On December 5, 2020 AbbVie (NYSE: ABBV) reported new data from the Phase 2 CAPTIVATE (PCYC-1142) clinical trial evaluating IMBRUVICA (ibrutinib) in combination with VENCLEXTA/VENCLYXTO (venetoclax) in previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) during an oral presentation session at the virtual 2020 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract #123) (Press release, AbbVie, DEC 5, 2020, View Source [SID1234572267]). The one-year disease-free survival (DFS) rate in patients randomized to placebo or ibrutinib after completing the combination regimen provides data to support a fixed-duration treatment that can offer CLL/SLL patients remission and time off treatment.

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"These results show the ibrutinib plus venetoclax combination providing continued disease-free survival for CLL patients once treatment is complete," said Dr. William Wierda, M.D., Professor, Department of Leukemia, University of Texas MD Anderson Cancer Center and principal study investigator. "It will be really exciting for patients to have a potential option in the future that can put them into remission and time off treatment."

These findings build on the previously reported results showing that this first-line combination regimen for CLL resulted in high rates of undetectable minimal residual disease (uMRD) in both peripheral blood (PB) (75% of patients) and in bone marrow (BM) (72% of patients). Undetectable MRD is defined as little to no cancer cells found after treatment. In the Confirmed uMRD group, one-year DFS rate was not significantly different for patients randomized to placebo (95.3%; 95% CI 82.7-98.8) versus ibrutinib (100%; 95% CI 100-100) (P=0.1475).

During the overall study period across all-treated patients (with median treatment duration of 29 months), most common grade 3/4 adverse events (≥5% of patients) were neutropenia (36%), hypertension (10%), thrombocytopenia (5%), and diarrhea (5%). The safety profile of the combination was consistent with known adverse events for ibrutinib and venetoclax individually and no new safety signals emerged.

"IMBRUVICA and VENCLEXTA/VENCLYXTO, individually, have truly transformed the way CLL and some other blood cancers are treated. Today, CLL can be treated without chemotherapy in the form of an oral pill, which is a remarkable advancement, compared to standards of care over the last decade," said Mohamed Zaki, M.D., Ph.D., vice president and global head of oncology development, AbbVie. "The results from this study will add to the evidence required for the development of this combination regimen as a potential new treatment option for CLL."

CLL is one of the two most common forms of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes).1 While these cancer cells start in the bone marrow, they then later spread into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 20,000 newly diagnosed patients every year.2,3 CLL is predominately a disease of the elderly, with a median age at diagnosis ranging from 65-70 years.4

According to the Leukemia & Lymphoma Society, MRD refers to the small number of cancer cells that remain in the body after treatment.5 The number of remaining cells may be so small that they do not cause any physical signs or symptoms and often cannot even be detected through traditional methods, this is known as undetectable MRD (uMRD). Doctors use MRD/uMRD to measure the effectiveness of treatment and to predict which patients are at risk of relapse.

There are additional ongoing company-sponsored trials exploring the potential of ibrutinib and venetoclax in combination for CLL treatment, including the Phase 3 GLOW study. Results from the ongoing GLOW study, assessing the ibrutinib plus venetoclax combination in comparison to chlorambucil plus obinutuzumab for first-line treatment of patients with CLL or SLL (NCT03462719), will be presented at an upcoming congress.

About CAPTIVATE
The CAPTIVATE study MRD cohort evaluated 164 patients between the ages of 18 and 70 years old with previously untreated CLL/SLL. Patients received 3 cycles of ibrutinib lead-in followed by 12 cycles of ibrutinib + venetoclax (Ibr 420 mg/day PO; Ven ramp-up to 400 mg/day PO). Patients with confirmed uMRD (defined as uMRD serially over ≥3 cycles, and in both PB and BM) after 12 cycles of ibrutinib + venetoclax were randomized 1:1 to receive double-blind treatment with placebo or ibrutinib. Patients who did not meet the definition of confirmed uMRD were randomized 1:1 to receive open-label treatment with ibrutinib or continued ibrutinib + venetoclax. Primary endpoint was 1-year DFS rate in the confirmed uMRD patients randomized to placebo vs ibrutinib; DFS was defined as survival without progression or MRD relapse (which was defined as an MRD level of 10-2). Key secondary endpoints were rates of uMRD (<10-4 by 8-color flow cytometry), response per iwCLL, adverse events (AEs), as well as progression-free survival (PFS). The safety profile of the combination was consistent with known adverse events for ibrutinib and venetoclax individually and no new safety signals emerged.

