Uncategorized – Page 15884 – 1stOncology™: Cancer Intelligence Service

ZIOPHARM Announces Presentation of Data from T-Cell Therapy Programs at ASH Annual Meeting

On December 10, 2017 ZIOPHARM Oncology, Inc. (Nasdaq:ZIOP), a biopharmaceutical company developing new gene and cell-based immunotherapies for cancer, reported data supporting its non-viral approach to rapid manufacture of chimeric antigen receptor (CAR)-modified T cells to treat patients with cancers were presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Atlanta (Press release, Ziopharm, DEC 10, 2017, View Source [SID1234522501]).

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ZIOPHARM is advancing its non-viral Sleeping Beauty (SB) platform towards point-of-care (P-O-C) for very rapid manufacturing of genetically modified CAR+ T cells. Data presented from first- and second-generation SB clinical trials demonstrate safety, tolerability, disease response, long-term survival, and persistence of infused CD19-specific CAR+ T cells. Preclinical studies showed that P-O-C CAR+ T cells co-expressing membrane-bound interleukin-15 (mbIL15) and a control switch manufactured within two days do not require activation or propagation in tissue culture to achieve anti-tumor effects and prolonged T-cell survival. Building on these data, the Company plans to initiate its first P-O-C clinical trial in 2018.

"Together, these results underpin the paradigm-shifting potential of our P-O-C platform by demonstrating the persistence of our Sleeping Beauty-modified T cells, optimization of the CAR, and pro-survival effect resulting from mbIL15 expression. This reinforces our plans to deliver genetically modified products in less than two days," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM Oncology. "The need for a non-viral approach for commercialization of cell therapy is becoming increasingly evident as the challenges of lengthier, more complex, and more expensive viral-based approaches are scaled up. We look forward to advancing Sleeping Beauty and our P-O-C approach with the goal of producing genetically modified T cells to fight cancers at a fraction of current costs and manufacturing time."

These ASH (Free ASH Whitepaper) presentations are based on clinical trials and research being conducted in collaboration with The University of Texas MD Anderson Cancer Center and Intrexon Corporation (NYSE:XON). The three posters and slides for one oral presentation are available in the Presentations and Publications section of the Company’s website, www.ziopharm.com.

Poster Presentation: "Long Term Follow up after Adoptive Transfer of CD19-Specific CAR+ T Cells Genetically Modified Via Non-Viral Sleeping Beauty System Following Hematopoietic Stem-Cell Transplantation (HSCT)"

Partow Kebriaei, M.D., Professor, Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas MD Anderson Cancer Center, presented updated results, building upon findings previously published in the Journal of Clinical Investigation. Two trials demonstrated that first-generation SB-modified CD19-specific CAR+ T cells appear to provide long-term cancer control when infused after hematopoietic stem-cell transplantation (HSCT) for patients with advanced CD19+ malignancies and could be detected years after administration in some recipients. All seven patients with advanced CD19+ non-Hodgkin’s lymphoma (NHL) that received autologous T cells were alive at a median survival of 40 months since infusion, with progression-free survival (PFS) reported at 86% and overall survival (OS) at 100%. For 19 patients with advanced CD19+ acute lymphoblastic leukemia (ALL) and NHL infused with allogeneic T cells following HSCT, nine patients were alive with a median survival of 31 months. The PFS rate and OS rates are 32% and 49%, respectively. Of the subset of eight patients who received donor-derived T cells after haploidentical HSCT, PFS and OS rates are 50% and 63%, respectively. Persistence of circulating SB-modified CAR+ T cells was demonstrated at two years in an autologous and allogeneic patient and for four years in two autologous patients.

