On June 15, 2015 CTI BioPharma reported findings from an investigator-sponsored Phase 2 trial in patients with either primary (de novo) acute myeloid leukemia (AML) or AML that has evolved from myelodysplastic syndrome (MDS) (Press release, CTI BioPharma, JUN 14, 2015, View Source;p=RssLanding&cat=news&id=2059047 [SID:1234505424]). Results showed the combination of tosedostat with low dose cytarabine/Ara-C (LDAC) resulted in an overall response rate (ORR) of 54 percent in elderly patients with AML – with 45 percent of patients achieving durable complete responses (CR). These final results were presented by Dr. Giuseppe Visani, Director of Hematology and Stem Cell Transplant Center at AORMN, Pesaro, Italy in a poster session (abstract #P564) during the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper), June 11-14, 2015 in Vienna, Austria.

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!

AML is the most common acute leukemia affecting adults, and its incidence increases with age. AML may develop from the progression of other diseases, such as MDS, which is a blood cancer that also affects the bone marrow and leads to a decrease in circulating red blood cells. Tosedostat is a potential first-in-class selective inhibitor of aminopeptidases, which are required by tumor cells to provide amino acids necessary for growth and tumor cell survival.

"Both the types and length of responses in this trial with tosedostat are very encouraging – particularly given the limited options and poor outcomes historically observed in elderly patients with acute myeloid leukemia, either de novo or secondary after myelodysplastic syndrome," said Dr. Visani. "Importantly, through this study we have also identified potential biomarkers that may help identify high-risk patients in which we are more likely to see these clinically meaningful results – the findings of which are quite compelling and warrant further study."

Findings Presented at EHA (Free EHA Whitepaper)
Final results presented at EHA (Free EHA Whitepaper) show that responding patients had a significant improvement in overall survival based on response rates compared to non-responding patients (p=0.018). In the intent-to-treat population (ITT), the ORR was 54 percent – with CR observed in 45 percent of patients (n=15/33). In the responding patients, the median time for achieving best response was 74 days (range: 22-145 days) and 55 percent (n=10/18) were still in remission after a median follow-up of 319 days. Safety analysis show that tosedostat in combination with LDAC was generally well tolerated. The primary adverse events observed were pneumonitis (12 percent), cardiac (6 percent), brain hemorrhage (3 percent), and asthenia (3 percent).

One of the secondary endpoints was to identify possible biomarkers associated with sensitivity and/or drug resistance. A gene expression profile (GEP) was performed on purified AML cells obtained from 29 patients. Analysis of these patient cells identified a molecular signature associated with clinical response (CR vs. no CR). Based on the differentially expressed genes (n=212), samples were divided according to either CR or no CR. Results showed that these differentially expressed genes were associated with relevant biological functions and pathways – including B-catenin (beta-catenin), TNFA-NFkB, ERB2, inflammatory response, and epithelial-mesenchimal transition – and showed that the achievement of a CR could be efficiently predicted by GEP.

"The results observed with tosedostat in acute myeloid leukemia add to a growing body of data showing the anti-tumor activity of this aminopeptidase inhibitor and the potential of using this approach to treat blood-related cancers," Alan K. Burnett, M.D., Global Lead for Myeloid Diseases at CTI BioPharma. "Based on the clinical data observed to date, we are advancing the development for tosedostat including the potential for a Phase 3 registrational study for primary acute myeloid leukemia or acute myeloid leukemia that evolves from myelodysplastic syndrome."

About the Study Design
The Phase 2 multicenter clinical trial was designed to assess tosedostat (orally once-daily) in combination with intermittent LDAC (twice daily) in 33 elderly patients (median age = 75 years) with either primary AML or secondary AML after MDS. Courses of LDAC were repeated every four weeks for up to eight cycles in the absence of disease progression or unacceptable toxicity. The primary objective was to exceed the upper limit of institutional expected CR rates (P0=10%, P1= 25%, α=0.05, 1-β=80%); secondary objectives include safety and toxicity, stable disease, overall survival, and progression-free survival as well as the identification of a possible biomarker associated with sensitivity and/or disease resistance through global gene expression profiling (GEP, Affymetrix Transciptome Array 2.0).

The poster for Abstract #P564 – "Tosedostat plus low dose cytarabine induces a high rate of responses that can be predicted by genetic profiling in AML: Final results of a Phase II multicenter study" – is available at www.ctibiopharma.com.

About Tosedostat
Tosedostat is an oral aminopeptidase inhibitor that has demonstrated anti-tumor responses in blood-related cancers and solid tumors in Phase 1-2 clinical trials. Tosedostat is currently being evaluated in multiple Phase 2 clinical trials for the treatment of patients with AML or high-risk MDS and are intended to inform the design of a Phase 3 registration study to support potential regulatory approval. Tosedostat is not approved or commercially available.