The depth of response achieved with this regimen is reflected in the 30-month progression-free survival (PFS) rate of ~95% across all treated patients, including the subset receiving placebo after the fixed duration treatment.

About Ibrutinib (IMBRUVICA)
IMBRUVICA (ibrutinib) is a once-daily, first-in-class BTK inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics, LLC, an AbbVie Company, and Janssen Biotech, Inc. (Janssen). The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.6,7 By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.8

Since its launch in 2013, IMBRUVICA has received 11 FDA approvals across six disease areas: chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; Waldenström macroglobulinemia; previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy* – and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.9

IMBRUVICA is now approved in 101 countries and has been used to treat more than 200,000 patients worldwide across its approved indications. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases. IMBRUVICA was one of the first medicines to receive FDA approval via the Breakthrough Therapy Designation pathway.

As of early 2019, the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 28 leading cancer centers devoted to patient care, research, and education, recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL and has Category 1 treatment status for treatment-naïve patients without deletion 17p. In February 2020, the NCCN Guidelines were updated to elevate IMBRUVICA with or without rituximab from other recommended regimens to a preferred regimen for the treatment of relapsed/refractory MCL. In September 2020, the NCCN guidelines were updated to elevate IMBRUVICA with or without rituximab as the only Category 1 preferred regimen for treatment-naïve WM patients.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA is the most comprehensively studied BTK inhibitor, with more than 150 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. For more information, visit www.IMBRUVICA.com.

*Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Side Effect Information
Before taking IMBRUVICA, tell your healthcare provider about all of your medical conditions, including if you:

have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA for any planned medical, surgical, or dental procedure.
have bleeding problems.
have or had heart rhythm problems, smoke, or have a medical condition that increases your risk of heart disease, such as high blood pressure, high cholesterol, or diabetes.
have an infection.
have liver problems.
are pregnant or plan to become pregnant. IMBRUVICA can harm your unborn baby. If you are able to become pregnant, your healthcare provider will do a pregnancy test before starting treatment with IMBRUVICA. Tell your healthcare provider if you are pregnant or think you may be pregnant during treatment with IMBRUVICA.
Females who are able to become pregnant should use effective birth control (contraception) during treatment with IMBRUVICA and for 1 month after the last dose.
Males with female partners who are able to become pregnant should use effective birth control, such as condoms, during treatment with IMBRUVICA and for 1 month after the last dose.
are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with IMBRUVICA and for 1 week after the last dose.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking IMBRUVICA with certain other medicines may affect how IMBRUVICA works and can cause side effects.

How should I take IMBRUVICA?

Take IMBRUVICA exactly as your healthcare provider tells you to take it.
Take IMBRUVICA 1 time a day.
Swallow IMBRUVICA capsules or tablets whole with a glass of water.
Do not open, break or chew IMBRUVICA capsules.
Do not cut, crush or chew IMBRUVICA tablets.
Take IMBRUVICA at about the same time each day.
If you miss a dose of IMBRUVICA take it as soon as you remember on the same day. Take your next dose of IMBRUVICA at your regular time on the next day. Do not take extra doses of IMBRUVICA to make up for a missed dose.
If you take too much IMBRUVICA call your healthcare provider or go to the nearest hospital emergency room right away.
What should I avoid while taking IMBRUVICA?

You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment with IMBRUVICA. These products may increase the amount of IMBRUVICA in your blood.
What are the possible side effects of IMBRUVICA?