Oral Presentation: "Shortening the Time to Manufacture CAR+ T Cells with Sleeping Beauty System Supports T-Cell Engraftment and Anti-Tumor Effects in Patients with Refractory CD19+ Tumors"

Dr. Kebriaei presented interim data from an ongoing second-generation trial demonstrating that the manufacture of SB-modified T cells could be shortened from four weeks to two weeks and that autologous T cells infused after lymphodepleting chemotherapy could be detected, and exhibited anti-tumor effects and an encouraging safety profile in patients with relapsed/refractory CD19+ malignancies. Complete responses at one month were reported in four of eight patients with either ALL (n=5), chronic lymphocytic leukemia (n=1), or diffuse large B-cell lymphoma (n=2), with two morphologic complete responses at three months. Follow up blood tests demonstrated sustained persistence of infused T cells and targeting of malignant and normal B cells. There were no dose limiting toxicities with only grade 1 or 2 adverse events being reported. T-cell dose escalation continues.

Poster Presentation, "CD19-Specific Chimeric Antigen Receptor-Modified T Cells with Safety Switch Produced Under ‘Point-Of-Care’ Using the Sleeping Beauty System for the Very Rapid Manufacture and Treatment of B-Cell Malignancies"

Rutul Shah, interim Head of Operations, Intrexon Human Therapeutics, presented preclinical findings showing T cells expressing CD19-specific CAR, mbIL15, and control (safety) switch were generated under P-O-C using the SB system. These T cells were manufactured in less than two days and did not require ex vivo activation or propagation and demonstrated potent anti-tumor effect and sustained CAR+ T-cell persistence in mice. These data support clinical evaluation of genetically modified T cells very rapidly manufactured using the SB system.

Poster Presentation, "Autologous T Cells Modified to Co-express CD33-Specific Chimeric Antigen Receptor and a Kill Switch for Treatment of CD33+ Acute Myeloid Leukemia"

Tim Chan, PhD, Senior Director, Intrexon Human Therapeutics, presented preclinical data supporting an ongoing Phase 1 study of CD33-specific CAR+ T-cell therapy for the treatment of relapsed or refractory acute myeloid leukemia. In vitro analyses demonstrated that CAR+ T cells exhibited redirected specificity for CD33. Co-expression of a kill switch was shown to eliminate CAR+ T cells by cetuximab-mediated antibody-dependent cellular cytotoxicity both in vitro and in vivo.

argenx to provide updates on Phase 1/2 clinical trials of ARGX-110 in Acute Myeloid Leukemia and Cutaneous T-Cell Lymphoma during American Society of Hematology Annual Meeting

On December 11, 2017 argenx (Euronext & Nasdaq: ARGX) a clinical-stage biotechnology company developing a deep pipeline of differentiated antibody-based therapies for the treatment of severe autoimmune diseases and cancer, reported that it will provide interim data from its Phase 1/2 clinical trial of ARGX-110 in acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) and an update on the Phase 2 part of its clinical trial with ARGX-110 in cutaneous T-cell lymphoma (CTCL) during a workshop being held in conjunction with the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place December 9-12, 2017 in Atlanta, Georgia (Press release, argenx, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2321978 [SID1234522502]).

The workshop is being held on Monday, December 11, 2017 at 12:00pm EST. A live webcast of the presentation will be available on the Company’s website at www.argenx.com. A replay of the webcast will be available for 90 days following the presentation.

argenx is evaluating the safety, tolerability and efficacy of ARGX-110 in an open-label, Phase 1/2 clinical trial in combination with azacitidine in newly diagnosed AML patients unfit for intensive chemotherapy. During the ASH (Free ASH Whitepaper) workshop today, argenx will announce interim results from the dose-escalation part of the Phase 1/2 clinical trial highlighting promising preliminary data from the first set of six AML patients. All six patients showed encouraging signs of clinical activity, including complete remission (3/6), complete remission with incomplete blood count recovery (1/6) and partial response (2/6). One of the patients that achieved a complete remission bridged to allogeneic stem cell transplant after five cycles. The preliminary data from the first set of patients suggest ARGX-110 is active both at the circulating and bone marrow blast levels and at the leukemic stem cell (LSC) level.

