On December 3, 2018 GlycoMimetics, Inc. (NASDAQ:GLYC) reported that new data on uproleselan-treated high risk patients with both relapsed/refractory and newly diagnosed AML were presented at an oral session during the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, GlycoMimetics, DEC 3, 2018, View Source [SID1234531812]). An analysis of clinical outcomes from the Phase 1/2 clinical study showed that uproleselan (GMI-1271) resulted in the majority of evaluable patients achieving a stringent level of measurable residual disease (MRD) negativity, an effect which translated into extended overall survival relative to matched, historical controls.1-4

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Additionally, an analysis of E-selectin ligand expression on leukemic cells demonstrated that detectable levels are present in every patient tested, providing strong clinical evidence of biological relevance in this disease setting. In bone marrow blasts, leukemic stem cell expression of E-selectin ligand correlated with leukemic blast E-selectin ligand expression (p<0.0001), consistent with the hypothesis that E-selectin-mediated interactions are a mechanism of chemoresistance. Additionally, investigators assessed the association between baseline E-selectin ligand expression and clinical outcomes using a log-rank test. In the R/R cohort of patients (n=22), this analysis demonstrated that ≥10% E-selectin ligand expression at baseline is correlated with prolonged survival (p<0.01) for patients treated with uproleselan. This observation is important since separately Chien et al. (Abstract 1513) report that high levels of E-selectin ligand in patients not treated with uproleselan correlate with worse clinical prognosis.

"The new MRD and correlative efficacy data in difficult-to-treat patients, when combined with the already encouraging response rate and survival results from this trial, further demonstrate the potential of uproleselan to be an important new treatment option in AML," said Daniel J. DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and the trial’s lead investigator. "The fact that more than half of the evaluable patients achieved a stringent level of MRD negativity is particularly noteworthy as uproleselan’s mechanism of action is to selectively disrupt the relationship between leukemic cells and the bone marrow microenvironment."

"It is now clearly established that patients with AML who express E-selectin ligands on their leukemic cells have more infiltrative, aggressive disease and significantly worse clinical outcomes when not treated with uproleselan," said Helen Thackray, M.D., FAAP, GlycoMimetics Senior Vice President, Clinical Development and Chief Medical Officer. "While we would expect patients with R/R AML and >10% E-selectin ligand expression on their leukemic blasts to do very poorly, it is extremely exciting to see that the addition of uproleselan is resulting in statistically significant improvements in clinical outcomes in these high-risk patients. This is completely counterintuitive to what you would expect and provides robust scientific evidence suggesting that uproleselan is exerting biologic activity."

The ASH (Free ASH Whitepaper) presentations referenced above include:

Publication Number: 331
TITLE: Uproleselan (GMI-1271), an E-Selectin Antagonist, Improves the Efficacy and Safety of Chemotherapy in Relapsed/Refractory (R/R) and Newly Diagnosed Older Patients with Acute Myeloid Leukemia: Final, Correlative and Subgroup Analyses

Publication Number: 1513
TITLE: E-Selectin Ligand Expression by Leukemic Blasts Is Associated with Prognosis in Patients with AML

References
1 Feldman et al, J Clin Oncol. 2005 Jun 20;23(18):4110-6.
2 Greenberg et al, J Clin Oncol. 2004 Mar 15;22(6):1078-86.
3 Lowenberg et al, N Engl J Med. 2009 Sep 24;361(13).
4 Lancet et al, Blood. 2014 May 22;123(21):3239-46.

About Uproleselan (GMI-1271)