IMBRUVICA may cause serious side effects, including:

Bleeding problems (hemorrhage) are common during treatment with IMBRUVICA, and can also be serious and may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs of bleeding, including: blood in your stools or black stools (looks like tar), pink or brown urine, unexpected bleeding, or bleeding that is severe or that you cannot control, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, dizziness, weakness, confusion, change in your speech, or a headache that lasts a long time or severe headache.
Infections can happen during treatment with IMBRUVICA. These infections can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms of an infection during treatment with IMBRUVICA.
Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with IMBRUVICA, but can also be severe. Your healthcare provider should do monthly blood tests to check your blood counts.
Heart rhythm problems (ventricular arrhythmias, atrial fibrillation and atrial flutter). Serious heart rhythm problems and death have happened in people treated with IMBRUVICA, especially in people who have an increased risk for heart disease, have an infection, or who have had heart rhythm problems in the past. Tell your healthcare provider if you get any symptoms of heart rhythm problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, chest discomfort, or you faint. If you develop any of these symptoms, your healthcare provider may do a test to check your heart (ECG) and may change your IMBRUVICA dose.
High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with IMBRUVICA. Your healthcare provider may start you on blood pressure medicine or change current medicines to treat your blood pressure.
Second primary cancers. New cancers have happened during treatment with IMBRUVICA, including cancers of the skin or other organs.
Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS.
The most common side effects of IMBRUVICA in adults with B-cell malignancies (MCL, CLL/SLL, WM and MZL) include:

diarrhea
tiredness
muscle and bone pain
rash
bruising
The most common side effects of IMBRUVICA in adults with cGVHD include:

tiredness
bruising
diarrhea
mouth sores (stomatitis)
muscle spasms
nausea
pneumonia
Diarrhea is a common side effect in people who take IMBRUVICA. Drink plenty of fluids during treatment with IMBRUVICA to help reduce your risk of losing too much fluid (dehydration) due to diarrhea. Tell your healthcare provider if you have diarrhea that does not go away.

These are not all the possible side effects of IMBRUVICA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of IMBRUVICA

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMBRUVICA for a condition for which it was not prescribed. Do not give IMBRUVICA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMBRUVICA that is written for health professionals.

Please click here for full Prescribing Information.

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

Uses and Important VENCLEXTA (venetoclax) U.S. Safety Information10

Uses
VENCLEXTA is a prescription medicine used:

to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:
are 75 years of age or older, or
have other medical conditions that prevent the use of standard chemotherapy.
It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information
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 healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines 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 healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA.It is important to keep your appointments for blood tests. Tell your healthcare 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 during treatment with 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.

Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects.

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 TLS.

Tell your healthcare 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 healthcare provider.
Before taking VENCLEXTA, tell your healthcare 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 healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare 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 healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for at least 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your healthcare 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 and for 1 week after the last dose.
What should I avoid while taking VENCLEXTA?
You should not drink grapefruit juice or 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 counts (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA and may pause dosing.
Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with VENCLEXTA. Your healthcare provider will closely monitor and treat you right away if you have a fever or any signs of infection during treatment with VENCLEXTA.
Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with VENCLEXTA.

The most common side effects of VENCLEXTA when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include low white blood cell counts; low platelet counts; low red blood cell counts; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of your arms, legs, hands, and feet.

The most common side effects of VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include nausea; diarrhea; low platelet count; constipation; low white blood cell count; fever with low white blood cell count; tiredness; vomiting; swelling of arms, legs, hands, or feet; fever; infection in lungs; shortness of breath; bleeding; low red blood cell count; rash; stomach (abdominal) pain; infection in your blood; muscle and joint pain; dizziness; cough; sore throat; and low blood pressure.

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

These are not all the possible side effects of VENCLEXTA. Call your doctor for medical advice about side effects.

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

If you cannot afford your medication, contact genentech-access.com/patient/brands/venclexta for assistance.

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.

About AbbVie in Oncology
At AbbVie, we strive to discover and develop medicines that deliver transformational improvements in cancer treatment by uniquely combining our deep knowledge in core areas of biology with cutting-edge technologies, and by working together with our partners – scientists, clinical experts, industry peers, advocates, and patients. We remain focused on delivering these transformative advances in treatment across some of the most debilitating and widespread cancers. We are also committed to exploring solutions to help patients obtain access to our cancer medicines. AbbVie’s oncology portfolio now consists of marketed medicines and a pipeline containing multiple new molecules being evaluated worldwide in more than 300 clinical trials and more than 20 different tumor types. For more information, please visit View Source

On December 5, 2020 Cellectis (Euronext Growth: ALCLS – Nasdaq: CLLS), a clinical-stage biopharmaceutical company focused on developing immunotherapies based on gene-edited allogeneic CAR T-cells (UCART), reported preliminary results from Cellectis’ dose escalation Phase 1 BALLI-01 study of UCART22 product candidate in relapsed/refractory B-cell Acute Lymphoblastic Leukemia (B-ALL) were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Cellectis, DEC 5, 2020, View Source [SID1234572342]). This is the first publicly released data from Cellectis’ BALLI-01 clinical trial .

