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Pacritinib Phase 3 Study Shows Positive Results In Patient Reported Outcomes Measuring Quality Of Life In Patients With Myelofibrosis

On June 12, 2015 CTI BioPharma and Baxter International reported new patient-reported outcome (PRO) data for pacritinib – an investigational oral multikinase inhibitor with specificity for JAK2 and FLT3 – from the Phase 3 PERSIST-1 study (Press release, CTI BioPharma, JUN 12, 2015, View Source;p=RssLanding&cat=news&id=2058786 [SID:1234505405]). As recently reported at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting, results show a significant reduction in the Total Symptom Score (TSS) (the proportion of patients with a 50 percent or greater reduction in TSS from baseline to Week 24), and in each individual common disease-related symptom, from baseline to Week 24, in patients treated with pacritinib compared to best available therapy (exclusive of a JAK inhibitor) (BAT). These PROs, as well as other quality of life measures, will be presented at the 20th Congress of European Hematology Association (EHA) (Free EHA Whitepaper) by Adam Mead, M.D., Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, London, United Kingdom in an oral presentation on Sunday, June 14, 2015 at 12:15 CEST (abstract #LB2072). These data were also selected for inclusion in the official EHA (Free EHA Whitepaper) Press Briefing which occurred today (Friday, June 12, 2015) at 08:30 CEST. As previously reported, the PERSIST-1 trial met its primary endpoint of spleen volume reduction of 35 percent or greater from baseline to Week 24 as measured by MRI/CT scan.

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Myelofibrosis is a rare blood cancer associated with significantly reduced quality of life and shortened survival. As the disease progresses, the body slows production of important blood cells and within one year of diagnosis the incidence of disease-related thrombocytopenia (very low blood platelet counts), severe anemia, and red blood cell transfusion requirements increases significantly. Among other complications, most patients with myelofibrosis present with enlarged spleens (splenomegaly), as well as many other potentially devastating physical symptoms such as abdominal discomfort, bone pain, feeling full after eating little, severe itching, night sweats, and extreme fatigue.

"Patient-reported outcomes are an important measure for understanding the potential benefit of a therapy on patients’ lives – particularly for a disease such as myelofibrosis where the symptoms have such a tremendous impact on the quality of patients’ daily lives," stated James A. Bianco, M.D., President and CEO of CTI BioPharma. "These new data from the PERSIST-1 study further support our belief, not only in the activity of pacritinib, but also the potential to positively impact patients’ daily lives by relieving the symptoms that accompany myelofibrosis."

"The PERSIST-1 trial has continued to generate positive and important findings for the hematology community," said David Meek, Head of Oncology at Baxter BioScience. "We look forward to advancing the clinical trial program of pacritinib as we work to realize the full potential of this investigational compound to help patients with serious blood cancers, such as myelofibrosis."

Study Details and Findings Presented at EHA (Free EHA Whitepaper)
PERSIST-1 is a randomized (2:1), controlled Phase 3 registration-directed trial comparing the efficacy and safety of pacritinib to BAT – which included a range of currently utilized off-label treatments – in 327 patients with myelofibrosis, regardless of the patients’ platelet counts. As previously reported at ASCO (Free ASCO Whitepaper), the trial met its primary endpoint of spleen volume reduction (35 percent or greater reduction from baseline to Week 24 by MRI/CT scan) in the intent-to-treat (ITT) population; these results included patients with severe or life-threatening thrombocytopenia. The study also measured patient-reported outcomes (PROs), the proportion of patients with a 50 percent or greater reduction in TSS from baseline to Week 24, which have become important for approval of new therapies and was one of the secondary endpoints of the study. As previously reported, patients treated with pacritinib experienced greater improvement in their disease-related symptoms (ITT patient population: 24.5 percent of pacritinib-treated patients vs 6.5 percent of BAT-treated patients, p<0.0001; evaluable patient population: 40.9 percent of pacritinib-treated patients vs 9.9 percent of BAT-treated patients, p<0.0001).

New data presented at EHA (Free EHA Whitepaper), which included results from multiple PROs measurement tools, showed:

Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS and MPN-SAF TSS 2.0)

When using the MPN-SAF TSS and MPN-SAF TSS 2.0, each of the six common disease-related symptoms from the TSS results showed improvements in abdominal discomfort (46 percent improvement with pacritinib vs no improvement with BAT); bone pain (32 percent improvement with pacritinib vs 8 percent improvement with BAT); feeling of early fullness (45 percent improvement with pacritinib vs 1 percent worsening with BAT); itching (48.5 percent improvement with pacritinib vs 10 percent improvement with BAT); night sweats (69.5 percent improvement with pacritinib vs no improvement with BAT); and fatigue (27.5 percent improvement with pacritinib vs 4 percent worsening with BAT). MPN-SAF TSS and MPN-SAF TSS 2.0 are specific sets of questions patients answer daily (via electronic diary) and which are based on a questionnaire originally developed by Ruben A. Mesa, M.D., Deputy Director of the Mayo Clinic Cancer Center in Scottsdale, Arizona, USA.

