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.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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 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.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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 Nordic Nanovector ASA (OSE: NANO) reported the updated results from its ongoing Lymrit 37-01 Phase 1/2 clinical trial of Betalutin (177Lu-satetraxetan-lilotomab) in subjects with relapsed non-Hodgkin lymphoma (NHL) at the 58th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) meeting (San Diego, CA, USA) (Press release, Nordic Nanovector, DEC 4, 2016, View Source [SID1234516900]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The updated data confirm Betalutin’s promising efficacy and favourable safety profile as a single agent in 38 relapsed NHL patients, having failed multiple prior regimens and being eligible for assessments. The results, based on the data cut-off date of 31 October 2016, were presented by the study’s Principal Investigator Dr. Arne Kolstad from the Department of Oncology at the Oslo University Hospital, Radiumhospitalet.

Key conclusions:

• In the 35 patients evaluable for efficacy, the Overall Response Rate (ORR) was 63%, with 29% Complete Responses (CR)

• The 21 evaluable patients in the study who received Betalutin at the dose of 15 MBq/kg with 40 mg/m2 lilotomab pre-dosing had an ORR of 62% and a CR of 38%; of these, the 16 patients enrolled in the Phase 2 expansion of Arm 1, had an ORR of 69% and a CR of 38%

• Durable responses have been observed with a median duration of response of 20.7 months for all patients in Arm 1

• Betalutin is well tolerated, with a predictable and manageable safety profile: most adverse events are haematological in nature, and all have been transient and reversible

• No dose-limiting toxicity (DLT) was reported in Arm 4 (15 MBq/kg Betalutin plus 100 mg/m2 lilotomab pre-dosing) and this regimen demonstrated lower bone marrow toxicity than Arm 1, 2 and 3. Arm 4 is now enrolling patients to evaluate the higher dosing regimen of 20 MBq/kg Betalutin plus 100 mg/m2 lilotomab.

The Lymrit 37-01 study is a Phase 1/2 open label, dose escalation study investigating the optimal lilotomab pre-dosing and Betalutin regimen in patients with relapsed NHL. Data from 38 patients are presented.

Dr. Arne Kolstad, MD commented: "The results we are presenting today are very encouraging and continue to highlight the potential of Betalutin to provide a new treatment option for NHL patients. These patients, particularly those who fail standard CD20-targeted immunotherapy and/or are too frail to receive chemotherapy, are desperately in need of alternative therapies that work through different and complementary mechanisms and are well tolerated. Betalutin is showing exciting promise in an increasing number of NHL patients and we look forward to the results from future studies that will hopefully confirm its attractive profile."

Dr. Lisa Rojkjaer, MD Nordic Nanovector’s Chief Medical Officer, commented: "These new data confirm the promising results for Betalutin, including durable responses in a number of patients, which were presented earlier this year at the AACR (Free AACR Whitepaper) meeting, and continue to demonstrate an encouraging clinical profile as a single agent for treating patients with relapsed NHL. The results also support escalating to a higher dosing regimen in the final stages of this Phase 1/2 study that will allow us to decide an optimal dosing regimen for the pivotal Phase 2 study, PARADIGME, expected in Q1 2017."

The poster (abstract 1780) is available at: View Source

On December 4, 2016 Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, reported that it will present initial clinical data from a Phase 1a/1b clinical trial evaluating the safety and preliminary anti-tumor activity of the selective HDAC6 inhibitor citarinostat (ACY-241), in combination with pomalidomide (Pom) (Pomalyst, Celgene) and dexamethasone (Dex) for the treatment of relapsed or relapsed-and-refractory multiple myeloma (RRMM) at the 58th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego, California (Press release, Acetylon, DEC 4, 2016, View Source [SID1234516901]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Early results of this study with citarinostat closely parallel recently published positive data for the Phase 2 trial of Acetylon’s first selective HDAC6 inhibitor ricolinostat in combination with Pom and Dex in multiple myeloma, and compare favorably to historical controls. In early follow-up data for Celgene’s MM-003 trial of Pom/Dex versus high dose Dex, there was a 17% overall response rate at 4.2 months. At a 4-month median follow up with citarinostat in combination with the same Pom/Dex regimen, we are seeing an impressive overall response rate of 46% as well as substantial improvement in progression free survival standing at 6.5 versus historical 4 months," said Robert Markelewicz, Senior Medical Director at Acetylon. "While these are still interim data, we are seeing that citarinostat combines favorably with Pom and Dex, and we will continue cohort expansion to explore selected biomarkers and confirm the dose and schedule for a planned pivotal trial."

Citarinostat (ACY-241) is an orally available selective HDAC6 inhibitor that is structurally similar to ricolinostat (ACY-1215), and administered in tablet form. The ACE-MM-200 study is a Phase 1a/1b clinical trial to determine the maximum tolerated dose, safety, and preliminary anti-tumor activity of citarinostat alone and in combination with pomalidomide and dexamethasone in patients with relapsed or relapsed-and-refractory multiple myeloma. Its sequential monotherapy/combination trial design allows patients access to combination therapy based on an established regimen starting in the second cycle of treatment, while establishing the safety, pharmacokinetics, and pharmacodynamics of citarinostat as both a monotherapy and in combination.

Initial results of the study suggest that citarinostat is well tolerated, with no maximum tolerated dose (MTD) observed at doses up to 480 mg once-a-day as a monotherapy and up to 360 mg once-a-day in combination with Pom/Dex. Tolerability in combination is similar to that reported for Pom/Dex alone. In 56 efficacy evaluable patients with a 4-month median follow-up, the confirmed overall response rate (ORR) was 46%, with a clinical benefit rate (CBR) of 59% and disease control rate (DCR) of 91%. The median duration of response (DOR) was 9.2 months and median progression-free survival (PFS) was 6.5 months. Notably, similar response rates were seen across the refractory subsets, including patients who were previously refractory to pomalidomide and daratumumab. A dose of 360 mg once-a-day was selected as the recommended Phase 2 dose for citarinostat based on similarly low incremental toxicity, higher PK/PD exposure, and similar clinical efficacy when compared to the 180 mg dose.

Details of the presentation are as follows:

Date: Sunday, December 4, 2016

Time: 6:00pm – 8:00pm PST

Location: Hall GH (San Diego Convention Center)

Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II

Abstract Number: 3307

Title: Selective HDAC6 Inhibitor ACY-241, an Oral Tablet, Combined with Pomalidomide and Dexamethasone: Safety and Efficacy of Escalation and Expansion Cohorts in Patients with Relapsed or Relapsed-and-Refractory Multiple Myeloma (ACE-MM-200 Study)

About HDAC6 Selective Inhibition

Citarinostat (ACY-241) and ricolinostat (ACY-1215) selectively inhibit the intracellular enzyme HDAC6, leading to an accumulation of excess protein and disrupting critical proliferative signals in malignant cells. Disruption of these molecular processes in cancer cells triggers programmed cell death, called "apoptosis," with little or no effect on normal cells. HDAC6 inhibition also enhances immune responses to cancer cells, both singly and in synergistic combination with immunomodulatory drugs (IMiDs), immune checkpoint inhibitor antibodies, and/or cytotoxic antibodies. Currently available HDAC drugs non-selectively affect the expression of numerous other genes in normal cells as well as cancer cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage, and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDAC6 is anticipated to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and to enable the development of optimized treatment regimens, including maximally effective combination drug therapies.

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).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"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.