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The BALLI-01 clinical trial presentation released at the ASH (Free ASH Whitepaper) Annual Meeting is available on the Cellectis website: https://bit.ly/CellectisASH2020

"We are encouraged by the promising preliminary data obtained from the first two lower dose levels of UCART22 following a standard fludarabine and cyclophosphamide lymphodepletion regimen from the BALLI-01 trial. The anti-leukemia activity observed in these patients with B-ALL who had been previously heavily pre-treated speaks to the validity of CD22 as a target in the CAR T-cell space, and demonstrates the promise of allogeneic cellular therapies to leapfrog the autologous CAR-T products. We have now started enrolling cohorts that include alemtuzumab, an anti-CD52 monoclonal antibody, in the lymphodepletion regimen, as we anticipate this may extend the window of persistence of our TALEN gene-edited allogeneic CAR T-cells," said Carrie Brownstein, MD, Chief Medical Officer, Cellectis. "Based on the strong progress of our partnered- and proprietary product candidate portfolio, which was presented at ASH (Free ASH Whitepaper), we are looking forward to presenting additional clinical data in 2021."

Characteristics

As of the November 2, 2020 data cutoff, 7 patients were enrolled and 5 patients received UCART22 cells. One patient failed screening and one patient was discontinued prior to the administration of UCART22 cells due to an adverse event related to the lymphodepletion.

Safety

No patient experienced a DLT, ICANS, GvHD, AESI1, nor UCART22-related Grade ≥3 adverse event (AE) nor serious adverse event (SAE). No patient discontinued treatment due to a UCART22-related treatment-emergent adverse event.

Anti-leukemic Activity

Two patients in Dose Level 1 achieved an objective response of complete remission with incomplete hematologic recovery (CRi) at Day 28, one of which attained a complete remission (CR) at Day 42 and received a transplant after subsequent therapy with inotuzumab. One patient in Dose Level 2 with refractory disease did achieve a noteworthy reduction in bone marrow blasts (60% at screening down to 13% at Day 28) after treatment with UCART22 product candidate and then progressed.

Host lymphocyte reconstitution was observed in all patients within the DLT period (range Day 9-Day 28). Correlative analysis of UCART cell expansion and persistence is ongoing.

UCART22 demonstrated preliminary signs of activity at low dose levels with fludarabine/cyclophosphamide (FC) lymphodepletion regimen, without unexpected nor significant treatment-related toxicities. Host immune recovery was observed early, supporting the addition of alemtuzumab to the FC lymphodepletion regimen which is expected to result in a deeper and more sustained T-cell depletion and thereby promote expansion and persistence of UCART22 cells. Enrollment into the Dose Level 2 cohorts with alemtuzumab is ongoing.

Treatment-emergent adverse events of interest with DL1 and DL2
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Graft-versus-host disease (GvHD) 0 0 0 0 0
Cytokine release syndrome (CRS) 2 1 0 0 0
ICANS 0 0 0 0 0
SAEs2 3 1 1
1 DLT: Dose Limiting Toxicity; GvHD: Graft versus Host Disease; AESI: adverse event of special interest; ICANS: immune effector cell-associated neurotoxicity syndrome; AE: Adverse Event; SAE: Serious Adverse Event
2 SAEs that are not related to UCART22 cells

About UCART22
UCART22 is one of Cellectis’ wholly owned, allogeneic, off-the-shelf gene-edited T-cell product candidates, designed for the treatment of relapsed and refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). Like CD19, CD22 is a cell surface antigen expressed from the pre-B-cell stage of development through mature B-cells. CD22 expression occurs in more than 90% of patients with B-ALL.

