On December 4, 2016 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported updated results from its Phase 2b STORM study of selinexor (KPT-330), including robust rates and duration of response, compelling overall survival and a favorable safety profile, in patients with heavily pretreated refractory multiple myeloma (MM) at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2016 annual meeting held December 3-6, 2016 in San Diego (Filing, 8-K, Karyopharm, DEC 4, 2016, View Source [SID1234516967]). Selinexor is the Company’s lead, novel, oral Selective Inhibitor of Nuclear Export (SINE) compound, in development for the treatment of a variety of malignancies, including MM and acute myeloid leukemia (AML).

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"The data presented today further support the rationale for selinexor as a promising new treatment for patients with refractory myeloma with no clearly beneficial treatment options," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "Based on the exciting STORM data and the existing unmet medical need, we have expanded the study to include additional patients with penta-refractory myeloma and expect to report top-line data from this study in early 2018."
Updated Phase 2b STORM Clinical Data in Refractory Multiple Myeloma

In an oral presentation titled, "Selinexor and Low Dose Dexamethasone in Patients with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib and Anti-CD38 Ab Refractory MM STORM Study," Dan T. Vogl, MD, MSCE, Assistant Professor of Medicine, Perelman School of Medicine, University of Pennsylvania, presented updated clinical data from the ongoing Phase 2b STORM study, a single-arm clinical trial evaluating selinexor in combination with low-dose dexamethasone in patients with quad-refractory or penta-refractory myeloma. Patients with quad-refractory disease have previously received two proteasome inhibitors (PIs) (bortezomib (Velcade) and carfilzomib (Kyprolis)) and two immunomodulatory drugs (IMiDs) (lenalidomide (Revlimid) and pomalidomide (Pomalyst)), and their disease is refractory to at least one PI, at least one IMiD, and has progressed following their most recent therapy. Patients with penta-refractory myeloma have quad-refractory disease that is also refractory to an anti-CD38 monoclonal antibody, such as daratumumab (Darzalex) or isatuximab.

Phase 2b STORM Efficacy

Category
N1 ORR (%) CBR (%) VGPR (%) PR (%) MR (%) SD (%) PD (%) NE (%)
Overall
78 16 (21% ) 26 (33% ) 4 (5% ) 12 (15% ) 10 (13% ) 27 (35% ) 9 (12% ) 16 (21% )
Quad
48 10 (21% ) 14 (29% ) 2 (4% ) 8 (17% ) 4 (8% ) 21 (44% ) 4 (8% ) 9 (19% )
Penta
30 6 (20% ) 12 (40% ) 2 (7% ) 4 (13% ) 6 (20% ) 6 (20% ) 5 (17% ) 7 (23% )
6 Doses/month
51 10 (20% ) 15 (29% ) 3 (6% ) 7 (14% ) 5 (10% ) 21 (41% ) 4 (8% ) 11 (2% )
8 Doses/month
27 6 (22% ) 11 (41% ) 1 (4% ) 5 (19% ) 5 (19% ) 6 (22% ) 5 (19% ) 5 (19% )
ORR=Objective Response Rate (VGPR+PR), CBR=Clinical Benefit Rate (VGPR+PR+MR), VGPR=Very Good Partial Response,
PR=Partial Response, MR=Minor Response, SD=Stable Disease, PD=Progressive Disease, NE=Non-Evaluable
1 One patient not included, did not have active myeloma