In addition, further data will be presented from the currently ongoing Phase 1/2 clinical trial of ARGX-110 in relapsed/refractory cutaneous T-cell lymphoma (CTCL) patients with confirmed overexpression of CD70 who have failed at least one line of prior therapy. The interim data analyses are from 22 patients, including 13 patients from the Phase 1 part of the trial, which has completed recruitment, and nine patients from the Phase 2 part of the trial. Of the 22 patients under analysis, there was one complete response, two partial responses and 10 with stable disease. ARGX-110 continues to show a favorable tolerability profile in CTCL patients.

Poster presentation at ASH (Free ASH Whitepaper)
argenx collaborators from the University of Bern/Inselspital presented a poster at ASH (Free ASH Whitepaper) highlighting the role of hypomethylating agents (HMA) in inducing upregulation of CD70 on LSCs, but not progenitor cells. There were additional data showing the synergistic effect of HMAs in combination with a variant of ARGX-110. More details can be found here. These data further validate the rationale to evaluate ARGX-110 in combination with azacitidine in the ongoing Phase 1/2 clinical trial.

About ARGX-110
ARGX-110 is a SIMPLE Antibody(TM) targeting CD70, an immune checkpoint target involved in hematological malignancies, several solid tumors and severe autoimmune diseases. ARGX-110 is designed to: i) block CD70, ii) kill cancer cells expressing CD70 through complement dependent cytotoxicity, antibody-dependent cell-mediated phagocytosis and enhanced antibody-dependent cell-mediated cytotoxicity and iii) restore immune surveillance against solid tumors (Silence K. et al. mAbs 2014; 6 (2):523-532). ARGX-110 is currently being evaluated in patients with hematological and solid tumors, including a Phase 1/2 trial in combination with azacitidine in patients with newly diagnosed AML and high-risk MDS and the Phase 2 part of a Phase 1/2 trial in patients with relapsed/refractory CTCL. Preclinical work on ARGX-110 in AML was performed in collaboration with the Tumor Immunology Lab of Prof. A. F. Ochsenbein at the University of Bern, who won, together with Prof. Manz from the University Hospital of Zürich, the prestigious 2016 Otto Naegeli Prize for his breakthrough research on CD70/CD27 signaling with therapeutic potential for cancer patients.

Four-Year Phase 3 Data Analysis Shows Durability of Response of Jakafi® (ruxolitinib) in Patients with Polycythemia Vera

On December 10, 2017 Incyte Corporation (Nasdaq:INCY) reported new 208-week (4-year) follow-up data from the ongoing, global, multi-center, open-label Phase 3 RESPONSE study of Jakafi (ruxolitinib) comparing the efficacy and safety of Jakafi with best available therapy (BAT) in patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea (HU) (Press release, Incyte, DEC 10, 2017, View Source;p=RssLanding&cat=news&id=2321950 [SID1234522490]). The pre-planned data analysis showed a durable primary response to Jakafi in patients with PV who are resistant to or intolerant of HU and the overall safety profile for Jakafi remained consistent with previously reported 80-week RESPONSE data.1 The results were shared in an oral presentation today at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2017 in Atlanta, Georgia.

"With 30 months of additional follow-up, the four-year RESPONSE data analysis presented today at ASH (Free ASH Whitepaper) further reinforces the potential of Jakafi as a long-term option for patients with PV," said Peg Squier, M.D., Ph.D., Head of U.S. Medical Affairs at Incyte. "Given the few treatment options available to treat this chronic and progressive blood cancer, these long-term safety and efficacy data are meaningful to patients with uncontrolled PV."

The 80-week follow-up results from RESPONSE confirmed that among patients who initially responded to Jakafi treatment, the probability of maintaining primary and hematocrit (Hct) responses for ≥ 80 weeks was 92% and 89%, respectively, and hence Jakafi could be an effective long-term treatment option for patients with PV who are HU-resistant or intolerant.

At the week 208 analysis, the overall long-term safety profile remained consistent with the 80-week data analysis and the response was durable. In both the Jakafi arm and the crossover population, around 30% of patients completed the study treatment and 37% of patients were still receiving treatment.

