Myeloproliferative Diseases
Conditions
Keywords
polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF)
Brief summary
Primary Objective: To evaluate efficacy and safety of ITF2357 in the treatment of patients with JAK2V617F positive myeloproliferative diseases \[Polycythemia Vera (PV), Essential Thrombocytosis (ET), Myelofibrosis (MF)\]. Efficacy was evaluated by ad hoc haematological and clinical criteria for PV and ET, and by internationally established response criteria (EUMNET criteria) for MF. Safety was evaluated by number of subjects experiencing an Adverse Event (AE), type, frequency, severity, timing and relatedness of AEs, including changes in vital signs and clinical laboratory results. Secondary Objective: To evaluate the JAK2 mutated allele burden by quantitative Real-Time Polymerase Chain Reaction (qRTPCR).
Detailed description
This is a non-randomized, open-label, Phase IIA pilot study testing efficacy and safety of ITF2357 in a population of patients with JAK2V617F positive myeloproliferative diseases. All recruited patients received an initial dose of 50 mg b.i.d. of ITF2357 that was subsequently escalated to 50 mg t.i.d. in case of lack of significant toxicity. Treatment lasted up to a maximum of 24 cumulative weeks of drug administration. The study was carried out in Italy. Enrolled patients were subjects of both genders, with an established diagnosis of polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) according to the revised WHO criteria.
Interventions
DRUGITF2357
50 mg b.i.d. PO every day. More precisely, ITF2357 was supplied as 50 mg hard gelatine capsules for oral administration.
Sponsors
Italfarmaco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed Informed Consent Form * Male or female, age ≥ 18 years * Confirmed diagnosis of PV/ET/MF according to the revised World Health Organisation criteria * JAK-2 V617F positivity * In need of cytoreductive therapy when hydroxyurea is not indicated (e.g. young patients) or when refractoriness to the drug is documented
Exclusion criteria
* Active bacterial or fungal infection requiring antimicrobial treatment on Day 1 * Patients of childbearing potential without a negative pregnancy test prior to initiation of the study drug * Pregnancy or lactation * A marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval \> 450 ms, according to Bazett's correction formula - see appendix G for the formula) * The use of concomitant medications that prolong the QT/QTc interval (see appendix F for full list) * Concomitant acute coronary syndromes; uncontrolled hypertension * New York Heart Association (NYHA) Grade II or greater congestive heart failure * History of any cardiac arrhythmia requiring medication (irrespective of its severity) * A history of additional risk factors for Torsade de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) * Active Epstein Barr Virus (EBV) infection (i.e. positive serology IgM) * Known HIV infection * Active hepatitis B and/or C infection * History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications * Eastern Cooperative Oncology Group (ECOG) performance status 3 or greater * Platelets count \<100x109/L within 14 days before enrolment * Absolute neutrophil count \<1.2x109/L within 14 days before enrolment * Percentage of blast cells in peripheral blood \>10% within 14 days before enrolment * Serum creatinine \>2xULN (Upper limit of normal) * Total serum bilirubin \>1.5xULN * Serum AST (aspartate aminotransferase) / ALT (alanine aminotransferase) \> 3xULN * Interferon alpha within 14 days before enrolment * Hydroxyurea within 14 days before enrolment * Anagrelide within 7 days before enrolment * Any other investigational drug within 28 days before enrolment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response | Every single week from week 1 to week 24 of treatment | Patients with Objective Response were defined as those patients achieving a complete, major, moderate or minor (only for Myelofibrosis patients) response during the experimental treatment course. The best response is reported hereunder by intensity of response. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in JAK2 Mutated Allele Burden | At screening, at week 12, at week 24, at the end of treatment (EOT) visit | This outcome was assessed by quantitative real time Polymerase Chain Reaction (RT PCR). At each time point, the number of patients is the following: Screening: N=29 Week 12: N=20 Week 24: N=18 EOT: N=24. End of treatment corresponds to the last visit performed before treatment discontinuation. |
| Number of Subject Experiencing an Adverse Event | At weekly visits (Days 8, 15, 22, 36, 43, 50, 64, 71, 78, 99, 127, 155); At monthly visits (Days 29, 57, 85 113, 141,169); at end of treatment visit | An adverse event (AE) is any untoward occurrence in a patient or clinical investigation subject administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The adverse events must to be followed to the end of study (28 days after the last study drug intake). A serious AE (SAE) is defined as an untoward (unfavourable) medical occurrence that at any dose results in death, or is life-threatening or requires inpatient hospitalisation or prolongation of existing hospitalisation, or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect. |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ITF2357 Initial dose of 50 mg b.i.d. that was subsequently escalated to 50 mg t.i.d in case of lack of significant toxicity.