Uproleselan (yoo’ pro le’sel an) is designed to block E-selectin (an adhesion molecule on cells in the bone marrow) from binding with blood cancer cells as a targeted approach to disrupting well-established mechanisms of leukemic cell resistance within the bone marrow microenvironment. In a Phase 1/2 clinical trial, uproleselan was evaluated in both newly diagnosed elderly and relapsed/refractory patients with AML. In both populations, patients treated with uproleselan together with standard chemotherapy achieved better than expected remission rates and overall survival compared to historical controls, which have been derived from results from third party clinical trials evaluating standard chemotherapy, as well as lower than expected induction-related mortality rates. Treatment in these patient populations was generally well tolerated, with fewer than expected adverse effects. The U.S. Food and Drug Administration (FDA) has granted uproleselan Breakthrough Therapy Designation for the treatment of adult AML patients with relapsed/refractory (R/R) disease. GlycoMimetics is currently implementing a comprehensive development program across the clinical spectrum of AML. This includes a company sponsored Phase 3 trial in R/R AML and two consortia-sponsored trials in newly diagnosed patients. One consortium trial is being sponsored by the NCI and will enroll newly diagnosed patients fit for intensive chemotherapy. The other trial is sponsored by the HOVON group in Europe and will enroll newly diagnosed patients unfit for intensive chemotherapy.

On December 3, 2018 Sesen Bio, Inc. (Nasdaq: SESN), a late-stage clinical company developing targeted fusion protein therapeutics for the treatment of people with cancer, reported the appointment of Dennis Kim, M.D., MPH, as chief medical officer (Press release, Sesen Bio, DEC 3, 2018, View Source [SID1234531828]). In this role, Dr. Kim will oversee the continued Phase 3 development of Vicinium, Sesen Bio’s lead targeted fusion protein, for patients with high-grade non-muscle invasive bladder cancer (NMIBC), as well as preparations for a marketing authorization submission and pre-commercial activities.

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"We are thrilled to welcome Dennis to the Sesen Bio team and look forward to leveraging his deep drug development experience, particularly as we approach both six and 12-month data readouts from our VISTA Trial of Vicinium," said Dr. Thomas Cannell, president and chief executive officer of Sesen Bio. "Dennis has an extensive track record of leading product candidates through development to approval and commercial launch. As the Vicinium program advances, his leadership will be instrumental in helping us bring this novel treatment to patients in need and achieving our mission of saving and renewing the lives of people with cancer."

Dr. Kim brings significant drug development and commercialization experience to Sesen Bio’s leadership team. He has played key roles in both the approval and commercial launch of more than 10 products in oncology and immunology. Prior to joining Sesen Bio, Dr. Kim held senior and leadership roles at Ipsen, Spectrum, Novartis, Biogen Idec, and Amgen. Previously, Dr. Kim was an Epidemic Intelligence Service Officer at the Centers for Disease Control and Prevention where he played active roles in environmental and infectious disease studies. Dr. Kim earned his bachelor’s degree in chemistry and biology from Harvard, his M.D. from Stanford University and his MPH from the University of California, Los Angeles.

"I am highly encouraged by the data generated to date with Vicinium in high-grade non-muscle invasive bladder cancer, and believe this therapy has the potential to change the way we treat bladder cancer," said Dr. Kim. "I am excited to work with the Sesen Bio team and board of directors to help propel Vicinium towards a potential approval so that we can help the many patients, and their families and physicians, who need a new and effective treatment option for this devastating cancer."

In connection with the appointment of Dr. Kim, Sesen Bio entered into an employment agreement with Dr. Kim that, among other things, provides for the grant of a non-statutory stock option outside of Sesen Bio’s 2014 Stock Incentive Plan as an inducement material to Dr. Kim’s entering into employment with Sesen Bio in accordance with Nasdaq Stock Market Listing Rule 5635(c)(4). The stock option to purchase 425,000 shares of the company’s common stock is being granted effective as of December 3, 2018. The stock option grant was approved by the independent compensation committee of the board of directors in accordance with Nasdaq Stock Market Listing Rule 5635(c)(4). This stock option will have an exercise price per share equal to the closing price per share of Sesen Bio’s common stock on The Nasdaq Global Market on December 3, 2018. The stock option will have a ten-year term and will vest over a four-year period, with 25 percent of the shares underlying the stock option award vesting on the first anniversary of the date of grant and an additional 6.25 percent of the shares underlying the stock option vesting at the end of each successive three-month period following the one-year anniversary of the date of grant of the stock options, subject to Dr. Kim’s continued service with the company through the applicable vesting dates.