1
LOGO Targeting Disease at the Nuclear Pore

All responses were adjudicated by an Independent Review Committee (IRC). Among the 78 evaluable patients (median seven prior treatment regimens), the overall response rate (ORR) was 21%, and included very good partial responses (VGPR) and partial responses (PR). Among the 48 patients in the quad-refractory group, the ORR was 21%. For comparison, in a similar quad-refractory patient population, the anti-CD38 monoclonal antibodies Darzalex and isatuximab had ORRs of 21% and 20%, respectively. Among the 30 patients in the penta-refractory group, the ORR was 20%. Clinical benefit rate (ORR + MR) was 32% (all patients), 29% (quad-refractory), and 37% (penta-refractory). To the Company’s knowledge, no other agents have reported response rates in patients with penta-refractory MM. Median overall survival (OS) was 9.3 months for all patients, greater than 11 months (median not reached) for patients with ³MR, and 5.7 months for patients who did not have any response (£SD). Median duration of response (DOR) was 5 months. Grade ³3 cytopenias were the most common side effects and were generally not associated with clinical sequellae. Nausea, anorexia and fatigue were the most common non-hematological side effects, primarily Grades 1 and 2, and were treatable with supportive care and/or dose modification. There were low rates of Grade ³3 non-hematologic toxicities, with no new safety signals identified. In particular, there was one reported case of Grade 4 infection (1.3%), one case of Grade 2 neuropathy (1.3%) and one reported case of sepsis (1.3%).
Dr. Vogl commented, "The quad- and penta-refractory populations are continuing to expand as patients live longer and cycle through a variety of treatment options, including immunomodulatory drugs, proteasome inhibitors, or anti-CD38 monoclonal antibodies, before their disease ultimately becomes refractory and non-responsive. In my experience, selinexor is the first agent to be specifically investigated in in this difficult to treat and currently underserved population. The response rate and duration suggest that selinexor has the potential to be an exciting new option for myeloma treatment."
Karyopharm to Host Multiple Myeloma-focused Dinner Reception and Webcast at ASH (Free ASH Whitepaper) 2016
On Monday, December 5, 2016, Karyopharm will host an investor and analyst dinner reception, which will feature a moderated panel discussion with recognized experts in the treatment of MM, updated selinexor data in MM, and a live Q&A session. Confirmed external speakers include:

• Daniel Auclair, PhD (Moderator), Multiple Myeloma Research Foundation

• Nizar Bahlis, MD, University of Calgary, Southern Alberta Cancer Research Institute

• Paul G. Richardson, MD, Dana Faber Cancer Institute, Jerome Lipper Multiple Myeloma Center

• Ravi Vij, MD, MBA, Washington University School of Medicine in St. Louis, Oncology Division

• Dan T. Vogl, MD, Abramson Cancer Center Clinical Research Unit, University of Pennsylvania
In addition, Michael Kauffman, MD, PhD, CEO of Karyopharm Therapeutics will be joining.
The event will take place during the ASH (Free ASH Whitepaper) 2016 annual meeting and interested parties can access a live webcast of the event beginning Monday, December 5, 2016 at 8:15 p.m. PT under "Events & Presentations" in the "Investors" section of the company’s website at View Source A replay of the webcast will be archived on the company’s website for 90 days following the event.
About Selinexor
Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor

Targeting Disease at the Nuclear Pore

suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 1,800 patients have been treated with selinexor and it is currently being evaluated in several mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), and in acute myeloid leukemia (SOPRA), diffuse large B-cell lymphoma (SADAL), and liposarcoma (SEAL), among others. Karyopharm plans to initiate a pivotal randomized Phase 3 study of selinexor in combination with bortezomib (Velcade) and low-dose dexamethasone (BOSTON) in patients with multiple myeloma in early 2017. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform the Company’s clinical development priorities for selinexor. The latest clinical trial information for selinexor is available at www.clinicaltrials.gov.

On December 4, 2016 ArQule, Inc. (Nasdaq: ARQL) reported that preclinical data was presented on Bruton’s tyrosine kinase (BTK) inhibitor, ARQ 531, in a poster presentation by The Ohio State University at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. The presentation highlighted preclinical studies of ARQ 531 in Chronic Lymphocytic Leukemia (CLL) (Press release, ArQule, DEC 4, 2016, View Source [SID1234516920]). ARQ 531 is an investigational, orally bioavailable, potent and reversible BTK inhibitor.