"These are clinically relevant long-term safety and efficacy results, and further support the use of Jakafi in PV patients who have an inadequate response to or are intolerant of hydroxyurea," said Srdan Verstovsek, M.D., Ph.D., medical oncologist and professor, Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, Texas.

About the RESPONSE Trial

RESPONSE is an ongoing, global, multi-center, open-label, Phase 3 trial comparing the efficacy and safety of Jakafi (ruxolitinib) with BAT in 222 patients (Jakafi, 110; BAT, 112) with PV who are resistant to or intolerant of hydroxyurea (HU).2

The primary response was a composite endpoint of the proportion of patients who achieved both hematocrit (Hct) control (defined as no phlebotomy eligibility from week 8 through week 32, with no more than 1 post-randomization phlebotomy eligibility up to week 8) and a spleen volume reduction of at least 35% from baseline at week 32. Phlebotomy eligibility was defined as an Hct >45% and at least 3 percentage points greater than baseline or an Hct >48%. Patients randomized to BAT could crossover (CO) to ruxolitinib at week 32 if they did not meet the primary endpoint, or after week 32 in case of disease progression (PBT eligibility, splenomegaly progression, or both).2

The primary endpoint of the RESPONSE study was achieved, demonstrating that Jakafi was superior to BAT at controlling Hct and reducing spleen volume at week 32.2 The 80-week follow-up results from RESPONSE have been published previously and confirmed that ruxolitinib could be an effective long-term therapy option for HU-resistant/intolerant (R/I) patients with PV.3

Durability of the primary response, overall clinicohematologic (CLHM) response (defined as Hct control, platelet count ≤ 400 × 109/L, white blood cell count ≤ 10 × 109/L, and spleen volume reduction ≥ 35% by imaging), as well as long-term safety were updated at week 208.1

At week 208, the Kaplan-Meier (KM) estimate of duration of primary response was 0.73 (95% CI: 0.49, 0.87), and the KM estimate of duration of absence of PBT eligibility was 0.73 (95% CI: 0.60, 0.83). The KM estimate of duration of at least 35% reduction in spleen volume was 0.86 (95% CI: 0.61, 0.95). Median duration of primary and CLHM responses has not been reached.1

Out of the 70 patients (63.6%) in the Jakafi arm who achieved an overall CLHM response at week 32, 21 had progressed by week 208. The KM estimate of duration of complete hematological remission (defined as Hct control, platelet count ≤ 400 × 109/L, and white blood cell count ≤ 10 × 109/L) at 208-weeks was 0.54 (95% CI: 0.31, 0.72). RESPONSE data also demonstrated that the KM estimate for overall survival at 5-years was 90.6% (95% CI: 80.1, 95.7) for patients treated with Jakafi compared to 87.7% (95% CI: 74.8, 94.3) for patients treated with BAT.1

At the week 208 analysis, 41 patients (37%) originally randomized to the Jakafi arm were still receiving therapy (median exposure, 225 weeks) versus no patients on BAT (median exposure, 34 weeks). Among patients in the Jakafi arm, 29% completed the treatment as per protocol. Of the 98 patients who crossed over to Jakafi after week 32, 38% remained on Jakafi (median exposure, 189 weeks) and 31% completed treatment. Other main reasons for the study drug discontinuations (Jakafi + CO patients) were disease progression (11% + 8%), patient decision (6% + 6%), and adverse events (14% + 14%).1

The most common adverse events in the Jakafi randomized arm (week 208 vs week 80) per 100 patient-years of exposure were anemia (9.3 vs 13.2), pruritus (7.3 vs 9.7), diarrhea (7.1 vs 9.7), headache (6.1 vs 10.5), arthralgia (5.9 vs 6.1), increased weight (5.6 vs 7.5) and muscle spasms (5.4 vs 7.9).

The 208-week results (Abstract #322) were presented as a part of an oral session (#634) on Sunday, December 10, 2017, 7:30-9:00 AM Eastern Time (8:15 AM), Building C, Level 2, C208-C210.

