma website.

About Voruciclib
The CDK family of proteins are important cell cycle regulators. CDK9 is a transcriptional regulator of the myeloid leukemia cell differentiation protein ("MCL1"), a member of the family of anti-apoptotic proteins which, when elevated, may prevent the cell from undergoing cell death. Inhibition of CDK9 blocks the production of MCL1, which is an established resistance mechanism to the B-cell lymphoma ("BCL-2") inhibitor venetoclax.

CDK9 is also a transcriptional regulator of MYC, a transcription factor regulating cell proliferation and growth which contributes to many human cancers and is frequently associated with poor prognosis and unfavorable patient survival. Targeting MYC directly has historically been difficult, but CDK9 is a transcriptional regulator of MYC and is a promising approach to target this oncogene.

In August 2018 MEI dosed the first patient in a dose ranging Phase 1b clinical trial of voruciclib as a single agent in patients with relapsed and/or refractory B-cell malignancies after failure of prior standard therapies to determine the safety, preliminary efficacy and maximum tolerated dose. We also plan to evaluate voruciclib in combination with venetoclax to assess synergies and the opportunity for combination treatments across multiple indications.