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ARQ 531 Poster Presentation Highlights

Title: The Bruton’s Tyrosine Kinase (BTK) Inhibitor ARQ 531 Effectively Inhibits Wild Type and C481S Mutant BTK and Is Superior to Ibrutinib in a Mouse Model of Chronic Lymphocytic Leukemia

Multi-targeted inhibition of cytokine, chemokine, and BCR pathways by ARQ 531 decreases activation, migration, and viability of CLL cells.
Unlike ibrutinib, ARQ 531 inhibits activation of C481S mutated BTK variants and maintains cytotoxicity in ibrutinib resistant clones.
ARQ 531 demonstrates remarkable efficacy in an in vivo TCL1 adoptive transfer model, improving survival to a greater extent than ibrutinib and restoring granulocyte production.
The company plans to complete preclinical studies and file an Investigational New Drug (IND) application in early 2017 to begin clinical testing later in the year.
The presentation can be viewed at View Source

"Irreversible kinase inhibitors directed at BTK have really changed the landscape of CLL but at extended follow up, we are beginning to see a subset of high risk patients who are relapsing," said Dr. Jennifer Woyach, M.D., of The Ohio State University College of Medicine. "Small molecules that target BTK that are not dependent upon the C481 site represent an exciting option for future clinical trials. We are excited to be working with ArQule on this project and look forward to initiating the first in man study with ARQ 531."

"We began our BTK discovery program in 2011 which ultimately lead to the selection of ARQ 531, a potent reversible inhibitor of both wild type and mutant BTK," said Dr. Giovanni Abbadessa, M.D., PhD., Vice President of Clinical Development, Translational Medicine and Medical Affairs at ArQule. "With the recent emergence in 2015 of BTK resistance we concentrated our efforts in this growing CLL patient population. We are pleased to be working with The Ohio State University to finish preclinical studies on this exciting program. We remain on track to file an IND application early next year."

About BTK and ARQ 531

ARQ 531 is an investigational, orally bioavailable, potent and reversible Bruton’s tyrosine kinase (BTK) inhibitor. Biochemical and cellular studies have shown that ARQ 531inhibits both the wild type and C481S-mutant forms of BTK. The C481S mutation is a known emerging resistance mechanism for first generation irreversible BTK inhibitors. ARQ 531 has high oral bioavailability as well as good ADME, pharmacokinetic and metabolic properties. The company plans to file an IND for ARQ 531 in early 2017. BTK is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers.

On December 5, 2016 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported data from the positive, pivotal Phase III GALLIUM study that compared Gazyva/Gazyvaro (obinutuzumab) plus chemotherapy followed by Gazyva/Gazyvaro alone head-to-head against MabThera/Rituxan (rituximab) plus chemotherapy followed by MabThera/Rituxan alone for people with previously untreated follicular lymphoma. At a pre-planned interim analysis in May 2016, an independent data monitoring committee determined that the study met its primary endpoint early. The results showed Gazyva/Gazyvaro-based treatment reduced the risk of disease worsening or death (progression-free survival; PFS, as assessed by investigator) by 34 percent compared to MabThera/Rituxan-based treatment (HR=0.66; 95% CI 0.51-0.85, p=0.0012). Median PFS was not yet reached. Adverse events with either Gazyva/Gazyvaro or MabThera/Rituxan were consistent with those seen in previous studies.
"Follicular lymphoma, the most common slow-growing form of non-Hodgkin lymphoma, is an incurable blood cancer characterized by cycles of remission and disease progression, and becomes harder to treat with every relapse," said Sandra Horning, M.D., Roche’s Chief Medical Officer and Head of Global Product Development. "This study of Gazyva/Gazyvaro-based treatment is the first and only Phase III trial to date to show superior progression-free survival compared to MabThera/Rituxan-based treatment, the current standard of care, in previously untreated follicular lymphoma."
The primary results from the GALLIUM study (Abstract #6) were presented during the Plenary Scientific Session of the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego by Dr. Robert Marcus, King’s College Hospital, London and the National Cancer Research Institute (NCRI), on Sunday, December 4 at 2:00 P.M. PST. Additionally, an analysis of minimal residual disease (MRD) status in the GALLIUM study (Abstract #613) was presented in a separate oral session by Dr. Christiane Pott, University Hospital Schleswig-Holstein, Kiel, Germany, and the German Low Grade Lymphoma Study Group (GLSG) on Monday, December 5 at 7:00 A.M. PST.
GALLIUM is the third positive Phase III study for Gazyva/Gazyvaro, following the CLL11 study in patients with previously untreated chronic lymphocytic leukaemia (CLL) and the GADOLIN study in patients with indolent (slow-growing) non-Hodgkin lymphoma whose disease progressed during or within six months of prior MabThera/Rituxan-based therapy. The results of the GALLIUM study will be submitted to health authorities around the world for approval consideration.
About the GALLIUM study
GALLIUM (NCT01332968) is a global Phase III open-label, multi-centre, randomised two-arm study examining the efficacy and safety of Gazyva/Gazyvaro plus chemotherapy followed by Gazyva/Gazyvaro alone for up to two years, as compared head-to-head against MabThera/Rituxan plus chemotherapy followed by MabThera/Rituxan alone for up to two years. Chemotherapies used were CHOP, CVP or bendamustine and were selected by each participating study site prior to beginning enrolment. GALLIUM included 1401 patients with previously untreated indolent non-Hodgkin lymphoma (iNHL), of which 1202 patients had follicular lymphoma. The primary endpoint of the study was investigator-assessed PFS in patients with follicular lymphoma, with secondary endpoints including PFS assessed by independent review committee (IRC), PFS in the overall study population (iNHL), response rate (overall response, ORR; and complete response, CR), overall survival (OS), and safety. The GALLIUM study is being conducted in cooperation with the GLSG (Germany), the East German Study Group Hematology and Oncology (OSHO; Germany) and the NCRI (United Kingdom).
A summary of the GALLIUM study results presented at ASH (Free ASH Whitepaper) is included below.