About Polycythemia Vera (PV)

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) and is typically characterized by elevated hematocrit, the percent volume of red blood cells in the blood, which can lead to a thickening of the blood and an increased risk of blood clots. An elevated white blood cell and/or platelet count may also be present.4 Patients with PV who fail to consistently maintain appropriate hematocrit levels have a four times higher risk of major thrombosis (blood clots) or cardiovascular death.5 Patients with PV can also suffer from an enlarged spleen and a significant symptom burden which may be attributed to thickening of the blood and lack of oxygen to parts of the body.6 Signs and symptoms of PV commonly include fatigue, itching, night sweats, bone pain, fever, and unexplained weight loss.7

Approximately 100,000 patients in the U.S. are living with PV.8 Current standard treatment for PV is phlebotomy (the removal of blood from the body) plus aspirin. When phlebotomy can no longer control PV, chemotherapy such as hydroxyurea, or interferon, is utilized in high-risk patients.9,10 Approximately one in four patients with PV are considered uncontrolled11,12 because they have an inadequate response to or are intolerant of hydroxyurea, the most commonly used chemotherapeutic agent for the treatment of PV.

About Jakafi (ruxolitinib)

Jakafi is a first-in-class JAK1/JAK2 inhibitor approved by the U.S. Food and Drug Administration for treatment of people with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea.

Jakafi is also indicated for treatment of people with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF, and post–essential thrombocythemia MF.

Jakafi is marketed by Incyte in the United States and by Novartis as Jakavi (ruxolitinib) outside the United States. Jakafi is a registered trademark of Incyte Corporation. Jakavi is a registered trademark of Novartis AG in countries outside the United States.

Important Safety Information

Jakafi can cause serious side effects, including:

Low blood counts: Jakafi (ruxolitinib) may cause your platelet, red blood cell, or white blood cell counts to be lowered. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will perform blood tests to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you develop or have worsening symptoms such as unusual bleeding, bruising, tiredness, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection during treatment with Jakafi. Tell your healthcare provider if you develop any of the following symptoms of infection: chills, nausea, vomiting, aches, weakness, fever, painful skin rash or blisters.

Skin cancers: Some people who take Jakafi have developed certain types of non-melanoma skin cancers. Tell your healthcare provider if you develop any new or changing skin lesions.

Increases in Cholesterol: You may have changes in your blood cholesterol levels. Your healthcare provider will do blood tests to check your cholesterol levels during your treatment with Jakafi.

The most common side effects of Jakafi include: low platelet count, low red blood cell counts, bruising, dizziness, headache.

These are not all the possible side effects of Jakafi. Ask your pharmacist or healthcare provider for more information. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Before taking Jakafi, tell your healthcare provider about: all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had tuberculosis (TB), or have been in close contact with someone who has TB, have or had hepatitis B, have or had liver or kidney problems, are on dialysis, had skin cancer or have any other medical condition. Take Jakafi exactly as your healthcare provider tells you. Do not change or stop taking Jakafi without first talking to your healthcare provider. Do not drink grapefruit juice while on Jakafi.

Women should not take Jakafi while pregnant or planning to become pregnant, or if breast-feeding.

Full Prescribing Information, which includes a more complete discussion of the risks associated with Jakafi, is available at www.jakafi.com.

IMBRUVICA® (ibrutinib) Patient-Reported Outcomes Data Detail Long-Term Improvement in Treatment Outcomes and Quality of Life Experience in Chronic Lymphocytic Leukemia (CLL) Patients

On December 9, 2017 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported new three-year follow-up data from the RESONATE-2 study (PCYC-1115/1116), which found that previously-untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients reported sustained improvements in measures of well-being with IMBRUVICA (ibrutinib) versus chemotherapy with chlorambucil (Press release, AbbVie, DEC 9, 2017, View Source [SID1234522453]). These new data provide the longest quality of life follow up for ibrutinib to date using patient-reported outcomes (PRO). Patients reported their quality of life outcomes for fatigue, mobility, self-care, usual activities, pain/discomfort and anxiety/depression. At 30 months, ibrutinib was also associated with a greater progression-free survival (PFS) rate of 85 percent versus chlorambucil, which had a PFS rate of 28 percent.