Patient Global Impression of Change (PGIC)
Based on the PGIC assessment – which measures a patient’s assessment of overall health on a 7-point scale ranging from "very much worse" to "very much improved" – approximately 80 percent of evaluable patients treated with pacritinib rated their condition as improved compared to approximately 20 percent with BAT.

European Organization for Research and Treatment of Cancer Quality-of-Life 30 Questionnaire (EORTC QLQ-C30)
A greater improvement was also reported by evaluable patients treated with pacritinib vs BAT across all components of the EORTC QLQ-C30 questionnaire, a well-validated measure of quality of life in cancer patients.

The most common adverse events occurring with pacritinib within 24 weeks, of any grade, were mild to moderate diarrhea (53.2 percent vs 12.3 percent with BAT), nausea (26.8 percent vs 6.6 percent with BAT), anemia (22.3 percent vs 19.8 percent with BAT), thrombocytopenia (16.8 percent vs 13.2 percent with BAT), and vomiting (15.9 percent vs 5.7 percent with BAT). Of the patients treated with pacritinib, 3 discontinued therapy and 13 patients required dose interruption (average one week) for diarrhea. Patients received a daily full dose of pacritinib over the duration of treatment. Gastrointestinal symptoms typically lasted for approximately one week and few patients discontinued treatment due to side effects. There were no Grade 4 gastrointestinal events reported.

About Pacritinib
Pacritinib is an investigational oral multikinase inhibitor with specificity for JAK2 and FLT3. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia, and lymphoma.

About Myelofibrosis
Myelofibrosis is a serious and life-threatening chronic blood cancer caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response and scars the bone marrow. The replacement of bone marrow with scar tissue limits its ability to produce red blood cells, prompting the spleen and liver to take over this function. Symptoms that arise from this disease include enlargement of the spleen, anemia, extreme fatigue, and pain. Myelofibrosis is a one of three main types of myeloproliferative neoplasms (MPN), which are a closely related group of hematological blood cancers.1 The estimated prevalence of MPNs suggest there are approximately 300,000 people living with the disease in the U.S. of which myelofibrosis accounts for approximately 18,000 patients.2 In Europe, there is a wide variation of prevalence observed across data sources. Myelofibrosis has a median age of 64 at the time of diagnosis2 and is a progressive disease with approximately 20 percent of patients eventually developing acute myeloid leukemia.3 The median survival for high-risk patients is less than one and a half years; median survival for myelofibrosis patients overall is approximately six years.4

About the PERSIST Phase 3 Development Program of Pacritinib
Pacritinib is currently being evaluated in two Phase 3 clinical trials, known as the PERSIST program, for patients with myelofibrosis. PERSIST-1 is a randomized (2:1), open-label, multinational Phase 3 clinical trial comparing the efficacy and safety of pacritinib with that of BAT, in 327 enrolled patients with primary and secondary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF), without exclusion for low platelet counts. PERSIST-2 is a randomized (2:1), open-label, multinational Phase 3 clinical trial evaluating pacritinib compared to BAT, including the approved JAK1/JAK2 inhibitor dosed according to product label for patients with myelofibrosis whose platelet counts are less than or equal to 100,000 per microliter. The trial is designed to enroll up to 300 patients in North America, Europe, Australia, New Zealand, and Russia.

Additional details are available at www.clinicaltrials.gov or www.PERSISTprogram.com.

CTI BioPharma and Baxter BioScience, which is expected to become Baxalta Incorporated in mid-2015, entered into a worldwide license agreement in November 2013 to develop and commercialize pacritinib. CTI BioPharma and Baxter will jointly commercialize pacritinib in the U.S. while Baxter has exclusive commercialization rights for all indications outside the U.S.

Agios Announces New Data from Ongoing Phase 1 Dose Escalation and Expansion Trial of AG-221 Showing Durable Clinical Activity in Patients with Advanced Hematologic Malignancies

On June 12, 2015 Agios Pharmaceuticals reported new data from the dose-escalation phase and expansion cohorts from the ongoing Phase 1 study evaluating single agent AG-221, a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-2 (IDH2), in advanced hematologic malignancies (Press release, Agios Pharmaceuticals, JUN 12, 2015, View Source;p=RssLanding&cat=news&id=2058805 [SID:1234505404]). The data will be presented at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place June 11-14, 2015 in Vienna.