On December 3, 2018 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today data from the primary analysis of the Phase III HAVEN 2 study evaluating Hemlibra (emicizumab-kxwh) prophylaxis in children younger than 12 years of age with hemophilia A with factor VIII inhibitors, including longer follow-up for once-weekly dosing and new data for less frequent dosing schedules (every two weeks or every four weeks) (Press release, Genentech, DEC 3, 2018, View Source [SID1234531845]). These data from the largest pivotal study in children with hemophilia A with factor VIII inhibitors were presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"Children with inhibitors are at increased risk of life-threatening bleeds and may experience frequent, repeated bleeding into joints," said Guy Young, M.D., director of Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, and professor of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California. "These updated data from HAVEN 2 showed that the majority of children with hemophilia A with factor VIII inhibitors treated with emicizumab-kxwh had zero treated bleeds across three different dosing schedules, reinforcing the ability of this medicine to provide sustained, effective bleed control."

In updated results from the HAVEN 2 study with a median of 11 additional months of data, 76.9 percent (95 percent CI: 64.8; 86.5) of children with hemophilia A with factor VIII inhibitors treated with Hemlibra once weekly (n=65) experienced zero treated bleeds. Importantly, once-weekly Hemlibra showed a 99 percent (95 percent CI: 97.7; 99.4) reduction in treated bleeds compared to prior treatment with bypassing agents (BPAs) as prophylaxis (n=15) or on-demand (n=3) in a prospective intra-patient comparison. New data also showed that 90 percent (95 percent CI: 55.5; 99.7) of children with factor VIII inhibitors receiving Hemlibra every two weeks (n=10) and 60 percent (95 percent CI: 26.2; 87.8) of children receiving Hemlibra every four weeks (n=10) experienced zero treated bleeds, demonstrating clinically meaningful bleed control at both dosing schedules. No cases of thrombotic microangiopathy (TMA) or thrombotic events occurred. The most common adverse events (AEs) in the HAVEN 2 study primary analysis were consistent with those previously observed in the interim analyses.

"The updated analysis from the HAVEN 2 study supports the potential of Hemlibra to control bleeds at less frequent subcutaneous dosing, providing parents and their children more flexibility to choose a treatment schedule that is right for them," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "Many children with hemophilia A with factor VIII inhibitors have already experienced the benefits of Hemlibra, and with these new positive data, we are confident that this treatment will continue to make a meaningful difference in their lives."

Hemlibra is approved in over 50 countries worldwide, including the U.S., EU member states and Japan, to treat people of all ages with hemophilia A with factor VIII inhibitors based on pivotal data that included interim results from the HAVEN 2 study. In October 2018, the U.S. Food and Drug Administration (FDA) also approved Hemlibra to treat people of all ages with hemophilia A without factor VIII inhibitors. Hemlibra is the only FDA-approved treatment for people with hemophilia A with and without factor VIII inhibitors that can be administered subcutaneously (under the skin) and at multiple dosing options (once weekly, every two weeks or every four weeks). Submissions to other regulatory authorities around the world are ongoing.

Hemlibra has been studied in one of the largest pivotal clinical trial programs in people with hemophilia A with and without factor VIII inhibitors, including four Phase III HAVEN studies (HAVEN 1, HAVEN 2, HAVEN 3 and HAVEN 4).

About HAVEN 2 (NCT02795767)

HAVEN 2 is a multicenter, open-label, clinical study in children younger than 12 years of age with hemophilia A with factor VIII inhibitors. The study is evaluating the efficacy, safety and pharmacokinetics of once-weekly, every two weeks or every four weeks subcutaneous administration of Hemlibra prophylaxis.

The HAVEN 2 primary analysis included 85 children (once-weekly dosing, n=65; every two week dosing, n=10; every four week dosing, n=10) with hemophilia A with factor VIII inhibitors. The median follow-up period for each cohort was 58 (range 17.9–92.6), 21.3 (range 18.6–24.1), and 19.9 (range 8.9–24.1) weeks, respectively. The prospective intra-patient comparison included 18 patients from the once-weekly cohort previously treated with BPAs either as prophylaxis (n=15) or on-demand (n=3) as part of a non-interventional study.

