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.

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 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 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.