Data as of May 1, 2015 from 177 patients (104 in dose escalation and 73 from the first four expansion cohorts) with advanced hematologic malignancies treated with single agent AG-221 showed durable clinical activity and a favorable safety profile. More than half of the 177 patients remain on treatment. The study had an overall response rate of 40 percent (63 of 158 response-evaluable patients, using the criteria below) and a complete remission rate of 16 percent (26 of 158 response-evaluable patients). Patients responding to AG-221 continue to show durable clinical activity on treatment for more than 15 months, with an estimated 76 percent of responders staying on treatment for six months or longer. The overall safety profile observed was consistent with previously reported data with more than 100 additional patients treated as of the last analysis.

This new data reflects responses in the evaluable population, which includes all patients with a pre-AG-221 screening assessment and day 28 or later response assessment or an earlier discontinuation for any reason. Patients with a screening assessment who were still on treatment, but had not reached the day 28 disease assessment, were excluded.

"The clinical profile of AG-221 continues to be impressive from the perspectives of response rate, durability, safety and unique mechanism of action," said Courtney DiNardo, M.D., lead investigator and assistant professor, leukemia at University of Texas MD Anderson Cancer Center. "Additionally, it is encouraging to see early proof-of-concept in myelodysplastic syndrome (MDS) and untreated acute myeloid leukemia (AML) given the need for more effective therapies for these patients."

"As the data from the AG-221 study continue to mature, we are compiling a robust dataset to quickly move this program into global registration studies later this year in collaboration with Celgene," said Chris Bowden, M.D., chief medical officer of Agios. "We are excited about the speed of enrollment we’ve seen to date in our four expansion cohorts and are on track to enroll our recently announced fifth expansion cohort of 125 patients with relapsed and/or refractory AML. With this progress, we are executing on our strategy to combine speed and breadth to reach people with hematologic malignancies in urgent need of better treatments."

About the Ongoing Phase 1 Trial for AG-221 in Advanced Hematologic Malignancies

AG-221 is currently being evaluated in an ongoing Phase 1 trial that includes a dose-escalation phase and four expansion cohorts of 25 patients each, evaluating patients with relapsed or refractory AML who are 60 years of age and older and transplant ineligible; relapsed or refractory AML patients under age 60; untreated AML patients who decline standard of care chemotherapy; and patients with other IDH2-mutant positive hematologic malignancies. Data reported here are from patients receiving AG-221 administered from 60 mg to 450 mg total daily doses in the dose escalation arm and 100 mg once daily in the first four expansion arms, as of May 1, 2015. The median age of these patients is 69 (ranging from 22-90). Treatment with AG-221 showed substantial reduction in the plasma levels of the oncometabolite 2-hydroxglutarate (2HG) to the level observed in healthy volunteers.

Safety Data

A safety analysis was conducted for all 177 treated patients as of May 1, 2015.

The majority of adverse events reported by investigators were mild to moderate, with the most common being nausea, fatigue, increased blood bilirubin and diarrhea.

The majority of serious adverse events (SAE) were disease related; SAEs possibly related to study drug were reported in 27 patients.
A maximum tolerated dose (MTD) has not been reached.
The all-cause 30-day mortality rate was 4.5 percent.

Efficacy Data

Sixty-three out of 158 response-evaluable patients achieved investigator-assessed objective responses for an overall response rate of 40 percent as of May 1, 2015.

Of the 63 patients who achieved an objective response, there were 26 (16 percent) complete remissions (CR), three CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), two CRs with incomplete hematologic recovery (CRi) and 18 partial remissions (PR).
Of the 111 patients with relapsed or refractory AML, 46 (41 percent) achieved an objective response, including 20 (18 percent) CRs, one CRp, 16 PRs, eight mCRs and one CRi.

Of the 22 patients with AML that had not been treated, seven achieved an objective response, including three CRs, two PRs, one mCR and one CRi.

Of the 14 patients with myelodysplastic syndrome (MDS), seven achieved an objective response, including two CRs, one CRp and four mCRs.

Responses were durable, with duration on study drug more than 15 months and ongoing. As of the analysis date, an estimated 88 percent of responses lasted three months or longer, and 76 percent of responses lasted six months or longer.

Upcoming Milestones for AG-221

Agios studies in IDH2-mutated solid and hematologic tumors are ongoing or planned for 2015 to further support development of AG-221.