The study met its primary endpoint and key secondary endpoints. Data presented at the 60th ASH (Free ASH Whitepaper) Annual Meeting showed:

HAVEN 2 (NCT02795767)
Hemlibra prophylaxis 1.5 mg/kg QW
(Arm A; n=65)*

Annualized bleeding rate [ABR] †
(95% CI)

Median ABR
(Interquartile range; IQR)

Treated bleeds (primary endpoint)**
0.3
(0.17; 0.50)

0.0
(0.00; 0.00)

All bleeds
3.2
(1.94; 5.22)

0.6
(0.00; 2.92)

Treated spontaneous bleeds
0.0
(0.01; 0.10)

0.0
(0.00; 0.00)

Treated joint bleeds
0.2
(0.08; 0.29)

0.0
(0.00; 0.00)

Treated target joint bleeds
Not estimable

0.0
(0.00; 0.00)

*Efficacy assessment was conducted only in patients aged <12 years who had spent at least 12 weeks on the study. Excludes three patients aged >12 years.

A loading dose of 3 mg/kg Hemlibra was given for four weeks followed by the maintenance dose listed.

† Estimated using negative binomial regression

**In patients receiving Hemlibra once weekly (Arm A), 76.9% (95% CI, 64.8; 86.5) experienced zero treated bleeds and 23.1% experienced 1–3 treated bleeds.

Hemlibra prophylaxis 3 mg/kg
Q2W
(Arm B; n=10)*

Hemlibra prophylaxis 6 mg/kg
Q4W
(Arm C; n=10)*

ABR (95% CI) †

0.2
(0.03; 1.72)

2.2
(0.69; 6.81)

Median ABR (IQR)
0.0
(0.00; 0.00)

0.0
(0.00; 3.26)

% patients with zero treated
bleeds
(95% CI)

90.0%
(55.5; 99.7)

60.0%
(26.2; 87.8)

% patients with 1-3 treated
bleeds
(95% CI)

10.0%
(0.3; 44.5)

40.0%
(12.2; 73.8)

*A loading dose of 3 mg/kg Hemlibra was given for four weeks followed by the maintenance dose listed.

† Estimated using negative binomial regression

The most common adverse reactions occurring in 10 percent or more of children treated with Hemlibra were common cold symptoms (nasopharyngitis; 37.5 percent), injection site reactions (29.5 percent), fever (pyrexia; 23.9 percent), upper respiratory tract infection (23.9 percent), cough (23.9 percent), diarrhea (15.9 percent), vomiting (15.9 percent), headache (14.8 percent), contusion (12.5 percent), fall (12.5 percent) and influenza (10.2 percent). No cases of TMA or thrombotic events occurred. Four patients tested positive for anti-drug antibodies (ADAs) to Hemlibra. Of these patients, two had ADAs with neutralizing potential based on reduced Hemlibra levels. As previously reported, the ADA in one of these patients resulted in reduced efficacy of Hemlibra and led to discontinuation of treatment. The other patient had no bleeds as of the clinical cut-off date of the study.

About Hemlibra

Hemlibra is a bispecific factor IXa- and factor X-directed antibody. It is designed to bring together factor IXa and factor X, proteins required to activate the natural coagulation cascade and restore the blood clotting process for hemophilia A patients. Hemlibra is a prophylactic (preventative) treatment that can be administered by an injection of a ready-to-use solution under the skin (subcutaneously) once weekly, every two weeks or every four weeks. Hemlibra was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed globally by Chugai, Roche and Genentech.

Hemlibra U.S. Indication

Hemlibra is a prescription medicine used for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children, ages newborn and older, with hemophilia A with or without factor VIII inhibitors.

Important Safety Information

What is the most important information to know about Hemlibra?