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1 Primary endpoint is PFS as assessed by investigator; median follow-up of 34.5 months
2 Measured by computerized tomography (CT) scans
3 MRD-negativity means no cancer can be detected in the blood or bone marrow using a specific highly sensitive test
4 Defined as any AE occurring during or within 24 hours of infusion of Gazyva/Gazyvaro or MabThera/Rituxan and considered drug-related
About Gazyva/Gazyvaro (obinutuzumab)
Gazyva/Gazyvaro is an engineered monoclonal antibody designed to attach to CD20, a protein expressed on certain B cells, but not on stem cells or plasma cells. Gazyva/Gazyvaro is designed to attack and destroy targeted B-cells both directly and together with the body’s immune system.
Gazyva/Gazyvaro is currently approved in more than 80 countries in combination with chlorambucil, for people with previously untreated chronic lymphocytic leukaemia. The approvals were based on the CLL11 study, showing significant improvements with Gazyva/Gazyvaro plus chlorambucil across multiple clinical endpoints, including PFS, overall response rate (ORR), complete response rate (CR), and minimal residual disease (MRD) when compared head-to-head with MabThera/Rituxan plus chlorambucil.
In February 2016, Gazyva was approved by the US Food and Drug Administration in combination with bendamustine followed by Gazyva alone for people with follicular lymphoma who did not respond to a Rituxan-containing regimen, or whose follicular lymphoma returned after such treatment. In June 2016, Gazyvaro was approved by the European Commission in combination with bendamustine followed by Gazyvaro maintenance in people with follicular lymphoma who did not respond or who progressed during or up to six months after treatment with MabThera or a MabThera-containing regimen. Both approvals were based on the phase III GADOLIN study, showing a significant improvement in progression-free survival with Gazyva/Gazyvaro-based therapy compared to bendamustine alone. Gazyva is marketed as Gazyvaro in the EU and Switzerland.
Additional combination studies investigating Gazyva/Gazyvaro with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are underway across a range of blood cancers.
About follicular lymphoma
Follicular lymphoma is the most common indolent (slow-growing) form of non-Hodgkin lymphoma (NHL), accounting for about one in five cases of NHL.2 It is considered incurable and relapse is common. It is estimated that more than 75,000 people are diagnosed with follicular lymphoma each year worldwide.3

On December 4, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported encouraging efficacy and safety findings from two separate studies evaluating ibrutinib (IMBRUVICA) as a combination therapy in two of the most common types of non-Hodgkin’s lymphoma: diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) (Press release, AbbVie, DEC 4, 2016, View Source [SID1234516911]). IMBRUVICA, a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

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In a Phase 1b study of patients with relapsed/refractory (R/R) DLBCL, the investigational combination of ibrutinib, rituximab, and escalating doses of lenalidomide were tested (abstract #473). Preliminary efficacy results demonstrated the highest response rate was observed in patients with the worst prognosis subtype (non-GCB) and in patients with transformed disease.1 These data will be presented today in an oral presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, CA.