On December 5, 2020 Sysmex Inostics, Inc., a global leader and pioneer in blood-based, high-sensitivity molecular testing for oncology, reported the poster "Ultrasensitive Measurable Residual Disease (MRD) Detection in Acute Myeloid Leukemia (AML) Using a Targeted Next Generation Sequencing (NGS) Panel" at the 62nd Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Virtual Meeting on Saturday, December 5th (Press release, Sysmex Inostics, DEC 5, 2020, View Source [SID1234572270]). Viewing time is between 7:00 AM and 3:30 PM (Pacific Standard Time)."

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AML is one of the deadliest blood cancers that takes over 10,000 lives in the U.S. each year. If cancer relapses after treatment, the prognosis is typically poor. Therefore, after initial treatment, patients are tested for MRD as a prognostic indicator of therapeutic effectiveness and relapse risk.

Groundbreaking FDA-approved AML therapeutics, such as ivosidenib, have been developed to target IDH1 mutations, which are present in about 5-10% of AML patients and can increase risk of relapse. Both newly diagnosed and relapsed/refractory AML patients with mutant IDH1 can benefit from IDH-directed therapy. In several clinical trials, the Sysmex Inostics OncoBEAM enhanced digital PCR technology has been used to monitor the levels of IDH mutations present in AML patients receiving targeted therapies. OncoBEAM technology is widely considered a gold standard for high sensitivity molecular testing and continues to be one of the most sensitive digital PCR approaches, capable of detecting mutations reliably at 0.02% mutant allele frequency (MAF).

Current NGS pan-heme panels lack sufficient sensitivity for reliable detection of molecular MRD, as their limits of detection are between 1-5% mutant allele frequency. Sysmex Safe-SeqS technology (SafeSEQ) dramatically expands the breadth of mutation detection for targets with established and emerging clinical validity for AML MRD while delivering comparable sensitivity to OncoBEAM. This highly sensitive, error-corrected NGS-based method can reliably detect molecular MRD present at levels as low as five mutant molecules, which is similar to the limit of detection observed across other SafeSEQ platform configurations and corresponds to 0.025% MAF for 20,000 genomic copies (66 ng of DNA) input.

In addition to demonstrating robust analytical performance, 100% overall agreement was observed between SafeSEQ and OncoBEAM for the detection of IDH1 mutations in clinical samples from AML patients. Furthermore, in almost all (94%) patients tested, at least one additional mutation outside of IDH1 was detected by the SafeSEQ AML MRD assay, which is consistent with previous observations that IDH mutations can co-occur with drivers in other genes such as NPM1 and may provide additive value for MRD detection.

"In order to deliver a powerful clinical tool for molecular MRD detection for AML patients, we developed the SafeSEQ AML MRD test to provide additional information across the most highly relevant genomic regions, with sensitivity comparable to the focused OncoBEAM method," said Matt Ryder, Director of Translational Science at Sysmex Inostics. "By offering reliable detection of molecular MRD with 50 to 100 times greater sensitivity versus ‘pan-heme’ NGS tests, the Plasma-SeqSensei AML MRD test will help accelerate clinical development of novel therapeutics and, ultimately, provide oncologists with more reliable information on which to base important decisions for their AML patients."

Poster number 1078, "Ultrasensitive Measurable Residual Disease (MRD) Detection in Acute Myeloid Leukemia (AML) Using a Targeted Next Generation Sequencing (NGS) Panel" presented by Hillary Sloane, Associate Director of Medical & Scientific Affairs at Sysmex Inostics, will be available Saturday, December 5th from 7:00 AM to 3:30 PM (Pacific Standard Time) at the 62nd ASH (Free ASH Whitepaper) Annual Meeting during the Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis poster session number 617.

On December 5, 2020 Sumitomo Dainippon Pharma Oncology, Inc., a developer of novel cancer therapeutics, reported that new data from the Phase 2 Zella 201 study evaluating the investigational agent alvocidib, a potent CDK9 inhibitor, in patients with MCL-1 dependent acute myeloid leukemia (AML) (Press release, Sumitomo Dainippon Pharma, DEC 5, 2020, View Source [SID1234572269]). These results were presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, being held virtually December 5-8, 2020.