Hemlibra increases the potential for blood to clot. Patients should carefully follow their healthcare provider’s instructions regarding when to use an on-demand bypassing agent or factor VIII, and the dose and schedule to use for breakthrough bleed treatment. Hemlibra may cause the following serious side effects when used with activated prothrombin complex concentrate (aPCC; FEIBA), including:

Thrombotic microangiopathy (TMA). This is a condition involving blood clots and injury to small blood vessels that may cause harm to one’s kidneys, brain, and other organs. Patients should get medical help right away if they have any of the following signs or symptoms during or after treatment with Hemlibra:
confusion
weakness
swelling of arms and legs
yellowing of skin and eyes
stomach (abdomen) or back pain
nausea or vomiting
feeling sick
decreased urination
Blood clots (thrombotic events). Blood clots may form in blood vessels in the arm, leg, lung, or head. Patients should get medical help right away if they have any of these signs or symptoms of blood clots during or after treatment with Hemlibra:
swelling in arms or legs
pain or redness in the arms or legs
shortness of breath
chest pain or tightness
fast heart rate
cough up blood
feel faint
headache
numbness in the face
eye pain or swelling
trouble seeing
If aPCC (FEIBA) is needed, patients should talk to their healthcare provider in case they feel they need more than 100 U/kg of aPCC (FEIBA) total.

Before using Hemlibra, patients should tell their healthcare provider about all of their medical conditions, including if they:

are pregnant or plan to become pregnant. It is not known if Hemlibra may harm an unborn baby. Females who are able to become pregnant should use birth control (contraception) during treatment with Hemlibra.
are breastfeeding or plan to breastfeed. It is not known if Hemlibra passes into breast milk.
Patients should tell their healthcare provider about all the medicines they take, including prescription medicines, over-the-counter medicines, vitamins, or herbal supplements. Patients should keep a list of them to show their healthcare provider and pharmacist when they get a new medicine.

How should patients use Hemlibra?

Patients should see the detailed "Instructions for Use" that comes with Hemlibra for information on how to prepare and inject a dose of Hemlibra, and how to properly throw away (dispose of) used needles and syringes.

Stop (discontinue) prophylactic use of bypassing agents the day before starting Hemlibra prophylaxis.
Patients may continue prophylactic use of factor VIII for the first week of Hemlibra prophylaxis.
What should patients know about lab monitoring?

Hemlibra may interfere with laboratory tests that measure how well blood is clotting and may cause a false reading. Patients should talk to their healthcare provider about how this may affect their care.

The most common side effects of Hemlibra include: redness, tenderness, warmth, or itching at the site of injection; headache; and joint pain.

These are not all of the possible side effects of Hemlibra. Patients should speak to their healthcare provider for medical advice about side effects.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Patients should not use Hemlibra for a condition for which it was not prescribed. Patients should not give Hemlibra to other people, even if they have the same symptoms that they have. It may harm them. Patients can ask their pharmacist or healthcare provider for information about Hemlibra that is written for health professionals.

Side effects may be reported to the FDA at (800) FDA-1088 or View Source Side effects may also be reported to Genentech at (888) 835-2555.

Please see the Hemlibra full Prescribing Information and Medication Guide for more important safety information including Serious Side Effects.

About hemophilia A

Hemophilia A is an inherited, serious disorder in which a person’s blood does not clot properly, leading to uncontrolled and often spontaneous bleeding. Hemophilia affects around 20,000 people in the United States, with hemophilia A being the most common form and approximately 50-60 percent of people living with a severe form of the disorder.

People with hemophilia A either lack or do not have enough of a clotting protein called factor VIII. In a healthy person, when a bleed occurs, factor VIII brings together the clotting factors IXa and X, which is a critical step in the formation of a blood clot to help stop bleeding. Depending on the severity of their disorder, people with hemophilia A can bleed frequently, especially into their joints or muscles. These bleeds can present a significant health concern as they often cause pain and can lead to chronic swelling, deformity, reduced mobility and long-term joint damage.

A serious complication of treatment is the development of inhibitors to factor VIII replacement therapies. Inhibitors are antibodies developed by the body’s immune system that bind to and block the efficacy of replacement factor VIII, making it difficult, if not impossible, to obtain a level of factor VIII sufficient to control bleeding.

On December 3, 2018 The National Comprehensive Cancer Network (NCCN) Oncology Research Program (ORP) reported plans to solicit and oversee research projects that evaluate cyclin dependent kinase (CDK)4 & 6 inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer and underlying mechanisms of resistance (Press release, Eli Lilly, DEC 3, 2018, View Source [SID1234531861]). Research funding will be provided by a $2 million grant from Eli Lilly and Company (NYSE: LLY).