"Though standard therapy can cure over half of patients with diffuse large B-cell lymphoma (the most common form of aggressive lymphoma), patients with relapsed or refractory disease do overall poorly with only less than a quarter of patients efficiently salvaged with current strategies including stem cell transplantation," said Andre Goy, M.D., Chairman and Executive Director at John Theurer Cancer Center at Hackensack University Medical Center in New Jersey and lead investigator of the study.* "We are encouraged by these results in a heavily pretreated and refractory population and look forward to further evaluating the efficacy of ibrutinib combination therapy with rituximab and lenalidomide in the Phase 2 portion of the study."

Separately at the meeting, data from a Phase 2 multicenter study showed that the combination of ibrutinib and rituximab produced favorable response rates in patients with previously untreated FL (abstract #1804). At a median time on study of 22 months, the overall response rate (ORR) was 85%, with 35% of patients achieving a complete response (CR).2 The data were presented in a poster presentation on Saturday, December 3.

"We are highly encouraged by this longer-term data showing strong and durable responses that appear to improve with an extended treatment duration," said Nathan Fowler, M.D., Associate Professor, Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX and lead investigator of the study.* "The results of the study to date suggest that the addition of ibrutinib to rituximab in the front-line follicular lymphoma setting provides enhanced outcomes over rituximab alone."

DLCBL is an aggressive B-cell lymphoma and the most common subtype of non-Hodgkin’s lymphoma. Despite 50-60% of patients being cured with standard chemo-immunotherapy, patients who relapse have poor outcomes.3 FL is the most common subtype of indolent non-Hodgkin’s lymphoma. It is often slow-growing, but is considered incurable in advanced stages. Over time, about one-third of FL cases advance to the fast-growing DLBCL.4

"The response rates observed with ibrutinib combination therapy in treatment-naïve follicular lymphoma and relapsed/refractory diffuse large B-cell lymphoma show promise for patients with two different types of non-Hodgkin’s lymphoma," said Darrin Beaupre, M.D., Ph.D., Head of Early Development and Immunotherapy at Pharmacyclics LLC, an AbbVie company. "We pioneered the development of BTK inhibition with ibrutinib, and we continue to progress our robust development program. Based on the encouraging Phase 2 study results in FL, we are initiating a Phase 3 study of the combination of ibrutinib and rituximab in the first-line setting."

About the Studies

Abstract #473: A multicenter, open-label phase 1b/2 study of ibrutinib in combination with lenalidomide and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma (Oral Presentation; Sunday, December 4, 4:30 PM PT)

Subjects with R/R DLBCL were treated with the investigational combination of ibrutinib 560 mg once daily, rituximab 375 mg/m2 on day one for six cycles and escalating doses of lenalidomide. Preliminary data for 45 patients showed responses on 15 mg, 20 mg, and 25 mg lenalidomide, with responses for patients with the non-GCB subtype (response-evaluable population) seen in more than half of the subjects. Patients with transformed disease also showed favorable responses. Overall, the treatment combination was tolerable. The most frequent Grade 3 or 4 adverse events (AEs) were neutropenia (38%), thrombocytopenia (11%), and maculopapular rash (11%). Based on safety data from this portion of the study, the Phase 2 portion of the trial is being initiated.1

Abstract #1804: Ibrutinib combined with rituximab in treatment-naïve patients with follicular lymphoma: Arm 1 + arm 2 results from a multicenter, open-label phase 2 study (Poster Presentation; Saturday, December 3, 5:30 PM – 7:30 PM PT)