ITF2357: 50 mg b.i.d. PO every day. More precisely, ITF2357 was supplied as 50 mg hard gelatine capsules for oral administration. | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Disease progression | 6 |
| Overall Study | QTc prolongation | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | ITF2357 |
|---|---|
| Age, Continuous | 55.6 years STANDARD_DEVIATION 10.7 |
| Region of Enrollment Italy | 29 participants |
| Sex: Female, Male Female | 14.0 Participants |
| Sex: Female, Male Male | 15.0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 29 |
| other Total, other adverse events | 29 / 29 |
| serious Total, serious adverse events | 3 / 29 |
Outcome results
Primary
Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response
Patients with Objective Response were defined as those patients achieving a complete, major, moderate or minor (only for Myelofibrosis patients) response during the experimental treatment course. The best response is reported hereunder by intensity of response.
Time frame: Every single week from week 1 to week 24 of treatment
Population: ITT population: all recruited patients who received study medication and for whom at least one on-study tumour evaluation is available.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ITF2357 | Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response | complete responders | 2 Participants |
| ITF2357 | Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response | major responders | 12 Participants |
| ITF2357 | Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response | moderate responders | 2 Participants |
| ITF2357 | Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response | minor responders | 1 Participants |
| ITF2357 | Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response | non responders | 12 Participants |
Secondary
Change in JAK2 Mutated Allele Burden
This outcome was assessed by quantitative real time Polymerase Chain Reaction (RT PCR). At each time point, the number of patients is the following: Screening: N=29 Week 12: N=20 Week 24: N=18 EOT: N=24. End of treatment corresponds to the last visit performed before treatment discontinuation.
Time frame: At screening, at week 12, at week 24, at the end of treatment (EOT) visit
Population: Intent-to-treat population: all recruited patients who received study medication and for whom at least one on-study tumour evaluation is available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ITF2357 | Change in JAK2 Mutated Allele Burden | screening | 54.0 percentage of change in allele burden | Standard Deviation 19.7 |
| ITF2357 | Change in JAK2 Mutated Allele Burden | week 12 | 49.4 percentage of change in allele burden | Standard Deviation 20.1 |
| ITF2357 | Change in JAK2 Mutated Allele Burden | week 24 | 47.1 percentage of change in allele burden | Standard Deviation 20 |
| ITF2357 | Change in JAK2 Mutated Allele Burden | EOT | 49.0 percentage of change in allele burden | Standard Deviation 21.5 |
Secondary
Number of Subject Experiencing an Adverse Event
An adverse event (AE) is any untoward occurrence in a patient or clinical investigation subject administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The adverse events must to be followed to the end of study (28 days after the last study drug intake). A serious AE (SAE) is defined as an untoward (unfavourable) medical occurrence that at any dose results in death, or is life-threatening or requires inpatient hospitalisation or prolongation of existing hospitalisation, or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect.
Time frame: At weekly visits (Days 8, 15, 22, 36, 43, 50, 64, 71, 78, 99, 127, 155); At monthly visits (Days 29, 57, 85 113, 141,169); at end of treatment visit
Population: safety population: all recruited patients who received at least one dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ITF2357 | Number of Subject Experiencing an Adverse Event | number of patients with AE | 29 Participants |
| ITF2357 | Number of Subject Experiencing an Adverse Event | number of patients with serious AE | 3 Participants |