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"This program is part of our ongoing efforts to improve the lives of people with cancer," said Wui-Jin Koh, MD, Chief Medical Officer, NCCN. "The NCCN ORP facilitates clinical investigation into important questions. In this instance, we’re managing research to understand mechanisms of resistance to CDK4 & 6 inhibitor treatment in metastatic breast cancer."

"We are excited to support NCCN to further understand the mechanisms of resistance to CDK4 & 6 inhibitors in advanced breast cancer, which is a central and critically important issue in this treatment landscape," said Maura Dickler, MD, Vice President of Late Phase Development, Lilly Oncology. "This work with NCCN is an example of our ongoing commitment to optimize treatment for people living with metastatic breast cancer."

CDK4 & 6 inhibitors have emerged as a key treatment in many patients with HR+ and HER2- metastatic breast cancer. However, resistance to CDK4 & 6 inhibitors, either intrinsic or acquired, can limit their effectiveness. This project seeks to support preclinical and clinical studies that elucidate mechanisms of resistance to CDK4 & 6 inhibitors and provide insights into how this resistance can be overcome or mitigated, resulting in potentially greater efficacy. Lilly will provide abemaciclib, a CDK4 & 6 inhibitor, for studies when needed. This endeavor by the NCCN ORP will utilize the scientific expertise from investigators across the 28 NCCN Member Institutions, and proposals will be reviewed and awarded by a scientific steering committee made up of experts from these NCCN institutions.

Earlier this year, the NCCN ORP was engaged by Lilly for a separate project, seeking scalable, reproducible interventions to address gaps in clinical care for treating gastric cancer. To learn more about the NCCN ORP, including ongoing clinical trials, recent publications, and shared resources, visit NCCN.org/ORP.

On December 3, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported results from the Phase 3 iLLUMINATE (PCYC-1130) trial, evaluating the chemotherapy-free, anti-CD20 combination of IMBRUVICA (ibrutinib) plus obinutuzumab (Gazyva) in patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (Press release, AbbVie, DEC 3, 2018, View Source [SID1234531878]). At a median follow-up of 31 months, study results showed IMBRUVICA plus obinutuzumab significantly prolonged progression-free survival (PFS) (median not reached [NR] vs. 19 months) with a 77 percent reduction in risk of progression or death versus chlorambucil plus obinutuzumab, the current National Comprehensive Cancer Network guidelines Category 1 treatment regimen (hazard ratio [HR] 0.23; 95% confidence interval [CI]: 0.15-0.37; P<0.0001).

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The data were presented today in an oral session at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (abstract #691) and were simultaneously published in The Lancet Oncology. Based on these data, a supplemental New Drug Application (sNDA) was recently accepted for Priority Review by the U.S. Food and Drug Administration (FDA) to expand the use of IMBRUVICA in combination with obinutuzumab in previously untreated CLL/SLL. IMBRUVICA is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"iLLUMINATE represents one of three IMBRUVICA Phase 3 studies in chronic lymphocytic leukemia being presented at this year’s ASH (Free ASH Whitepaper). Results from the iLLUMINATE study support the use of IMBRUVICA as a chemotherapy-free, anti-CD20 combination treatment option versus the current National Comprehensive Cancer Network guidelines Category 1 treatment of chlorambucil plus obinutuzumab," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "These latest findings, in addition to seven-year long-term data and a Late-Breaker at this year’s ASH (Free ASH Whitepaper), add to the robust amount of data supporting the use of IMBRUVICA as backbone therapy in CLL and SLL."

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 SLL is a slow-growing lymphoma biologically similar to CLL in which too many immature white blood cells cause lymph nodes to become larger than normal.4 Both CLL and SLL are predominately diseases of the elderly, with a median age at diagnosis ranging from 65-70 years.5

"For years, we had to rely on chemotherapy as the only treatment option for patients with previously untreated chronic lymphocytic leukemia and small lymphocytic lymphoma," said Carol Moreno, M.D., Ph.D., Consultant Hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Barcelona, Spain, and lead study investigator of iLLUMINATE. "We’re pleased to share results from iLLUMINATE that help show that it is possible to provide efficacious treatment for patients with CLL and SLL without the use of chemotherapy."