The new RESONATE-2 data will be presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition on Dec. 9 in Atlanta (abstract #1746). IMBRUVICA is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"In the RESONATE-2 study, patients who were treated with ibrutinib reported greater and sustained improvements in overall health and well-being and experienced decreased disease-related symptoms," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "For patients with chronic lymphocytic leukemia, a disease that affects primarily older patients, quality of life is an important consideration that should be factored into treatment choices initially and throughout long-term use."

CLL is the most common form of leukemia in adults and is a type of cancer that can form from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes). 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.1 with approximately 19,000 newly diagnosed patients every year.2 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.3 CLL/SLL are predominately diseases of the elderly, with a median age of 71 at diagnosis.

About the Presentation

Abstract #1746: Prolonged Improvement in Patient-Reported Outcomes (PROs) and Well-being in Older Patients With Treatment-Naïve (TN) Chronic Lymphocytic Leukemia Treated With Ibrutinib (Ibr): 3-Year Follow-up of the RESONATE-2 Study
Poster Presentation; Saturday, December 9, 5:30 – 7:30 p.m. ET

At a median follow up of three years, ibrutinib treatment resulted in significantly longer PFS (median, not reached versus 15 months with chlorambucil), with an 87% reduction in risk of progression or death versus chlorambucil (HR 0.130; 95% CI: 0.081, 0.208). The PFS rate for ibrutinib was 85% versus 28% with chlorambucil. Greater and sustained improvements in PROs were observed with ibrutinib, resulting in significantly greater improvements over time versus chlorambucil (via FACIT-F and EQ-5D-5L Visual Analogue Scale by repeated measures).

In chlorambucil patients with progressive disease, PROs improved after crossing over to ibrutinib. Approximately 87% of patients on ibrutinib (versus 52% on chlorambucil) had decreased/normalized lymphadenopathy within 2 months, which was sustained through 36 months, and disease symptoms, including fatigue and night sweats, improved more frequently for patients on ibrutinib. A greater proportion of patients with baseline cytopenia showed sustained hematologic improvement with ibrutinib versus chlorambucil for hemoglobin (90% versus 45%) and platelets (83% versus 46%).

Patients 65 years and older (median age 73) were randomized to receive 420mg ibrutinib once daily until progressive disease or chlorambucil for up to 12 months. Median treatment duration was 34.1 months on ibrutinib versus 7.1 months on chlorambucil. Further data showed the burden of hematologic support medical resource utilization was less with ibrutinib versus chlorambucil in the first year and subsequently continued to decrease.

The most common adverse events (AEs) of any grade with ibrutinib were diarrhea (47%), fatigue (33%), and cough (30%). Eight Grade 3 or higher AEs had a prevalence of less than 3% in ibrutinib patients and generally decreased or were stable over time. During the first year of treatment, patients on ibrutinib versus chlorambucil experienced less Grade 3 or higher neutropenia (8% and 18%), anemia (6% and 8%), and thrombocytopenia (2% and 5%); other common Grade 3 or higher AEs were pneumonia (5% and 2%), hypertension (4% and 0%), and infections as combined term (17% and 8%). Grade 3 or higher bleeding occurred in 7% of ibrutinib patients over the 3-year follow up. AEs leading to treatment discontinuation occurred in 16% with ibrutinib over 3 years versus 23% for chlorambucil over 7 months of therapy, respectively.

