Primary objective: To establish the MSSD 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: safety, PK, PK/PD,…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
myelofibrose
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
DLT
Secondary outcome
Safety parameters, PK, platelets, cytokines, spleen length, proportion of
patients achieving *50% reduction in palpable spleen length at Week 24, Change
in spleen length as measured by palpation from Study Day 1 to Week 24.
Background summary
For a significant population of thrombocytopenic MF patients there are limited
data about the safety of INC424 (a JAK inhibitor) or what might be an
appropriate dose, since in all studies conducted to date with INC424, baseline
PLT count of * 100 x109/L has been an inclusion criterion. However,
thrombocytopenia is a frequent event in MF. A previous phase I/II study, has
established thrombocytopenia as the DLT of INC424 in MF patients with a MTD of
both 25 mg b.i.d. and 100 mg qd. The incidence of grade * 3 thrombocytopenia in
this trial was 20% at 10 mg b.i.d., 2.9% at 15 mg b.i.d. and 36% at 25 mg
b.i.d. The higher incidence of grade * 3 thrombocytopenia in the 10 mg b.i.d.
dose group compared to 15 mg b.i.d. can be partially explained by the more
frequent presence of patients with low baseline PLT counts in the former dose
group compared to the latter one. Thrombocytopenia occurred rapidly and
resolved with drug interruptions or dose decreases. Some patients continued to
receive INC424 while their platelet count ranged between 50 and 100 x109/L, but
no patients with platelet counts below 100 x109/L have initiated INC424
therapy, and therefore the MTD for patients with low platelets needs to be
directly established.
The purpose of this phase Ib clinical trial is to directly evaluate the safety
of INC424 in the low-PLT MF population and to establish the Maximum Safe
Starting Dose.
Study objective
Primary objective: To establish the MSSD 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: safety, PK, PK/PD, estimate of efficacy.
Study design
Open-label, dose finding phase Ib study. For each patient, the study consists
of 2 parts: Core phase and Extension phase.
1. Core period (1st 168 days). Patient is enrolled in a or b (only difference
between both groups is the dose of INC424)
o Dose-escalation: Subsequent cohorts (3-6 pats). Increasing doses of INC424
until MSSD has be dreached. Approx. 62 patients.
o Safety expansion phase. 20 patients in total (10 patients from each stratum),
additional to those treated at the MSSD during dose escalation, will be treated
at the respective MSSD for their stratum.
2. Extension period (after day 168): Patient will visit hospital once in 12
weeks. In addition, blood is drawn for safety labs every 12 weeks (6 weeks
after each hospital visit).
Study is terminated with an EOT visit.
See also protocol page 33.
Intervention
Treatment with INC424.
Study burden and risks
Risk: Adverse events of study medication.
Burden:
Study visits with an interval of 1, 2, 4 and eventually 6 weeks.
Blood draws 15-30 ml/visit; every visit.
Regular pregnancy testing.
Physical examination every 2-4, later on 12weeks.
ECG every 4-8 weeks (until day 168)
Questionnaire (quality of life) every 4-8 weeks (until day 168).
Diary (daily) about symptoms (1st 6 months only) and use of study medication.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
* 18 years of age or older
* Diagnosed with Primary Myelofibrosis (MF), Post-Polycythemia Vera-Myelofibrosis or Post-Essential Thrombocythemia-Myelofibrosis irrespective of JAK2 mutation status, guided by the criteria outlined in the 2008 WHO criteria for PMF.
* MF requiring therapy must be classified at least as intermediate risk level 1, as defined by the International Working Group (see protocol page 42 for details).
* Palpable spleen of at least 5 cm.
* Active symptoms of MF (see protocol page 42 for details).
* 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).
* INR and PTT < 1.5 x ULN.
* ECOG performance status 0, 1, 2.
Exclusion criteria
* Pregnant or nursing women.
* Patients of childbearing potential who are unwilling to take appropriate contraceptive measures.
* Treatment with hematopoietic growth factor receptor agonists for at least 30 days prior to receiving the first dose of study drug.
* Any history of PLT counts <45 x 109/L within 30 days prior to Screening. See protocol page 43 for exceptions.
* Any history or predisposition to clinically significant bleeding, platelet dysfunction and/or bleeding diathesis.
* Treated concurrently with a potent systemic inhibitor or a potent systemic inducer of CYP3A4.
* Life expectancy of less than 6 months.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | clinicaltrials.gov; registratienummer n.n.b. |
| EudraCT | EUCTR2010-023055-29-NL |
| CCMO | NL40146.078.12 |