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Preliminary findings from the open-label, randomized, multicenter study indicated that alvocidib was well tolerated with a manageable safety profile in combination with cytarabine and mitoxantrone in an exploratory arm of patients with newly diagnosed, high-risk MCL-1 dependent AML. Alvocidib in combination showed preliminary signs of clinical activity in the study, with 62% (n=8 of 13) of evaluable patients achieving complete remission/complete remission with incomplete count recovery. Of the patients that responded, 75% (n=6 of 8) achieved complete remission after the first treatment cycle. Although all patients included in this cohort were determined to be MCL-1 dependent, there was no association of complete remission with increasing MCL-1 dependence. The most frequently observed treatment-emergent non-hematologic adverse events of Grade 3 or higher were diarrhea, tumor lysis syndrome, hypocalcemia, sepsis and hypotension.1

Sumitomo Dainippon Pharma Oncology (SDP Oncology) will also be presenting details regarding the trial design of a Phase 1 study evaluating TP-3654, a PIM kinase inhibitor, in patients with intermediate-2 and high-risk primary or secondary myelofibrosis. In addition, SDP Oncology and its parent company, Sumitomo Dainippon Pharma Co. Ltd., will be presenting Phase 1 data evaluating alvocidib in combination with cytarabine and mitoxantrone in patients with relapsed/refractory AML or cytarabine and daunorubicin in patients with newly diagnosed AML. Finally, preclinical data evaluating how dubermatinib (TP-0903), an oral AXL kinase inhibitor, modulates CART19 will be presented.

"These findings presented at the ASH (Free ASH Whitepaper) Annual Meeting represent the first data evaluating the clinical activity of alvocidib in patients with newly diagnosed, high-risk, MCL-1-dependent AML," said Patricia S. Andrews, CEO and Global Head of Oncology, SDP Oncology. "The completion of this study marks a milestone for SDP Oncology as we continue to learn more about the optimal patient population that may benefit from alvocidib. The breadth of updates we presented at ASH (Free ASH Whitepaper) 2020 from across our pipeline demonstrate our commitment to advancing purposeful science by transforming new discoveries into meaningful therapeutic options for patients with cancer."

Below are the details for the SDP Oncology and Sumitomo Dainippon Pharma presentations:

Abstract Title

Details

Presenter

Zella 201: A Biomarker-Guided Phase II
Study of Alvocidib Followed by
Cytarabine and Mitoxantrone in MCL-1
Dependent Acute Myeloid Leukemia
(AML): Results of Newly Diagnosed High-
Risk Exploratory Arm

Abstract #1045

Saturday, December 5 at
7:00 a.m. PST

Virtual Poster Presentation

Joshua F. Zeidner, M.D.

University of North Carolina

A Phase 1 Study of TP-3654, an Orally-
Delivered PIM Kinase Inhibitor, in
Patients with Intermediate-2 or High-Risk
Primary or Secondary Myelofibrosis

Abstract #1251

Saturday, December 5 at
7:00 a.m. PST

Virtual Poster Presentation

Claudia Lebedinsky, M.D.

Sumitomo Dainippon
Pharma Oncology, Inc.

Axl-RTK Inhibition Modulates Monocyte
Immune Response to Enhance the Anti-
Tumor Effects of CD19 Redirected
Chimeric Antigen Receptor T Cells in
Preclinical Models

Abstract #1430

Saturday, December 5 at
7:00 a.m. PST

Virtual Poster Presentation

Reona Sakemura, M.D., Ph.D.

Mayo Clinic, Rochester, MN

Phase 1 Study of Alvocidib (DSP-2033) in
Combination with
Cytarabine/Mitoxantrone (ACM) or
Cytarabine/Daunorubicin (A+7+3) in
Japanese Patients (pts) with Acute
Myeloid Leukemia (AML)

Abstract #2831

Monday, December 7 at
7:00 a.m. PST

Virtual Poster Presentation

Yasuyoshi Morita, M.D.
Kindai University,
Higashiosaka, Osaka, Japan

For more information about SDP Oncology’s pipeline and clinical trials, please visit the company’s virtual booth at the ASH (Free ASH Whitepaper) Annual Meeting here.