Continue to enroll patients in the fifth expansion cohort of 125 patients with IDH2 mutant-positive AML who are in second or later relapse, refractory to second-line induction or re-induction treatment, or have relapsed after allogeneic transplantation.

Initiate combination trials to evaluate AG-221 as a potential frontline treatment for patients with AML and a broad range of hematologic malignancies in the second half of 2015.

Initiate a global Phase 3 registration-enabling study in relapsed/refractory AML patients that harbor an IDH2 mutation in the second half of 2015.

Continue dose escalation in the Phase 1/2 trial in patients with advanced solid tumors, including glioma and angioimmunoblastic T-cell lymphoma (AITL) that carry an IDH2 mutation in 2015.

Agios Announces New Data from Ongoing Phase 1 Trial of AG-120 Showing Durable Clinical Activity in Patients with Advanced Hematologic Malignancies

On June 12, 2015 Agios Pharmaceuticals reported new data from the ongoing Phase 1 study evaluating single agent AG-120, a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-1 (IDH1), in advanced hematologic malignancies presented at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place June 11-14, 2015 in Vienna (Press release, Agios Pharmaceuticals, JUN 12, 2015, View Source;p=RssLanding&cat=news&id=2058807 [SID:1234505403]).

Data as of May 1, 2015 from 57 patients with advanced hematologic malignancies showed durable clinical activity and a favorable safety profile, with 25 patients on study as of the analysis. The study had an overall response rate of 31 percent (16 of 52 response-evaluable patients) and a complete remission rate of 15 percent (8 of 52 response-evaluable patients). Data continue to show durable clinical activity for AG-120, with responding patients on treatment for up to 11 months, and an estimated 79 percent of responders on treatment at three months. The overall safety profile remains consistent with 40 additional patients treated as of the last analysis.

"The durable clinical activity observed with AG-120 in such a refractory patient population is impressive," said Stéphane de Botton, M.D., the principal investigator at the Institut de Cancérologie Gustave Roussy, Villejuif, France. "These findings provide additional evidence that AG-120 can inhibit the IDH1-mutant protein allowing for cancer cells to appropriately mature. AG-120 has the potential to improve outcomes in patients with IDH1 mutant cancers."

"These encouraging data represent the tremendous progress to date in our AG-120 program, as this therapy is proving to be well tolerated and effective, with an objective response rate of 31 percent of treated patients and duration on study up to 11 months," said Chris Bowden, M.D., chief medical officer of Agios. "Along with the insight gained from the AG-221 program, we are excited to move the AG-120 program forward rapidly with our partner Celgene. Our goal is to reach patients in need quickly, as evidenced by the recent announcement of our plans to initiate three expansion cohorts as part of the Phase 1 study."

About the Ongoing Phase 1 Trial for AG-120 in Advanced Hematologic Malignancies

AG-120 is being evaluated in an ongoing Phase 1 trial in patients with AML and other IDH1-mutant positive advanced hematologic malignancies. Data reported are from patients receiving AG-120 administered from 100 mg to 1,200 mg total daily doses as of May 1, 2015. The median age of these patients is 68 (ranging from 38-89). Treatment with AG-120 showed substantial reduction in the plasma levels of the oncometabolite 2-hydroxglutarate (2HG) to the level observed in healthy volunteers.

This new data reflects responses in the evaluable population, which includes all patients with a pre-AG-120 screening assessment and day 28 or later response assessment or an earlier discontinuation for any reason. Patients with a screening assessment who were still on treatment, but had not reached the day 28 disease assessment, were excluded.

Safety Data

A safety analysis was conducted for all 57 treated patients as of May 1, 2015.

The majority of adverse events reported by investigators were mild to moderate, with the most common being fatigue, diarrhea, pyrexia and nausea.

35 serious adverse events (SAEs) were reported, the majority being disease related, with four cases of leukocytosis potentially related to AG-120.

A maximum tolerated dose (MTD) has not been reached.

13 deaths were reported, and all were considered unrelated to AG-120.

Efficacy Data

Sixteen out of 52 response-evaluable patients achieved investigator-assessed objective responses for an overall response rate of 31 percent as of May 1, 2015.

Of the 16 patients who achieved an objective response, there were eight complete remissions (CR), one complete remission with incomplete platelet recovery (CRp), three marrow complete remissions (mCR) and four partial remissions (PR).

Responses were durable, with duration on study drug as long as 11 months and ongoing. As of the analysis date, an estimated 79 percent of responders were on treatment for three months or longer, and 50 percent of responders were on treatment for six months or longer.

Upcoming Milestones for AG-120

Agios studies in IDH1-mutated solid and hematological tumors are ongoing or planned for 2015/2016 to further support the speed and breadth of development of AG-120.