Additional Presentation on RESONATE-2 at ASH (Free ASH Whitepaper) 2017

A separate presentation at ASH (Free ASH Whitepaper) this year will also discuss the RESONATE-2 clinical trial (with a median follow up of 35.7 months) as part of a cross-trial comparison. The data compares ibrutinib as a single-agent therapy and six different chemoimmunotherapy regimens from additional Phase 3 studies in patients with CLL as a first-line therapy, reviewing results in PFS, overall survival (OS) and safety measures. The six chemoimmunotherapy regimens included as part of the cross-trial comparison are fludarabine, cyclophosphamide and rituximab (FCR); bendamustine and rituximab (BR); obinutuzumab and chlorambucil; rituximab and chlorambucil; and ofatumumab and chlorambucil. This data will also be presented at ASH (Free ASH Whitepaper) on Dec. 9 (abstract #1750).

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2017, which includes 12 oral presentations, please click here.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking 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 as well as other serious, debilitating conditions.4 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).5

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially 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 previously-treated 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.
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.6 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, 90,000 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 up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half 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 14% to 29% of patients. 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 (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.
Monitor complete blood counts monthly.

Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 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 (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%).

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 (62%), neutropenia (61%), diarrhea (43%), anemia (41%), musculoskeletal pain (30%), rash (30%), bruising (30%), nausea (29%), fatigue (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%), thrombocytopenia (16%), and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9% (WM [6%] 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%), muscle spasms (29%), stomatitis (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.

DRUG INTERACTIONS

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

CYP3A Inhibitors: Dose adjustment may be recommended.

SPECIFIC POPULATIONS

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

IMBRUVICA® (ibrutinib) Pooled Analysis Suggests Benefit in Progression-Free Survival (PFS) at 3.5 Years in Patients with Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL)

On December 9, 2017 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported pooled analysis results of the longest follow-up data to date in Bruton’s tyrosine kinase (BTK) inhibition for relapsed/refractory (R/R) mantle cell lymphoma (MCL) patients treated with IMBRUVICA (ibrutinib) (Press release, AbbVie, DEC 9, 2017, View Source [SID1234522454]). The analysis found that, at three years, 45 percent of patients were able to achieve overall survival (OS) and 26 percent had disease progression-free survival (PFS). The pooled analysis also found that patients who were treated with ibrutinib earlier, after their first relapse/progression, experienced higher rates of OS and PFS.1 The analysis is comprised of data from a total of 370 patients in three different clinical trials: SPARK, RAY and PCYC-1104, and one ongoing Phase 3b extension study, CAN3001, which is eligible to patients who continue to benefit from ibrutinib therapy upon completing a previous ibrutinib clinical trial.2 MCL is an aggressive B-cell malignancy in which most patients relapse after their first line of therapy and receive a poor prognosis.

These data will be presented in an oral presentation at the 59th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting and Exposition on Dec. 9 at 12:00 p.m. ET in Atlanta (abstract #151).1 IMBRUVICA is a first-in-class BTK inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"IMBRUVICA continues to provide a beneficial treatment option for patients with relapsed/refractory mantle cell lymphoma," said Thorsten Graef, M.D., Ph.D., Head of Clinical Development at Pharmacyclics LLC, an AbbVie company. "Prior to the discovery and introduction of IMBRUVICA, people diagnosed with MCL had limited treatment options. This long-term data analysis adds to our growing understanding of IMBRUVICA’s potential treatment benefits for previously-treated MCL patients."

MCL is one of several subtypes of B-cell non-Hodgkin’s lymphoma (NHL) and represents about six percent (about 4,200) of new cases of NHL each year in the U.S. MCL usually begins with lymph node enlargement and can potentially spread to other tissues such as the bone marrow and liver.3 Median overall survival for MCL patients is three to four years.4

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2017, which includes 12 oral presentations, please click here.

