A Phase Ib, open-label, dose-finding study of the JAK inhibitor INC424 tablets administered orally to patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera-Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia-Myelofibrosis (PET-MF) and baseline platelet counts = 50 x109/L and <100 x109/

• Conditions: Primary Myelofibrosis (PMF), Post-Polycythemia Vera-Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia-Myelofibrosis (PET-MF); MedDRA version: 14.0Level: PTClassification code 10028537Term: MyelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

• Registration Number: EUCTR2010-023055-29-AT
• Lead Sponsor: ovartis Pharma Services AG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2011-02-23
• Last Update Posted: 17 July 2012

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 62

Inclusion Criteria

1. Patients 18 years of age or older
2. Patients must be diagnosed with PMF, PPV-MF or PET-MF irrespective of JAK2
mutation status, guided by the criteria outlined in the 2008 World Health Organization (WHO) criteria for PMF (Table 2 in Tefferi and Vardiman, 2008, Appendix 1a), and the proposed criteria for PPV-MF and PET-MF outlined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) (Table 1 in Barosi et al, 2008, Appendix 1b).
3. Patients with myelofibrosis requiring therapy must be classified as high risk (3 or more prognostic factors) OR intermediate risk level 2 (2 or more prognostic factors) OR intermediate risk level 1 (1 or more prognostic factors). The prognostic factors, defined by the International Working Group (Cervantes et al, 2009) are:
• age > 65 yrs
• presence of constitutional symptoms (weight loss > 10% of the baseline value in the year preceding MF diagnosis, unexplained fever, or excessive night sweats persisting for more than 1 month)
• marked anemia (Hgb < 10g/dL)*
• leukocytosis (history of WBC > 25 x109/L)
• circulating blasts >= 1%
* A hemoglobin value < 10 g/dL must be demonstrated during the Screening for patients who are not transfusion dependent. Patients receiving regular transfusions of packed red blood cells will be considered to have hemoglobin < 10 g/dL for the purpose of evaluation of risk factors
1. Patients must have palpable spleen of at least 5 cm from the costal margin to the point of greatest splenic protrusion
2. Patients must have active symptoms of MF as demonstrated by one symptom score of at least 5 (0-10 point scale) or two symptom scores of at least 3 (0 to 10 point scale) on the Screening Symptom Form, SSF (Appendix 2)
3. Patients must fulfill all the following criteria both at Screening and at Study Day 1:
• PLT counts < 100 x 109/L and >= 75 x 109/L for the first stratum of the trial or PLT
counts < 75 x 109/L and >= 50 x 109/L for the second stratum
• coagulation parameters as follows: INR and PTT < 1.2 x ULN, fibrinogen > 0.8 x
ULN and D-dimer or fibrinogen degradation products (FDP) within normal limits
NOTE: If at the planned day of study treatment initiation the PLT counts are outside
the permitted range, for the respective stratum, then an additional PLT count
assessment will be conducted in <= 7 days. The treatment will be started only if the
PLT value of the additional assessment is within the permitted range for the respective stratum. The day at which the treatment will eventually start will be defined as the Study Day 1 (see also Section 6.1.1)
4. Patients with ANC >= 1.5 x 109/L at Screening
5. Patients with peripheral blood blast count of < 5% at Screening
6. Patients with an ECOG performance status of 0, 1, or 2 at Screening (Appendix 11)
7. Patients must have discontinued all drugs used to treat underlying MF disease no later than 30 days or 5 half-lives (whichever is longer) prior to Screening visit
8. Patients who have not previously received treatment with a JAK inhibitor
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

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. Patients 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 patients and their understanding confirmed (Appendix III)
3. Patients undergoing treatment with hematopoietic growth factor receptor agonists (i.e. erythropoietin (EPO), granulocyte colony stimulating factor (GCSF), romiplostim, eltrombopag) for at least 30 days prior to receiving the first dose of study drug
4. Patients with any history of PLT counts < 45 x 109/L within 30 days prior to Screening, except during treatment for a myeloproliferative neoplasm or treatment with cytotoxic therapy for any other reason. Patients who have received PLT transfusion within 30 days prior to Screening.
5. Any history or predisposition to clinically significant bleeding
6. Any history of platelet dysfunction and/or coagulopathy
7. Any use of drugs that interferes with coagulation or inhibits PLT function (Appendix IV)
8. Patients with inadequate liver or renal function as demonstrated by:
• encephalopathy grade 1 or more, as per West Haven Criteria (Appendix V)
• known hepatocellular disease (e.g. active hepatitis or cirrhosis)
• direct bilirubin >= 0.5 mg/dL
• alanine aminotransferase (ALT) > 2.5 x ULN
• MDRD-eGFR < 30 mL/min/1.73m2 or on dialysis (Appendix VI)
9. Patients with clinically significant bacterial, fungal, parasitic or viral infection which require therapy. Patients with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed
10. Patients with known active hepatitis A, B or C at Screening or with known HIV positivity
11. Patients being treated concurrently with a potent systemic inhibitor of CYP3A4 at the time of Screening (ketoconazole, clarithromycin, itraconazole, nefazodone or telithromycin, see Appendix VII)
12. Patients 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)
13. Patients must not currently have the option of stem cell transplantation at the time of the screening assessments, either because they are not a candidate for the procedure, in the investigator’s expert judgment, or because a suitable donor is not available
14. Patients 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
15. Patients with currently rapid or paroxysmal atrial fibrillation, currently uncontrolled or unstable angina, recent (approximately 6 months) myocardia

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: • To establish the Maximum Safe Starting Dose of INC424 in patients with MF and baseline PLT count < 100 x 109/L and >= 75 x 109/L (first stratum) and PLT count < 75 x 109/L and >= 50 x 109/L (second stratum);Secondary Objective: • To characterize the safety of INC424<br>• To characterize the pharmacokinetics of INC424 in this patient population<br>• To characterize the pharmacokinetic-pharmacodynamic relationship of this population<br>• To obtain estimates of efficacy<br>;Primary end point(s): Incidence rate of Dose Limiting Toxicities (DLT)