About Acute Myeloid Leukemia and Myelodysplastic Syndrome
AML is a cancer characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age.1 The symptoms of AML are caused by the replacement of normal bone marrow with leukemic cells, which causes a drop in red blood cells, platelets, and normal white blood cells, leading to infections and bleeding. AML progresses rapidly and is typically fatal within weeks or months if left untreated. In 2015, approximately 20,830 new cases of AML are expected to be diagnosed in the United States and an estimated 10,460 are expected to die from the disease.2 While AML may occur at any age, adults at least 60 years of age are more likely than younger people to develop the disease.2 Although a substantial proportion of younger individuals who develop AML can be cured, AML in the elderly typically responds poorly to standard therapy with few complete remissions.

AML may develop from the progression of other diseases, such as MDS. MDS are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells. MDS is often referred to as a "bone marrow failure disorder."

On June 13, 2015 Novartis reported long-term safety and efficacy results from the pivotal Phase III RESPONSE study evaluating Jakavi (ruxolitinib) for the treatment of patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea (Press release, Novartis, JUN 13, 2015, View Source [SID:1234505425]). A preplanned analysis of the study at 18 months demonstrated that 80% of patients with inadequately controlled PV treated with Jakavi experienced a durable response of sustaining hematocrit less than 45% without the use of phlebotomy and reducing spleen size, two key measures of disease control, for at least one year[1]. Findings were presented at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Vienna, Austria.

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!

"Polycythemia vera can lead to serious complications if inadequately controlled, and these data demonstrate the ability of Jakavi to provide a durable and comprehensive clinical benefit in this patient population," said lead study investigator Jean-Jacques Kiladjian, MD, PhD, Hôpital Saint-Louis et Université Paris Diderot. "There is currently a significant unmet need for patients with polycythemia vera who are unable to tolerate or control their disease on other treatments. For these patients, Jakavi represents a valuable new option as confirmed by results from the long-term Phase III study."

PV is a rare and incurable blood cancer associated with an overproduction of blood cells that can cause serious cardiovascular complications, such as blood clots, stroke and heart attack[3]. Approximately 25% of patients with PV develop resistance (inadequate response) to or intolerance (unacceptable side effects) of hydroxyurea and are considered to have inadequately controlled disease[2]. This is typically defined as hematocrit levels greater than 45%, elevated white blood cell count and/or platelet count, and may be accompanied by debilitating symptoms and/or an enlarged spleen[2],[4],[5].

In the Phase III study, 83% of patients with PV randomized to Jakavi were still receiving treatment at 18 months (median exposure of 111 weeks) compared to 0 patients on the best available treatment arm. Results also show that Jakavi-treated patients who achieved hematocrit control without phlebotomy had an 89% probability of maintaining their response for 18 months from the time of their initial response and all patients who had an initial spleen response maintained their reduction in spleen size. Of the patients on the Jakavi arm at week 32, 90% of patients did not have a phlebotomy between weeks 32 and 80. In addition, patients treated with Jakavi who achieved complete hematologic remission at week 32 had a 69% probability of maintaining their response for at least 18 months from the time of their initial response[1]. A separate analysis of the study at 18 months demonstrated treatment with Jakavi also led to sustained control of white blood cell and platelet levels, important PV hematologic parameters, with the largest reductions for patients with the most elevated values at baseline[6].

"Until the recent European Commission approval of Jakavi for the treatment of adult patients with polycythemia vera, there were limited alternative treatments available for these patients," said Bruno Strigini, President, Novartis Oncology. "These long-term data not only reinforce the robust evidence we have surrounding Jakavi in polycythemia vera, but also our commitment to bringing new and innovative therapies to people with blood cancers."

Overall, Jakavi was well tolerated. In the Jakavi-treatment arm, the rate for Grade 3 or 4 anemia and thrombocytopenia was 0.9 and 2.6 events per 100 patient-year exposure, respectively, and did not increase from the week 48 analysis. The most common non-hematologic adverse events (AEs) in the Jakavi arm were headache, diarrhea, pruritus and fatigue, which were mainly Grade 1 or 2. Treatment discontinuation due to AEs remained low in the Jakavi arm (4.5%)[1].

About the Pivotal Clinical Trial
RESPONSE is a global, randomized, open-label trial conducted at more than 90 trial sites. 222 patients with PV resistant to or intolerant of hydroxyurea were randomized 1:1 to receive either Jakavi (starting dose of 10 mg twice daily) or best available therapy, which was defined as investigator-selected monotherapy or observation only. The Jakavi dose was adjusted as needed throughout the trial. In the Jakavi arm, patients had a PV diagnosis for a median of 8.2 years and had previously received hydroxyurea for a median of approximately three years. Most patients (>80%) had received at least two phlebotomies in the last 24 weeks prior to screening. Patients were classified as intolerant or resistant to hydroxyurea based on the modified European LeukemiaNet (ELN) defined criteria[1].

