Phase III study of efficacy and safety in polycythemia Vera subjects who are resistant or intolerant of hydroxyurea
- Conditions
- Polycythemia veraMedDRA version: 19.0Level: LLTClassification code 10036061Term: Polycythemia veraSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2010-020807-57-NL
- Lead Sponsor
- ovartis Pharma Services AG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 200
1. Subjects 18 years of age or older.
2. Subjects must be diagnosed with PV for at least 24 weeks prior to Screening according to the 2008 World Health Organization criteria (Table 2 in Tefferi and Vardiman, 2008; Appendix 1).
3. Subjects 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 five criteria (modified from Barosi et al, 2009A; Appendix 2):
• HU Resistance, defined after 12 weeks into a course of HU therapy at a dose of at least 2 grams/day OR at the subject’s maximally tolerated dose if that dose is less than 2 grams/day:
a.Need for phlebotomy to keep hematocrit < 45%, OR
b. Platelet count > 400 x 109/L AND white blood cell count > 10 x 109/L, OR
c. Failure to reduce splenomegaly extending greater than 10 cm below the costal margin by more than 50%, as measured by palpation.
•HU Intolerance:
a. Absolute neutrophil count < 1.0 x 109/L OR platelet count < 100 x 109/L OR hemoglobin < 100 g/L (i.e. 10 g/dL) at the lowest dose of HU required to achieve a response (with response modified from Barosi et al, 2009B: hematocrit < 45% without phlebotomy AND/OR all of the following three items: platelet count = 400 x 109/L, white blood cell count = 10 x 109/L, and non-palpable spleen), OR
b. 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
- CTCAE version 3.0 Grade 3-4, OR
- more than 1 week of CTCAE version 3.0 Grade 2, OR
- permanent discontinuation of HU, OR
- interruption of HU until toxicity resolved, OR
- hospitalization due to HU toxicity.
4. Subjects must have required
a. at least 2 phlebotomies within the 24 weeks prior to Screening, AND
b. at least one phlebotomy within the 16 weeks prior to Screening, AND
c. The most distant and the most recent phlebotomy within the 24 weeks prior to Screening must be at least 4 weeks apart
OR subjects will be considered to have met this criterion if they have required a phlebotomy within the 16 weeks prior to Screening AND they exhibit a hematocrit > 45% at Screening
5. Patients with splenomegaly, defined as
a. Spleen palpable below the costal margin, provided that MRI (or CT in applicable patients) spleen assessment during Screening confirms that the spleen is enlarged, defined with a volume of = 450 cm3, OR
b. Spleen non palpable below the costal margin due to body habitus (e.g., in obese subjects), provided that MRI (or CT in applicable patients) spleen assessment during Screening confirms that the spleen is enlarged, defined with a volume of = 450 cm3
6. Subjects with ANC = 1.5 x 109/L and PLT = 100 x 109/L at Screening.
7. Subjects with peripheral blood blast count of 0% at Screening
8. Subjects with an ECOG performance status of 0, 1 or 2 (Appendix 5) at Screening and Baseline.
9. Subjects on a therapeutic regimen for PV must have been on a stable dose and schedule for at least 2 weeks prior to Screening and no less than 4 weeks prior to randomization (Study Day 1).
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 150
Subjects eligible for this study must not meet any of the following criteria:
1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception (confirmed by a positive hCG laboratory test > 5 mIU/mL) and until the termination of gestation.
2. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method.
• Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide (Appendix 3).
• Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent.
• Reliable contraception should be maintained throughout the study and for 5-half lives of study drug after study treatment discontinuation.
• Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
• 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.
3. Subjects with inadequate liver or renal function at Screening as demonstrated by:
a. Encephalopathy Grade 2 or more as per Child-Pugh System. (Appendix 12)
b. Known hepatocellular disease (for example, hepatitis B or C, cirrhosis or other hepatocellular disease)
c. Direct bilirubin = 2 X upper limit of laboratory normal (ULN).
d. Alanine aminotransferase (ALT) > 2.5x ULN.
e. MDRD-eGFR < 30 mL/min/1.73m2 or on dialysis.
4. Subjects with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral INC424 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
5. Subjects with clinically significant bacterial, fungal, parasitic or viral infection which requires therapy:
• Subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
• Subjects with known active hepatitis A, B or C at Screening or with known HIV positivity.
6.Subjects with diagnosed primary immunodeficiency syndromes such as X-Linked Agammaglobulinemia and Common Variable Immune Deficiency
7. Subjects with an 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.
8. Subjects with clinically significant cardiac disease (NYHA Class III or IV; Appendix 6).
9. Subjec
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method