About Abstract #691: Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab as First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results from Phase 3 iLLUMINATE

Oral presentation: Monday, December 3 at 10:30 a.m. PST

In the Phase 3 iLLUMINATE (PCYC-1130) study, newly diagnosed CLL patients were randomized to receive IMBRUVICA 420 milligrams (mg) once daily continuously in combination with obinutuzumab 1000 mg intravenously over six cycles (n=113); or chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle plus obinutuzumab 1000 mg intravenously over six cycles (n=116). The primary endpoint was PFS, as assessed by an Independent Review Committee (IRC). The study also evaluated: PFS for patients with high-risk features (unmutated IGHV, del11q, del17p or TP53 mutation); rate of undetectable minimal residual disease (MRD); overall response rate (ORR); overall survival (OS); and safety.

At a median follow-up of 31.3 months, ibrutinib plus obinutuzumab significantly prolonged the IRC-assessed PFS compared to chlorambucil plus obinutuzumab, with a 77 percent reduction in risk of progression or death (median NR vs. 19 months; hazard ratio [HR] 0.23; 95% CI: 0.15-0.37; P<0.0001). At 30 months, the IRC-assessed PFS rates were 79 percent and 31 percent with ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab, respectively. The investigator-assessed PFS was also significantly improved with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab (median NR vs. 21.9 months; HR 0.26; 95% CI: 0.16-0.42; P<0.0001).

The PFS in the IMBRUVICA plus obinutuzumab arm in the high-risk population, including those with unmutated IGHV, del11q, del17p, or TP53 mutation was assessed, with an 85 percent reduction in risk of progression or death (median not reached vs. 14.7 months; HR 0.15; 95% CI: 0.09-0.27; P<0.0001). In addition, IRC-assessed ORR was higher in the ibrutinib plus obinutuzumab arm versus the chlorambucil plus obinutuzumab arm (88% vs. 73%); complete response (CR)/complete response with incomplete blood recovery (CRi) rates were also higher with 19 percent versus eight percent, respectively. The investigator-assessed ORR was also higher in the ibrutinib plus obinutuzumab arm versus the chlorambucil plus obinutuzumab arm (91% vs. 81%); CR/CRi rates were also higher with 41 percent versus 16 percent, respectively. Depth of remission as reflected by undetectable MRD in blood and/or bone marrow was greater in patients with ibrutinib plus obinutuzumab, with 35 percent of patients showing undetectable MRD compared to 25 percent of patients with chlorambucil plus obinutuzumab. OS rates at 31 months were 86 percent for the ibrutinib arm compared to 85 percent for the chlorambucil arm.

Most common Grade 3 or higher adverse events (AEs) in the ibrutinib plus obinutuzumab arm versus chlorambucil plus obinutuzumab arm were neutropenia (43% vs. 63%), thrombocytopenia (35% vs. 25%), diarrhea (34% vs. 10%), cough (27% vs. 12%), infusion-related reactions (25% vs. 58%), arthralgia (22% vs. 10%), pyrexia (19% vs. 26%), anemia (17% vs. 25%), and nausea (12% vs. 30%). Ibrutinib plus obinutuzumab also seemed to decrease the risk of infusion reactions related to the use of obinutuzumab.

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2018, please visit: View Source

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by inhibiting a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.6 IMBRUVICA blocks signals that tell malignant B-cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).7

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
In August 2018, IMBRUVICA plus rituximab was approved for adult patients with WM.
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.

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.8 IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 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. To date, more than 135,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to IMBRUVICA in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,011 patients exposed to IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,011 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension has occurred in 12% of 1,011 patients treated with IMBRUVICA in clinical trials with a median time to onset of 5 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (9%) including non-skin carcinomas (2%) have occurred in 1,011 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, neutropenia (58%)*, diarrhea (42%), anemia (39%)*, rash (31%), musculoskeletal pain (31%), bruising (31%), nausea (28%), fatigue (27%), hemorrhage (23%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (36%)*, thrombocytopenia (15%)*, and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustments may be recommended.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.