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

• Register: EUCTR
• Last refreshed on: 26 February 2018
• Main ID: EUCTR2010-020807-57-BE
• Date of registration: 08/12/2010
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: Phase III study of efficacy and safety in Polycythemia Vera subjects who are restistant 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: 08/02/2011
• 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): Therapeutic exploratory (Phase II): Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV):

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: Clinical Trial Information Desk
• Affiliation: Novartis Pharma AG

• Name: Clinical Trial Information Desk
• Affiliation: Novartis Pharma AG

Key inclusion & exclusion criteria

Inclusion criteria:
Subjects eligible for inclusion in this study have to meet all of the following 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 at least 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 (defined as CTCAE version 3.0 Grade 3-4 or more than 1-week of CTCAE version 3.0 Grade 2) HU-related non-hematological toxicities, such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis or fever at any dose of HU.
4. Subjects must have required at least 2 phlebotomies, each due to inadequate hematocrit control, in the 24 weeks prior to Screening AND at least 1 phlebotomy due to inadequate hematocrit control in the 12 weeks prior to Screening, with the interval between the two most recent phlebotomies being <= 13 weeks. OR subjects will be considered to have met this criterion if they have required a phlebotomy due to inadequate hematocrit control within the 13 weeks prior to Screening AND they exhibit a hematocrit > 45% at Screening
5. Palpable spleen measuring 5 cm or greater from the costal margin to the point of greatest splenic protrusion
6. Subjects must have at least one of the following at Screening:
a. WBC > 15 x 109/L.
b. PLT > 600 x 109/L.
7. Subjects with ANC >= 1.5 x 109/L at Screening.
8. Subjects with peripheral blood blast count of 0% at Screening.
9. Subjects with an ECOG performance status of 0, 1 or 2 (Appendix 5) at Screening and Baseline.
10. 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 80
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 220

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.
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• 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 w

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

Health Condition(s) or Problem(s) studied

Polycythemia vera
MedDRA version: 19.1 Level: LLT Classification code 10036061 Term: Polycythemia vera System Organ Class: 100000004864

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

Intervention(s)

Trade Name: Jakavi
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.

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 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

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)

CINC424B2301

Source(s) of Monetary Support

Novartis Pharma Services AG