Updated data were presented for 80 patients with FL receiving two different administration schedules of ibrutinib and rituximab (Arm 1, 60 patients; Arm 2, 20 patients). In Arm 1 at a median time on study of 22 months, the ORR was 85%, with 35% CR. Median time to best response was 2.7 months. With a median time on study of 15 months in Arm 2, ORR was 75%, with 35% CR. Median time to best response was 4.3 months. Median duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were not reached in either arm.2

In Arm 1, patients received ibrutinib 560 mg once daily until disease progression or unacceptable toxicity and rituximab 375 mg/m2 once weekly for four weeks. In Arm 2, patients received ibrutinib 560 mg once daily for eight weeks, then concurrent rituximab once weekly for four weeks, followed by ibrutinib 560 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed ORR. Secondary endpoints included DOR, PFS and OS.2

Treatment was well tolerated, with no new safety signals with longer follow up. AEs were primarily Grade 1 or 2. The most common AEs included fatigue (68%), diarrhea (52%), nausea (47%), headache (30%), cough, myalgia, maculopapular rash (28% each), and muscle spasms (23%) in Arm 1, and fatigue (80%), diarrhea (60%), nausea (55%), myalgia (45%), maculopapular rash (35%), and headache, cough and muscle spasms (25% each) in Arm 2. Common Grade 3 or 4 AEs in either Arm 1 or 2 included maculopapular rash (5% and 10%, respectively), fatigue (7% and 5%), pyrexia (3% and 10%) and diarrhea (2% and 10%).2

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits 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.5,6 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.5

IMBRUVICA is approved to treat patients with CLL/SLL including patients with 17p deletion, patients with mantle cell lymphoma who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.5

IMBRUVICA was one of the first medicines to receive U.S. 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 nearly 30 (n=27) company-sponsored trials underway, 14 of which are Phase 3. In addition, there are more than 40 (n=44) investigator-sponsored trials taking place around the world. To date, more than 65,000 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 postsurgery depending upon the type of surgery and the risk of bleeding.

Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.

Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients 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 (eg, 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 antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies – Other malignancies (range, 5% 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, 4% to 13%).

Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, 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.

ADVERSE REACTIONS

The most common adverse reactions (?20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia** (64%), thrombocytopenia** (63%), diarrhea (43%), anemia** (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia (21%).

**Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

The most common Grade 3 or 4 non-hematologic adverse reactions (?5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

Please see Full Prescribing Information: View Source

On December 4, 2016 Kite Pharma, Inc. (Nasdaq:KITE) reported that it has initiated the rolling submission with the U.S. Food and Drug Administration (FDA) of the Biologics License Application (BLA) for KTE-C19 as a treatment for patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant (ASCT) (Press release, Kite Pharma, DEC 4, 2016, View Source [SID1234516910]). The pivotal ZUMA-1 study supporting this submission enrolled patients with chemorefractory diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL), three subtypes of aggressive NHL. The company expects to complete its BLA submission by the end of the first quarter of 2017.

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"I am both proud and appreciative of the Kite team and our clinical investigators, who have helped to make this key milestone possible," said Arie Belldegrun, M.D., FACS, Chairman, President, and Chief Executive Officer of Kite. "This is an important first step toward Kite’s biggest goal – bringing to market a potentially life-saving treatment for patients suffering from aggressive NHL."

Kite also announced that the United States Adopted Name, or USAN, for KTE-C19 will be axicabtagene ciloleucel.

Axicabtagene ciloleucel (KTE-C19) received Breakthrough Therapy Designation (BTD) by the FDA in December 2015. If approved, Kite plans to commercially launch KTE-C19 in 2017. Kite is also planning a regulatory submission to the European Medicines Agency (EMA) for axicabtagene ciloleucel in 2017. Kite was granted access to Priority Medicines (PRIME) regulatory support in 2016 by the EMA for axicabtagene ciloleucel (KTE-C19) for the treatment of refractory DLBCL.

About axicabtagene ciloleucel

Kite Pharma’s lead product candidate, axicabtagene ciloleucel, is an investigational therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. Axicabtagene ciloleucel has been granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) by the U.S. Food and Drug Administration (FDA) and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.