Health Condition 1: null- Polycythemia Vera
Conditions
Interventions
Intervention1: INC424/ ruxolitinib: Oral INC424, starting dose 10 mg bid (approximately 12 hours apart: morning and night), to be increased or decreased (5 mg steps) per standerdized dosing paradigm a
Sponsors
Novartis Healthcare Pvt Ltd
Eligibility
Inclusion criteria
Inclusion criteria: 1.Confirmed diagnosis of PV according to the revised World Health Organization (WHO) criteria 2. Non palpable spleen at screening and baseline 3. Hct requirement: a. A Hct between 40 and 45% inclusive within 14 days of Baseline, and: ? at least 2 phlebotomies within the 24 weeks prior to Screening, and ? the 2 phlebotomies are at least 4 weeks apart. Or, b. Hct > 45% and ? required at least one phlebotomy within the 16 weeks prior to Screening ? Must go through the Hct control period to achieve an Hct level between 40 and 45% inclusive within 14 days of Baseline. 4. Patients must have a treatment history for PV that meets the definition of resistance or intolerance to hydroxyurea (HU) by exhibiting at least one of the following criteria (with response modified from Barosi et al 2009a): ? HU Resistance: defined after 12 weeks into a course of HU therapy at a dose of at least 2 grams/day or at the patient?s maximally tolerated dose if that dose is less than 2 grams/day: 1. Need for phlebotomy to keep Hct 2. Platelet count > 400 x 109/L AND white blood cell count > 10 x 109/L, or ? HU Intolerance: 1. Absolute neutrophil count hemoglobin a response as defined below (modified from Barosi et al 2009b): ? Hct - platelet count = 400 x 109/L, - white blood cell count = 10 x 109/L, - and non-palpable spleen, or 2. Presence of leg ulcers or other unacceptable HU-related non-hematological toxicities (such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis or fever at any dose of HU), defined as: ? severe AE that significantly impacted daily activities (equivalent to CTCAE version 4.0 Grade 3-4), or ? more than 1 week of a moderate AE that impacted some daily activities (equivalent to CTCAE version 4.0 Grade 2), or ? permanent discontinuation of HU, or ? interruption of HU until toxicity resolved, or ? hospitalization due to HU toxicity. If the patient meets the definition for both resistance and intolerance, they will be considered resistant for stratification purposes. 5. ECOG performance status of less than or equal to 2 at Screening and Baseline.
Exclusion criteria
Exclusion criteria: Lab abnormalities 1. Inadequate liver or renal function at screening as demonstrated by: ? Hepatic encephalopathy Grade 2 or more, ? Hepatocellular disease (for example, hepatitis B or C, cirrhosis), ? Direct bilirubin = 2 ? Upper Limit Normal (ULN). Direct bilirubin should be measured if total bilirubin is greater than 2 ? ULN, ? Alanine aminotransferase (ALT) greater than 2.5 ? ULN, ? Modification of Diet in Renal Disease estimate glomerular filtration rate (MDRDeGFR) less than 30 mL/min/1.73m2 or on dialysis, 2. Platelet count less than 100 ?109/L or an Absolute Neutrophil Count (ANC) less than 1 ? 109/L at screening. 3. Peripheral blood blast count greater than 0% at screening. Concurrent diseases 4. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral ruxolitinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection). 5. Clinically significant bacterial, fungal, parasitic or viral infection which require therapy: ? For acute bacterial infections requiring antibiotic use, screening/enrollment should be delayed until the course of antibiotic therapy has been completed. ? Known active hepatitis A, B or C at Screening or with known HIV positivity. ? Diagnosed primary immunodeficiency syndromes such as X-Linked Agammaglobulinemia and Common Variable Immune Deficiency 6. Active malignancy over the previous 5 years except treated cervical intraepithelial neoplasia, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin, with no evidence for recurrence in the past 3 years. 7. Clinically significant cardiac disease (NYHA Class III or IV;), or thromboembolic event within the past 6 months. 