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) - ND

• Register: EUCTR
• Last refreshed on: 19 February 2018
• Main ID: EUCTR2010-020807-57-IT
• Date of registration: 24/12/2010
• Prospective Registration: Yes
• Primary sponsor: NOVARTIS FARMA
• Public 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) - ND
• 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) - ND
• Date of first enrolment: 28/04/2011
• Target sample size: 300
• 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: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: yes; Other specify the comparator: Migliore terapia disponibile individuata dallo s
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Germany, Hungary, Italy, Netherlands, Spain, United Kingdom

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 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 • 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 nonhematological 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? yes
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:
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. Subjects of childbearing potential who are unwilling to take appropriate precautions (from Screening through Follow-up) to avoid becoming pregnant or fathering a child. Females of non-childbearing potential are defined as women who (a) are = 55 years of age with history of amenorrhea for 1 year with serum FSH levels > 40 mIU/mL, OR (b) are surgically sterile for at least 12 weeks. For females of childbearing potential, or for males, appropriate precautions (at least
two birth control methods) are those that are at least 99% effective in preventing the occurrence of pregnancy. These methods should be communicated to the subjects and their understanding confirmed 3. Subjects with inadequate liver or renal function at Screening as demonstrated by:
a. Encephalopathy Grade 2 or more as per Child-Pugh System. 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) 9. Subjects receiving PEG-IFN-alpha-2a within 5 weeks of Screening or having a prior history of 32P therapy. 10. Subjects being treated concurrently with a potent systemic inhibitor of CYP3A4 at the time of Screening (ketoconazole, clarithromycin, itraconazole, nefazodone or telithromycin). 11. Subjects being treated concurrently with any prohibited medications 12. Subjects who have previously received treatment with a JAK inhibitor 13. Subjects being treated concurrently with any investigational agent or prior participation in an investigational study within 30 days prior to enrollment or within 5-half lives of the investigational product, whichever is longer. 14. Subjects who are unable to comprehend or are unwilling to sign an informed consent form (ICF) 15. Subjects with active alcohol or drug addiction that would interfere with their ability to comply with the study requirements 16. Subjects with an uncontrolled intercurrent illness or any concurrent condition that, in the investigator’s opinion, would jeopardize the safety of the subject or compliance with the protocol.


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

Health Condition(s) or Problem(s) studied

POlycythemia vera
MedDRA version: 9.1 Level: LLT Classification code 10036061

Intervention(s)

Product Name: INC424
Product Code: INC424
Pharmaceutical Form: Tablet
Current Sponsor code: INC424
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Trade Name: ONCOCARBIDE
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Hydroxycarbamide
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Primary Outcome(s)

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.

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. To determine the proportion of subjects achieving a durable spleen volume reduction. To estimate the proportion of subjects achieving a durable complete hematologic remission. To estimate the proportion of subjects achieving a durable phlebotomy independence. To estimate the duration of both the absence of phlebotomy eligibility and reduction in spleen volume. To determine the overall clinicohematologic response rate. To estimate the proportion of subjects achieving a durable complete or partial clinicohematologic response. To estimate the duration of the overall clinicohematologic response. To evaluate the safety of INC424 and Best Available Therapy.

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

Secondary ID(s)

2010-020807-57-BE

CINC424B2301