About Alvocidib

Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in the ongoing Phase 2 Zella 202 study in patients with acute myeloid leukemia (AML) who have either relapsed from or are refractory to venetoclax in combination with azacitidine or decitabine (NCT03969420). Alvocidib is also being evaluated in Zella 102, a Phase 1b/2 study in patients with myelodysplastic syndromes (MDS) in combination with azacitidine or decitabine (NCT03593915) and in a Phase 1 study in patients with relapsed or refractory AML in combination with venetoclax (NCT03441555).

About CDK9 Inhibition and MCL-1

MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.2 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.3 MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.2,4 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).5,6 Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.5 Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.2

About TP-3654

TP-3654 is an investigational second-generation selective PIM kinase inhibitor currently under evaluation in a Phase 1 study in patients with myelofibrosis (NCT04176198) and a Phase 1 study in patients with advanced solid tumors (NCT03715504).

About PIM Kinase

PIM kinases are major effectors of JAK/STAT proliferative signaling downstream of multiple growth factors and cytokines.7 PIM is overexpressed in cancers and it may enhance the ability of fibroblasts to differentiate into myofibroblasts.7

About Dubermatinib (TP-0903)

Dubermatinib is an investigational oral AXL receptor tyrosine kinase (RTK) inhibitor under evaluation in a Phase 1a/b study in patients with advanced solid tumors (NCT02729298) and an ongoing study in collaboration with the Leukemia & Lymphoma Society as part of the Beat AML Clinical Trial (NCT03013998). SDP Oncology is exploring parallel clinical development paths for dubermatinib in both solid and hematologic malignancies.

About AXL Kinase

AXL belongs to the TAM (Tyro3, AXL and Mer) family of receptor tyrosine kinases and is overexpressed in many human cancers.8 It plays a key role in tumor cell proliferation, survival, metastasis, cellular adhesion, and avoidance of the immune response. The overexpression of AXL is associated with a poor patient prognosis and drug resistance.9

On December 5, 2020 Bioniz Therapeutics, Inc., ("Bioniz") reported positive clinical data in an oral presentation at the 62nd ASH (Free ASH Whitepaper) Annual Meeting And Exposition (ASH 2020) from the company’s Phase 1/2 clinical study of BNZ-1 for the treatment of patients with relapsed or refractory cutaneous T-cell lymphoma (rCTCL), a rare, aggressive cancer (Press release, Bioniz Therapeutics, DEC 5, 2020, prnewswire.com/news-releases/bioniz-announces-positive-clinical-data-of-bnz-1-first-anti-cytokine-therapy-to-demonstrate-efficacy-in-treating-refractory-cutaneous-t-cell-lymphoma-301186824.html [SID1234572268]). BNZ-1, a novel immuno-modulator drug candidate, is a multi-cytokine inhibitor of three interleukins (IL-2, IL-9, and IL-15) and is the lead asset from the company’s platform of first-in-class peptide therapeutics that selectively and simultaneously inhibits multiple cytokines to treat cancer and autoimmune diseases.

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"These data validate our platform technology with the first efficacy demonstration of BNZ-1, a novel multi-cytokine inhibitor, and assisted us in the design of a pivotal clinical trial for CTCL, which the company expects to begin in 2021," said Dr. Nazli Azimi, Founder, President, and CEO of Bioniz Therapeutics and co-inventor of BNZ-1. "We believe the efficacy of BNZ-1 in rCTCL, a challenging and progressive disease, is due to the drug’s multi-modal mechanism of action. BNZ-1 was specifically designed as a multi-cytokine inhibitor to integrate inhibition of malignant cells, activation of tumor immunity, and suppression of inflammation. In addition to the positive efficacy data, we are extremely encouraged that the BNZ-1 treatment was well tolerated, which could support long-term treatment for these patients."

The Phase 1/2 clinical study was designed as a multi-center, open-label, dose-escalation study of BNZ-1 to assess its safety and activity as a single systemic agent in rCTCL patients that have failed the standard of care and other available treatment options (up to seven prior skin-directed and systemic therapies). The primary endpoint of the study was overall safety after four weeks of treatment. There was a three-month treatment extension to further evaluate safety and clinical response at week 17. Long-term extension (LTE) was available for patients who benefited from BNZ-1 treatment.