Initiate three expansion cohorts to evaluate AG-120 in 175 patients with IDH1-mutated advanced hematologic malignancies (125 in relapsed and/or refractory AML, 25 in untreated AML and 25 in basket IDH1-mutant positive cancers).

Present first data from the Phase 1 trial in advanced solid tumors at a medical conference in the second half of 2015.

Begin combination trials to evaluate AG-120 as a potential frontline treatment of IDH1-mutated AML and a broad range of hematologic malignancies in the second half of 2015.

Intend to initiate a global registration-enabling Phase 3 study in AML patients that harbor an IDH1 mutation in the first half of 2016.

Novartis data at EHA show increased PFS benefit of Farydak® in new subgroup of patients with previously treated multiple myeloma

On June 12, 2015 Novartis reported results from a pivotal Phase III clinical trial exploratory subgroup analysis showing a 7.8-month improvement in median progression-free survival (PFS) when using Farydak (panobinostat, previously known as LBH589) in combination with bortezomib* and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma who had received two or more prior regimens, including bortezomib and an immunomodulatory agent (IMiD)[1] (Press release, Novartis, JUN 12, 2015, View Source [SID:1234505401]). Findings are being presented in an oral session at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Vienna.

"I am encouraged by these results because they show that therapy with Farydak, in combination with bortezomib and dexamethasone, translates into a meaningful prolongation in progression-free survival (by 7.8 months) for multiple myeloma patients previously treated with IMiDs and bortezomib who received 2 or more prior regimens," said study investigator Jesús San Miguel, MD, Director of Clinical and Translational Medicine, Clínica Universidad de Navarra, Pamplona, Spain. "These data also provide physicians with a better understanding of the clinical use of Farydak, a histone deacetylase inhibitor, a promising new drug class for this difficult-to-treat patient population with a high unmet need."

These data are from a subgroup analysis of 147 patients with relapsed or relapsed and refractory multiple myeloma who had received two or more prior regimens, including bortezomib and an IMiD, in the Phase III, randomized, double-blind, placebo-controlled, multicenter global registration trial called PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA). This subgroup excluded patients who received only one prior regimen. The analysis showed that in this subgroup, median PFS increased to 12.5 months in the panobinostat-treatment arm compared to 4.7 months in the placebo plus bortezomib and dexamethasone arm (hazard ratio=0.47 [95% confidence interval (CI), 0.31-0.72]). Treatment with panobinostat in combination with bortezomib and dexamethasone when compared to the placebo arm also led to an increase in complete/near complete response rates (21.9% versus 8.1%) and overall response rate (58.9% versus 39.2%)[1].

Common grade 3/4 non-hematologic adverse events (AEs) in the panobinostat-treatment arm compared to the placebo arm for this subgroup included diarrhea (33.3% versus 15.1%), asthenia/fatigue (26.4% versus 13.7%) and peripheral neuropathy (16.7% versus 6.8%). The most common grade 3/4 hematologic laboratory abnormalities in the panobinostat-treatment arm compared to the placebo arm were thrombocytopenia (68.1% versus 44.4%), lymphopenia (48.6% versus 49.3%) and neutropenia (40.3% versus 16.4%). The percentage of on-treatment deaths in the panobinostat-treatment arm compared to the placebo arm in this subgroup was similar (6.9% versus 6.8%)[1].

"These findings, which follow the recent FDA approval of Farydak, provide clinicians with additional evidence on the value of this new treatment to help optimize the management of multiple myeloma," said Bruno Strigini, President, Novartis Oncology. "Multiple myeloma is often complicated because patients who stop responding or become resistant to therapies have limited treatment options. Therefore, these patients may benefit from therapies like Farydak."

Panobinostat, in combination with bortezomib and dexamethasone, was approved as Farydak by the US Food and Drug Administration (FDA) in February 2015 for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an IMiD[4]. This indication is approved under accelerated approval based on PFS reported in a separate analysis of 193 patients in the PANORAMA-1 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The FDA has approved a risk evaluation and mitigation strategy (REMS) for Farydak. The REMS program serves to inform and educate healthcare professionals about the risks that may be associated with Farydak treatment. Farydak is the first histone deacetylase (HDAC) inhibitor available to patients with multiple myeloma[5]. As an HDAC inhibitor, its epigenetic activity may help to restore cell function in multiple myeloma[6].

