Phase III study of efficacy and safety in Polycythemia Vera subjects who are resistant or intolerant of hydroxyurea.

• Register: EUCTR
• Last refreshed on: 15 October 2018
• Main ID: EUCTR2010-020807-57-DE
• Date of registration: 10/12/2010
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: Phase III study of efficacy and safety in Polycythemia Vera subjects who are resistant or intolerant of hydroxyurea.
• Scientific title: Randomized, open label, multicenter phase III study of Efficacy and Safety in Polycythemia vera subjects who are resistant to or intolerant of hydroxyurea: JAK iNhibitor INC424 tablets verSus bEst available care (The RESPONSE Trial)
• Date of first enrolment: 10/03/2011
• Target sample size: 200
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-020807-57
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: yes; Other trial design description: Designed to compare the efficacy and safety of INC424 to Best Available Therapy (BAT) in PV subjects; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: yes; Other specify the comparator: Best available therapy as selected by Investigator; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Belgium, Canada, China, France, Germany, Hungary, Italy, Japan, Korea, Republic of, Netherlands, Russian Federation, Spain, Thailand, Turkey, United Kingdom

Contacts

• Name: Medizinischer Infoservice
• Affiliation: Novartis Pharma GmbH

• Name: Medizinischer Infoservice
• Affiliation: Novartis Pharma GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
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
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
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. Subject

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Polycythemia vera
MedDRA version: 18.1 Level: LLT Classification code 10036061 Term: Polycythemia vera System Organ Class: 100000004864

Intervention(s)

Product Name: Ruxolitinib
Product Code: INC424
Pharmaceutical Form: Tablet
INN or Proposed INN: Ruxolitinib
CAS Number: 1092939-17-7
Current Sponsor code: INC424
Other descriptive name: INCB018424
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Primary Outcome(s)

Main Objective: To compare the efficacy of INC424 to Best Available Therapy (BAT) as assessed by both the absence of phlebotomy eligibility and reduction in spleen volume.

Secondary Objective: • To compare the proportion of subjects randomized to INC424 vs Best Available Therapy achieving both durable absence of phlebotomy eligibility and durable spleen volume reduction
• To compare the proportion of subjects randomized to INC424 vs Best Available Therapy achieving complete hematologic remission

Primary end point(s): Proportion of subjects achieving a response at Week 32, with response defined as having achieved both of the following:

• The absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32, with no more than one phlebotomy eligibility occurring post-randomization and prior to the Week 8 visit;
• A reduction in spleen volume as assessed by Imaging (see Section 6.2.1) = 35% from baseline at Week 32.

Timepoint(s) of evaluation of this end point: refer to protocol section 9.4

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: refer to protocol section 9.5

Secondary end point(s): Key secondary:
Proportion of all randomized subjects who achieve the primary endpoint and who remain free from progression 48 weeks after randomization.

Response Start
Start of response is the date when a = 35% reduction from baseline in spleen volume as assessed by Imaging (see Section 6.2.1) was first documented, providing that response was ongoing at the time of the Week 32 spleen volume assessment.

Progression (end of response)
The end of response is defined as the first occurrence of either one of the following:
1. The first of two consecutive hematocrit assessments that confirms phlebotomy eligibility;
2. A spleen volume assessment by Imaging (see Section 6.2.1) that is reduced by < 35% from the baseline AND that is = 25% increased relative to the volume determined at the time of the best documented spleen volume response;
3. Death due to any cause;
4. Development of MF as evidenced by bone marrow biopsy;
5. Development of acute leukemia, as evidenced by bone marrow blast counts of at least 20%, or peripheral blast counts of at least 20% lasting at least 2 weeks.

Secondary ID(s)

2010-020807-57-BE

CINC424B2301

Source(s) of Monetary Support

Novartis Pharma Services AG