Abstract #151: Median 3.5-year Follow-Up of Ibrutinib Treatment in Patients with Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis
Oral presentation: Saturday, December 9, 2017, 12:00 PM ET

The pooled analysis includes results from a total of 370 patients from two Phase 2, open-label studies (SPARK and PCYC-1104), one Phase 3, open-label study (RAY), and an additional follow-up of 87 patients across these studies who enrolled in a long-term open-label extension study (CAN3001). Patients enrolled in SPARK, RAY and PCYC-1104 received ibrutinib 560mg orally once daily until progressive disease or unacceptable toxicity. Study inclusion and exclusion criteria were similar across SPARK, PCYC-1104 and RAY, requiring patients to have received at least one prior therapy for MCL and be chemotherapy-free for at least 3 weeks. However, patients in SPARK were required to have already received rituximab and bortezomib, and patients in RAY were required to have already received rituximab. Patients who continued to benefit from ibrutinib therapy at the end of the studies were eligible to enroll in CAN3001, a Phase 3b open-label study, which provides continued access to ibrutinib for patients who have completed an ibrutinib clinical study. Safety reporting in CAN3001 was limited to grade 3/4 adverse events (AEs) and serious adverse events (SAEs). This pooled analysis was limited to patients on ibrutinib therapy, excluding crossover patients. Investigator-assessed tumor response, progression-free survival (PFS), and overall survival (OS) were evaluated. PFS and OS were analyzed by number of prior lines of therapy and best tumor response. Patients in CAN3001 were censored from OS analysis upon treatment or study discontinuation.

With 3.5 years (41 months) of follow-up, the proportion of patients achieving complete response (CR) increased to 26.5%. In addition, 36% (95% CI, 0.31-0.42) and 26% (0.20-0.32) of patients treated with ibrutinib were progression free at 2 and 3 years, respectively, and the median PFS was 13 months. The median PFS in patients with one prior line of therapy was 33.6 (range, 19.4-42.1) months. The median period for patients achieving CR was 46.2 (range, 42.1-not estimable) months. Patients with favorable baseline disease characteristics were more likely to remain on ibrutinib for more than 3 years. Overall, 53% (95% CI, 0.47-0.58), 45% (0.39-0.50), and 37% (0.25-0.49) of patients were alive at 2, 3, and 5 years, respectively, and the median OS was 26.7 months.

In the pooled analysis, the median duration of follow-up was 41.1 months (95% CI, 37.3-42.5) and median exposure to ibrutinib was 11.1 months (range: 0.03-72.1). Eighty-three patients were treated with ibrutinib for 3 or more years, and 40 patients were treated with ibrutinib for 4 or more years. Fifty-four of 87 (62.1%) patients enrolled in CAN3001 remain on ibrutinib. Patients had a median of 2 (range: 1-9) prior lines of therapy before receiving ibrutinib.

Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 79.7% of patients, with the new onset events decreasing after the first year. Cumulative incidence of any major hemorrhage was 7.3%, and new onset events decreased after the first year. The most common grade 3 or higher TEAEs were neutropenia (17.0%), thrombocytopenia (12.2%), pneumonia (11.9%), anemia (9.5%), atrial fibrillation (5.9%) and hypertension (5.1%). Most of these AEs were more common during the first year of ibrutinib treatment. Treatment-emergent SAEs occurred in 61.9% patients and new onset SAEs decreased over time (incidence: 47.3%, 33.9%, 29.6%, 25.3%, and 12.5% for Years 1, 2, 3, 4, and > 4, respectively). The data from this pooled analysis have not been reviewed by the U.S. Food and Drug Administration and they are not in the approved label for IMBRUVICA.

About the U.S. Food and Drug Administration (FDA) Approval of IMBRUVICA to Treat R/R MCL
The FDA approved IMBRUVICA (ibrutinib) as a single agent for the treatment of adult patients with MCL who have received at least one prior therapy based on the overall response rate (ORR) seen in the Phase 2 study, PCYC-1104, an open-label, multi-center, single-arm trial of 111 previously-treated MCL patients. IMBRUVICA was administered orally at 560-mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin’s lymphoma (NHL) criteria.5 The efficacy results, which were published in the New England Journal of Medicine in 2013, demonstrated a 68% overall response rate with 47% of patients having a partial response and 21% having a complete response. The median duration of response was 17.5 months.5

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking 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 as well as other serious, debilitating conditions.6 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially 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 previously treated 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.
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 Breakthrough Therapy Designation pathway.