About PANORAMA-1 subgroup analysis
PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) is a Phase III, randomized, double-blind, placebo-controlled, multicenter global registration trial of 768 patients in 215 clinical trial sites evaluating panobinostat in combination with bortezomib and dexamethasone against placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. In the exploratory study presented at EHA (Free EHA Whitepaper), a subgroup of 147 patients with relapsed or relapsed and refractory multiple myeloma who received two or more prior regimens, including bortezomib and an IMiD, were analyzed for outcomes and safety. This subgroup excluded patients who received only one prior regimen[1].

The primary endpoint of the trial was PFS. Data on overall survival, the key secondary endpoint of the trial, are not yet mature. Other secondary endpoints include overall response rate, duration of response, and safety[1].

About multiple myeloma
Epigenetics is the cell programming that governs gene expression and cell development[5]. In multiple myeloma, the normal epigenetic process is disrupted (also called epigenetic dysregulation), resulting in the growth of cancerous plasma cells, potential resistance to current treatment, and ultimately disease progression[7],[8].

Multiple myeloma impacts approximately 1 to 5 in every 100,000 people globally[3]. Multiple myeloma is a cancer of the plasma cells, a kind of white blood cell present in bone marrow-the soft, blood-producing tissue that fills the center of most bones. The cancer is caused by the production and growth of abnormal cells within the plasma, which multiply and build up in the bone marrow, pushing out healthy cells and preventing them from functioning normally[9]. Multiple myeloma is an incurable disease with a high rate of relapse (when the cancer returns) and resistance (when the therapy stops working), despite currently available treatments[2]. It typically occurs in individuals 60 years of age or older, with few cases in individuals younger than 40[10].

Farydak Important Safety Information
Farydak can cause serious side effects, including diarrhea and heart problems.

Diarrhea is common with Farydak and can be severe. Patients should tell their healthcare provider (HCP) right away if they have abdominal (stomach) cramps, loose stool, diarrhea, or feel like they are becoming dehydrated. HCPs may prescribe medicines to help prevent or treat these side effects. Taking or using stool softeners or laxative medicines may worsen diarrhea, patients should talk to their HCP before taking or using these medicines.

Farydak can cause severe heart problems which can lead to death. Risk of heart problems may be increased with a condition called "long QT syndrome" or other heart problems. Patients should call their HCP and get emergency medical help right away if they have any of the following symptoms of heart problems: chest pain, faster or slower heart beat, palpitations (feel like heart is racing), feel lightheaded or faint, dizziness, blue colored lips, shortness of breath, or swelling in legs.

Farydak can cause severe bleeding which can lead to death. It may take patients longer than usual to stop bleeding while taking Farydak. Patients should tell their HCP right away if they get any of the following signs of bleeding: blood in stools or black stools (look like tar), pink or brown urine, unexpected bleeding or bleeding that is severe or that cannot be controlled, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, feeling dizzy or weak, confusion, change in speech, or headache that lasts a long time.

Farydak is a prescription medicine used, in combination with bortezomib and dexamethasone, to treat people with a type of cancer called multiple myeloma after at least two other types of treatment have been tried. It is not known if Farydak is safe and effective in children.

Patients should tell their HCP about all of the medicines they take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

Patients should take Farydak exactly as the HCP tells them to take it. The HCP will tell patients how much Farydak to take and when to take it. The HCP may change the dose or stop treatment temporarily if patients experience side effects. Patients should not change the dose or stop taking Farydak without first talking with their HCP.

Patients should avoid eating star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice while taking Farydak. These foods may affect the amount of Farydak in the blood.

Low blood cell counts are common with Farydak and can be severe. Low platelet count (thrombocytopenia) can cause unusual bleeding or bruising under the skin. Low white blood cell count (neutropenia) can cause infections. Low red blood cell count (anemia) may make a patient feel weak, tired, or they may get tired easily, look pale, or feel short of breath.

There is an increased risk of infection while taking Farydak. Patients should contact their HCP right away if they have a fever or have any signs of an infection including sweats or chills, cough, flu-like symptoms, shortness of breath, blood in phlegm, sores on body, warm or painful areas on body, or feeling very tired.

Patients should call their HCP right away with any of the following symptoms of liver problems: feel tired or weak, loss of appetite, dark amber colored urine, upper abdominal pain, yellowing of skin or the white of eyes.

The most common side effects of Farydak include tiredness, nausea, swelling in arms or legs, decreased appetite, fever and vomiting. Patients should tell their HCP if they have any side effect that is bothersome or that does not go away.

Please see full Prescribing Information, including Boxed WARNING, for Farydak (panobinostat) capsules, at
View Source

Farydak has been approved for use in the US and Chile; elsewhere, Farydak (LBH589) is an investigational agent and has not been approved by regulatory authorities.