The primary endpoint of the trial was the proportion of patients whose hematocrit was controlled without phlebotomy eligibility from week 8 through 32 (with no more than one phlebotomy eligibility between randomization and week 8) and whose spleen volume was reduced by 35% or more from baseline as assessed by imaging at week 32. Patients in the trial who were deemed to be eligible for phlebotomy had hematocrit that was greater than 45% and had increased three or more percentage points from the time they entered the trial (e.g., at baseline), or hematocrit greater than 48%. A second, preplanned analysis was performed at 80 weeks (18 months) evaluating durability of primary response, hematocrit control, spleen size reduction, complete hematologic remission and safety. Also at this 80 week data cutoff, a separate analysis evaluating hematologic parameters was assessed by baseline level[1].

About Polycythemia Vera
PV is a rare and incurable blood cancer associated with an overproduction of blood cells in the bone marrow that affects roughly one to three people per 100,000 globally[3],[7]. The disease is driven by the dysregulation of the JAK-STAT pathway[8]. It is typically characterized by elevated hematocrit, the volume percentage of red blood cells in whole blood, which can lead to a thickening of the blood and an increased risk of blood clots, as well as an elevated white blood cell and platelet count[3]. This can cause serious cardiovascular complications, such as stroke and heart attack, resulting in increased morbidity and mortality[9]. Additionally, patients with PV may have an enlarged spleen and symptoms that are frequent and burdensome, with an overall impact on quality of life similar to that seen with myelofibrosis[5],[10].

A common PV treatment includes phlebotomy, a procedure to remove blood from the body to reduce the concentration of red blood cells, which is used to help maintain a hematocrit level below 45%[3],[9]. However, phlebotomy is usually unsuitable as a permanent treatment option due to its inability to control symptoms or effectively manage the overproduction of red blood cells, therefore cytoreductive agents, such as hydroxyurea, may be added[9]. For patients requiring phlebotomy in combination with hydroxyurea, hematocrit may fluctuate and remain at unsafe levels for significant periods of time[11]. Unfortunately, approximately 25% of patients with PV become resistant to or intolerant of hydroxyurea treatment according to ELN criteria, resulting in inadequate disease control and an increased risk of progression[2].

About Jakavi
Jakavi (ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases. Jakavi is approved by the European Commission for the treatment of adult patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea and for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. Jakavi is approved in more than 80 countries for patients with myelofibrosis, including countries in the European Union, Canada, Japan and countries in Asia, Latin and South America. Additional worldwide regulatory filings are underway in myelofibrosis and PV.

Novartis licensed ruxolitinib from Incyte Corporation for development and commercialization outside the United States. Jakavi is marketed in the United States by Incyte Corporation as Jakafi for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea and for the treatment of patients with intermediate or high-risk myelofibrosis.

The recommended starting dose of Jakavi in PV is 10 mg given orally twice daily. The recommended starting dose of Jakavi in myelofibrosis is 15 mg twice daily for patients with a platelet count between 100,000 cubic millimeters (mm3) and 200,000 mm3, and 20 mg twice daily for patients with a platelet count of >200,000 mm3. Doses may be titrated based on safety and efficacy. There is limited information to recommend a starting dose for myelofibrosis and PV patients with platelet counts between 50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these patients is 5 mg twice daily, and patients should be titrated cautiously[12].

Jakavi is a registered trademark of Novartis AG in countries outside the United States. Jakafi is a registered trademark of Incyte Corporation. The safety and efficacy profile of Jakavi has not yet been established outside the approved indications.

Jakavi Important Safety Information for Treatment of Myelofibrosis (MF) and Polycythemia Vera (PV)
Jakavi can cause serious side effects, including a decrease in blood cell count and infections. Complete blood count monitoring is recommended. Dose reduction or interruption may be required in patients with any hepatic impairment or severe renal impairment or in patients developing hematologic adverse reactions such as thrombocytopenia, anemia and neutropenia. Dose reductions are also recommended when Jakavi is co-administered with strong CYP3A4 inhibitors or fluconazole. Use of Jakavi during pregnancy is not recommended, and women should avoid becoming pregnant during Jakavi therapy. Women taking Jakavi should not breast feed. Progressive multifocal leukoencephalopathy (PML) has been reported. Physicians should be alert for neuropsychiatric symptoms suggestive of PML. Hepatitis B viral load (HBV-DNA titer) increases have been reported in patients with chronic HBV infections. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines. Non-melanoma skin cancer (NMSC) has been reported in Jakavi treated patients. Periodic skin examination is recommended. Very common adverse reactions in MF (>10%) include urinary tract infections, anemia, thrombocytopenia, neutropenia, hypercholesterolemia, dizziness, headache, alanine aminotransferase increased, aspartate aminotransferase increased, bruising and weight gain. Common adverse reactions in MF (1 to 10%) include herpes zoster and flatulence. Uncommon adverse reactions in MF include tuberculosis. Very common adverse reactions in PV (>10%) include anemia, thrombocytopenia, hypercholesterolemia, hypertriglyceridemia, dizziness, alanine aminotransferase increased and aspartate aminotransferase increased. Common adverse reactions in PV (1 to 10%) include urinary tract infections, herpes zoster, weight gain, constipation and hypertension.