8. History of progressive multifocal leukoencephalopathy (PML) 9. Patients with any concurrent condition that, in the Investigator?s opinion would jeopardize the safety of the patient or compliance with the protocol. Medication history 10. Receiving PEG-IFN-alpha-2a within 5 weeks of Screening or having a prior history of 32P therapy. 11. Being treated concurrently with a potent systemic inhibitor of CYP3A4 at the time of Screening (ketoconazole, clarithromycin, itraconazole, nefazodone or telithromycin,. 12. Being treated concurrently with any prohibited medications 13. Previously received treatment with a JAK inhibitor. 14. Being treated concurrently with any investigational agent or prior participation in an investigational study within 30 days prior to the first dose of study drug or within 5-halflives of the investigational product, whichever is longer. Ability to comply with protocol 15. Patients who are unable to comprehend or unwilling to sign an informed consent form (ICF) 16. Patients with active alcohol or drug addiction that would interfere with their ability to comply with the study requirements. Pregnancy and birth control 17. Sexually active males must use a condom during intercourse while taking the drug and for five half-lives after stopping treatment and should not father a child in this period. 18. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To compare the efficacy of ruxolitinib to BAT as assessed by Hct control at Week 28.Timepoint: Proportion of patients achieving Hct control at Week 28 as defined by: ? Hct less than 45% at Week 16 and maintained until Week 28, and ? No phlebotomy from Week 4 to Week 28, with no more than one phlebotomy occurring post randomization and prior to the Week 4 visit. | — |
Secondary
| Measure | Time frame |
|---|---|
| To compare the efficacy of ruxolitinib to BAT as assessed by peripheral blood count remission at Week 28.Timepoint: Proportion of patients achieving a peripheral blood count remission at Week 28 as defined by: ? Hct less than 45% at Week 16 and maintained until Week 28, and ? WBC less than 10 x109/L at Week 16 and maintained until Week 28, and ? Platelets less than or equal to 400 x 109/L at Week 16 and maintained until Week 28, and ? No phlebotomy from Week 4 to Week 28, with no more than one phlebotomy occurring post randomization and prior to the Week 4 visit.;To compare the efficacy of ruxolitinib to BAT as assessed by durable Hct control at Week 52Timepoint: Proportion of patients achieving a Hct control at Week 52 as defined by: ? Hct less than 45% at Week 16 and maintained until Week 52, and ? No phlebotomy from Week 4 to Week 28, with no more than one phlebotomy occurring post randomization and prior to the Week 4 visit, and ? In the BAT arm, no change in the treatment regimen or crossover to the ruxolitinib arm;To compare the efficacy of ruxolitinib to BAT as assessed by durable peripheral blood count remission at Week 52.Timepoint: Proportion of patients achieving a PBCR at Week 52 as defined by: ? Hct less than 45% at Week 16 & maintained until 52, & ? WBC less than 10 x109/L at Week 16 & maintained until 52, ? Platelets less than or equal to 400 x 109/L at Week 16 & maintained until 52, ? No phlebotomy from Week 4 to 52, with NMT one phlebotomy occurring post randomization & prior to the Week 4 visit, & ? In the BAT arm, no change in the treatment regimen or crossover to the ruxolitinib arm.;To assess change in ECOG statusTimepoint: Change in ECOG status from baseline to Week 28.;To assess change in spleen lengthTimepoint: Change from Baseline in spleen length at each scheduled visit;To compare the efficacy of ruxolitinib to BAT as assessed by partial remission based on the ELN and IWG-MRT criteria at Week 28.Timepoint: Prop | — |
Countries
Australia, Belgium, Canada, France, Germany, Hungary, India, Israel, Italy, Poland, Republic of Korea, Russian Federation, Spain, Switzerland, Turkey
Contacts
Public ContactDr Manish Mistry
Novartis India Ltd.
Outcome results
None listed