Novartis drug Arzerra® improved median progression-free survival by 54% in patients with relapsed chronic lymphocytic leukemia

On June 12, 2015 Novartis reported data from the Phase III COMPLEMENT 2 study showing that treatment with Arzerra (ofatumumab) plus fludarabine and cyclophosphamide significantly improved median progression-free survival (PFS) by 54% compared to treatment with fludarabine and cyclophosphamide alone (28.9 months vs 18.8 months, respectively; p=0.0032) in patients with relapsed chronic lymphocytic leukemia (CLL) (Press release, Novartis, JUN 12, 2015, View Source [SID:1234505400]). Results are being presented at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Vienna.

"There are limited treatment options for patients who have stopped responding to current CLL treatments, which happens in many patients with this disease over time," said Tadeusz Robak, Professor of Hematology, Department of Hematology, Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland. "These data showed that the addition of ofatumumab to fludarabine and cyclophosphamide extended the amount of time before a patient’s CLL progressed, and further add to the body of evidence supporting the potential use of ofatumumab for these patients."

The most commonly diagnosed adult leukemia in Western countries, CLL accounts for approximately 1 in 4 cases of leukemia[1],[2]. Most CLL patients experience disease progression despite initial response to therapy and may require additional treatment[3].

In this clinical study, median PFS was improved by 54% in patients receiving Arzerra (ofatumumab) in combination with fludarabine and cyclophosphamide (n=183) compared to those receiving fludarabine and cyclophosphamide alone (28.9 months vs 18.8 months, respectively; HR 0.67 [95% CI: 0.51, 0.88]; p=0.0032). Additionally, patients receiving ofatumumab in combination with fludarabine and cyclophosphamide had a higher overall response rate (ORR) compared to those receiving fludarabine and cyclophosphamide alone (84% vs 68% of patients, respectively; p=0.0003), with a better complete response (CR) rate (27% vs 7% of patients, respectively), compared to those receiving fludarabine and cyclophosphamide alone (n=182). Median overall survival (OS) was 56.4 months for patients receiving ofatumumab in combination compared to 45.8 months for patients receiving fludarabine and cyclophosphamide alone (HR 0.78 [95% CI: 0.56, 1.09]; p=0.1410). The safety profile observed in this trial was consistent with other trials of ofatumumab and no new safety signals were observed. The most common AEs (>=5%) reported were neutropenia, thrombocytopenia, anemia, nausea, leukopenia, vomiting, pyrexia, rash, fatigue, and pneumonia.

"The results from the COMPLEMENT 2 study validate the benefit of Arzerra treatment in combination with fludarabine and cyclophosphamide in certain patients with CLL," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "We look forward to sharing the data with regulatory authorities."

About COMPLEMENT 2
COMPLEMENT 2 (NCT00824265) is an open-label, two-arm, randomized, Phase III study, which included 365 patients with relapsed CLL in 18 countries. Patients in the study were randomized 1:1 to receive treatment with up to six cycles of Arzerra (ofatumumab) in combination with fludarabine and cyclophosphamide or up to six cycles with fludarabine and cyclophosphamide alone.

The primary endpoint of the study was PFS as assessed by an Independent Review Committee (IRC) according to the International Workshop for Chronic Lymphocytic Leukaemia (iwCLL) updated 2008 National Cancer Institute-sponsored Working Group (NCIWG) guidelines[4]. Secondary endpoints included ORR, CR, OS, patient reported outcomes, time to response, duration of response (DoR), time to progression, time to next therapy (TTNT), safety assessments, and quality of life.

Results from additional secondary endpoints showed that DoR was 29.6 months vs 24.9 months, respectively (HR 0.77 [95% CI: 0.56, 1.05]; p=0.0878) for the patients receiving ofatumumab in combination compared to those receiving fludarabine and cyclophosphamide alone. Time to progression was 42.1 months in those receiving ofatumumab in combination compared to 26.8 months in those receiving fludarabine and cyclophosphamide alone (HR 0.63 [95% CI: 0.45, 0.87]; p=0.0036).

More patients receiving ofatumumab in combination (74%) experienced grade 3 or greater adverse events (AEs) compared to those receiving fludarabine and cyclophosphamide alone (69%). A higher incidence of Grade >=3 neutropenia was observed in patients receiving ofatumumab with fludarabine and cyclophosphamide compared with those receiving fludarabine and cyclophosphamide alone (53% vs 39%, respectively) but a substantially higher rate of infection was not reported. Grade 3/4 infusion-related reactions (IRRs) were reported in 4% of patients receiving ofatumumab in combination with fludarabine and cyclophosphamide. IRRs led to discontinuation of study treatment in <1% of patients receiving ofatumumab in combination with fludarabine and cyclophosphamide. No fatal IRRs were reported.