In the dose ranging part of the study, 15 patients (stages IB and IVB) were enrolled across the four dose cohorts (0.5, 1, 2, and 4 mg/kg) for intravenous weekly dosing. BNZ-1 showed activity in all doses as determined by early signs of clinical efficacy and pharmacodynamic biomarkers. The 2 mg/kg dose was selected based on pharmacokinetic/pharmacodynamic (PK/PD) relationship and clinical efficacy, and the cohort was expanded to 19 patients. A total of 30 patients were treated in the study. Clinical efficacy was measured by Modified Severity Weighted Assessment Tool (mSWAT) and Global Response Score (GRS), as defined previously (Olsen E. et al. 2011).

In the expanded cohort of 2 mg/kg (n=19), BNZ-1 demonstrated overall response rate of 63.2% as measured by GRS, which is primarily driven by the mSWAT score. A positive response typically occurred soon after treatment initiation, persisted for the duration of treatment, and in a number of patients, improved over time with this positive trend extending into the follow-up period off-treatment. Twelve patients participated in the LTE, and 11 patients achieved and sustained their response (ORR of 91.7%). BNZ-1 treatment was well tolerated with no dose-limiting toxicities, drug-related serious side effects, or lab abnormalities.

"CTCL is incurable with current standard therapies, which are typically tolerated by patients only for a limited time due to many side effects that are associated with these approved treatments," said Dr. Christiane Querfeld, Director of the Cutaneous Lymphoma Program at the City of Hope, and principal investigator of the study. "On average, these CTCL patients have disease that had progressed and failed up to seven prior skin-directed and systemic therapies, so it’s extremely encouraging to see the impressive safety and robust efficacy with BNZ-1. A therapy that can stabilize this progressive disease and is well tolerated without major side effects will be a major advancement in helping CTCL patients."

Additional data from the efficacy study of 19 patients (2 mg/kg) are as follows:

Two patients reached a partial response as early as four weeks after initiating BNZ-1 treatment; one patient reached a complete response at 13 weeks, and the response persisted until 30 weeks when the study was closed-out.
Seven patients (37%) had stable disease with BNZ-1 treatment; no disease recurrence or relapse was observed during the study period.
Three patients who enrolled early during the dose-ranging part of the study and responded to BNZ-1 treatment participated in the study for 73 weeks (about 17 months); the duration of response for these patients was about 62 weeks (about 15 months).
For patients that were enrolled later as part of the cohort expansion, the duration of the treatment ranged from four to 30 weeks, and the duration of response ranged from four to 26 weeks (median 12 weeks). The shorter duration of treatment was due to study close out per protocol.
The PD analysis revealed a dose-dependent reduction of Treg cells which plateaus at 2 mg/kg dose (expanded cohort); BNZ-1 also lowered the CD8 T-cell activation markers in some patients that responded to BNZ-1 treatment.
Dr. Azimi explained, "The reduction in Treg cells may contribute to the BNZ-1 efficacy by unleashing the patients’ immune response that drives the anti-tumor attack. The lowered CD8 T-cell activation might help with controlling the inflammation that is commonly associated with this disease." She also added, "Our drug candidates are small peptides that target a shared receptor in a family of cytokines, but only selectively inhibit functionally redundant cytokines. Therefore, in terms of functionality, they are similar to bi- or multi-specific antibodies. We believe this to be an elegant approach to block disease-driving cytokines that utilize a common receptor, without interfering with the rest of the healthy cytokine network. This can provide better target specificity and safety relative to agents, such as JAK inhibitors, that non-specifically inhibit the signaling pathways downstream to all the cytokines."

About Refractory Cutaneous T-cell Lymphoma (rCTCL)
Cutaneous T-cell lymphomas (CTCLs) are a rare, aggressive, heterogeneous group of non-Hodgkin’s lymphomas that manifest primarily in the skin. Although a wide array of therapeutic options are available for early-stage CTCL, not all patients respond, resulting in refractory CTCL (rCTCL) with limited treatment options and a poor prognosis.

About BNZ-1
The company’s lead product candidate, BNZ-1, is a selective inhibitor of cytokines IL-2, IL-9, and IL-15, which are potent T-cell growth factors and key disease drivers in CTCL. Bioniz is also evaluating BNZ-1 for the treatment of autoimmune diseases, including alopecia areata and vitiligo, which are also driven by unregulated T-cell biology.