Arzerra is not approved in combination with fludarabine and cyclophosphamide for relapsed CLL. Novartis will further analyze data from the COMPLEMENT 2 study and plans to share the results with regulatory agencies to evaluate the potential for future regulatory filings.

About Arzerra
Arzerra (ofatumumab) is a human monoclonal antibody that is designed to target the CD20 molecule found on the surface of chronic lymphocytic leukemia (CLL) cells and normal B lymphocytes.

In the United States, Arzerra is approved for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate. In the European Union, Arzerra is approved for use in combination with chlorambucil or bendamustine for the treatment of patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based therapy. Arzerra is also approved for first-line use in Russia, Iceland, Norway, Luxembourg and Brazil.

In more than 50 countries worldwide, Arzerra is also indicated as monotherapy for the treatment of patients with CLL who are refractory after prior treatment with fludarabine and alemtuzumab.

Arzerra is marketed under a co-development and collaboration agreement between Genmab and Novartis, as successor in interest to GSK.

Important Safety Information for Arzerra (ofatumumab)
Treatment with Arzerra may cause side effects, some of which are serious and life-threatening.

Treatment with Arzerra may cause a side effect called an infusion reaction, which may be serious. Before treatment with Arzerra, doctors will prescribe 3 types of medicine to their patients to help reduce the risk of an infusion reaction, including a steroid (to reduce swelling and other symptoms of inflammation), a pain reliever, and an antihistamine (to reduce allergic reactions). Even though patients receive these medicines, they may still have an infusion reaction. If an infusion reaction occurs, the doctor will stop their patient’s treatment with Arzerra so the infusion reaction can be treated. Patients should tell their doctor or seek medical treatment right away if they have any of these symptoms while receiving Arzerra or within 24 hours after receiving Arzerra: fever, chills, rash, hives, chest pain, back pain, stomach pain, swelling, dizziness, blurred vision, drowsiness, headache, cough, wheezing, or trouble breathing.

Treatment with Arzerra may cause hepatitis B virus (HBV) infection to reoccur, which may cause serious liver problems and death. Patients who are newly exposed to HBV during or following treatment with Arzerra may experience serious liver problems and death. Patients should tell their doctor if they have had HBV infection or are a carrier of HBV. Before starting Arzerra, doctors will do a blood test to check for HBV infection. In some patients, additional blood tests may be done during and several months after treatment. Patients should call their doctor right away if they feel more tired than usual or notice a yellowing of the skin or eyes. These may be symptoms of hepatitis.

Progressive multifocal leukoencephalopathy (PML) is a rare brain infection that can occur with treatment with Arzerra. PML causes severe disability and can lead to death. Patients should call their doctor right away if they notice new medical problems or problems that are getting worse, such as confusion, dizziness or loss of balance, difficulty talking or walking, or strength, vision or other problems that have lasted over several days.

Tumor lysis syndrome (TLS), including the need for a hospital stay, can occur with treatment with Arzerra. TLS is caused by the fast breakdown of cancer cells, which then release their contents into the blood. This may lead to serious problems, including kidney failure or an abnormal heartbeat. Doctors may do a blood test to check their patients for TLS and may give medicines before starting treatment with Arzerra to help prevent TLS.

Arzerra can cause low blood cell counts (white blood cells, platelets, and red blood cells). These low blood cell counts can be severe and, in some cases, lead to death. Low white blood cells counts (neutropenia), can happen during treatment. Neutropenia can occur 42 days or longer after the end of treatment with Arzerra and may also last between 24 and 42 days after the last treatment dose. Doctors should regularly check their patient’s blood to see if they have low blood cell counts. Patients should call their doctor right away if they have any bleeding, bruising, red or purple spots on their skin, paleness, worsening weakness, tiredness, cough that will not go away, fever, chills, congestion, or any flu-like symptoms while receiving Arzerra.

After a patient receives Arzerra, they should not receive live vaccines until the doctor who prescribed Arzerra has told them that they may do so.

The most common side effects with Arzerra include infusion reactions, feeling tired, low white blood cell count, shortness of breath, pneumonia, rash, fever, nausea, cough, bronchitis, diarrhea, upper respiratory tract infection, and low red blood cell count.

Treatment with Arzerra can increase patients’ chances for getting infections. Some infections, such as pneumonia, bronchitis, and sepsis (a blood infection), can be serious, and in some cases, life-threatening. Patients should call their doctor right away if they have a cough that will not go away, fever, chills, congestion, or any flu-like symptoms while receiving Arzerra. These symptoms may be signs of a serious infection.