Safety and efficacy study of INC424 in patients with myelofibrosis

• Register: EUCTR
• Last refreshed on: 27 February 2017
• Main ID: EUCTR2010-024473-39-PL
• Date of registration: 09/11/2011
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: Safety and efficacy study of INC424 in patients with myelofibrosis
• Scientific title: An open-label, multicenter, expanded access study of INC424 for patients with primary myelofibrosis (PMF) of post polycythemia vera myelofibrosis (PPV MF) or post-essential thrombocythemia myelofibrosis (PET-MF)
• Date of first enrolment: 12/01/2012
• Target sample size: 2500
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-024473-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Algeria, Argentina, Austria, Belgium, Brazil, Canada, Colombia, Czech Republic, Egypt, Germany, Greece, Hungary, Ireland, Israel, Italy, Kuwait, Mexico, Morocco, Poland, Portugal, Russian Federation, Saudi Arabia, Slovakia, South Africa, Spain, Thailand, Tunisia, United Arab Emirates, Venezuela, Bolivarian Republic of

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:
1. Patients must give written informed consent according to local guidelines prior to any screening procedures.

2. Patients must not be eligible for another ongoing INC424 clinical trial.

3. Male or female patients aged = 18 years of age.

4. Patients must be diagnosed with PMF, PPV-MF or PET-MF, according to the 2008 revised International Standard Criteria , irrespective of JAK2 mutation status.

5. Patients with PMF requiring therapy must be classified as high risk (3 prognostic factors) OR intermediate risk level 2 (2 prognostic factors, no more), OR intermediate risk level 1 with an enlarged spleen at the screening visit (assessment to occur at the Screening Visit). The prognostic factors, defined by the International Working Group (Cervantes 2009) are described in Section 1.1 and Section 5.2 and should be evaluated at the Screening Visit.

6. Patients with Intermediate-1 and splenomegaly, must have a palpable spleen measuring 5 cm or greater from the costal margin to the point of greatest splenic protrusion.

7. Patients with a peripheral blood blast percentage count of < 10%.

8. Patients with adequate liver function defined as total bilirubin or direct bilirubin = 2.0 x ULN, and ALT = 2.5 x ULN.

9. Patients with adequate renal function defined as serum creatinine
= 2 x ULN.

10. Patients with an ECOG performance status of 0, 1, or 2

11. Women of childbearing potential must have had a negative serum pregnancy test within 14 days prior to the administration of study drug.

12. Patients must have recovered or stabilized sufficiently from any adverse drug reactions associated with prior treatments before beginning treatment with INC424.

13. Fedratinib pretreated patients with documented complete physical
examination including full neurologic examination and cardiology
assessment, thiamine level testing, and MRI of the brain if indicated
based on signs or symptoms. Patients pretreated with fedratinib should
have completed or be receiving thiamine supplementation according to
the investigator's instructions.
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. Patients eligible for hematopoietic stem cell transplantation (suitable
candidate and a suitable donor is available).

2. Patients with a history of malignancy in the past 3 years, except for treated early stage squamous or basal cell carcinoma in situ.

3. Patients receiving any medications listed in the "Prohibited
Medications" listing

4. Impairment of GI function or GI disease that may significantly alter
the absorption of INC424

5. Patients with cardiac disease which in the Investigator's opinion may
jeopardize the safety of the patient or the compliance with the protocol.

6. Patients with currently uncontrolled or unstable angina, rapid or
paroxysmal fibrillation or recent (approximately 6 months) myocardial
infarction or acute coronary syndrome.

7. Patients with clinically significant bacterial, fungal, parasitic or viral
infection that requires therapy. Patients with acute bacterial infections
requiring antibiotic use should delay screening/enrollment until the
course of antibiotic therapy has been completed.

8. Patients with known active hepatitis A, B, C or who are HIV-positive.

9. Patients with inadequate bone marrow reserve at baseline visit as
demonstrated by:
(a) ANC that is = 1000/µL.
(b) Platelet count that is <50,000/µL without the assistance of growth
factors, thrombopoietic factors or platelet transfusions.

10. Patients with any history of platelet counts < 50,000/µL or ANC
<500/µL except during treatment for a MPD or treatment with cytotoxic
therapy for any other reason.

11. Patients with coagulation parameters (PT, PTT, INR) >1.5 x ULN.

12. Patients with known hypersensitivity to INC424 or other JAK1/JAK2
inhibitors, or to its excipients.

13. Patients receiving ongoing treatment with another investigational
medication or having been treated with an investigational medication
within 30 days of screening or with fedratinib within 14 days of screeing.

14. Pregnant or nursing (lactating) women, where pregnancy is defined
as the state of a female after conception and until termination of
gestation, confirmed by a positive ßHCG laboratory test (> 5 mIU/mL).

15. Women of child-bearing potential, defined as all women
physiologically capable of becoming pregnant, unless they are using
highly effective methods of contraception throughout the study duration inclusive of 28 days safety follow-up.

16. Patients who are unable to comprehend or are unwilling to sign an
ICF.

17. Patients with active alcohol or drug addiction that would interfere
with their ability to comply with the study requirements.

18. Patients with any concurrent condition that, in the Investigator's
opinion, would jeopardize the safety of the patient or compliance with
the protocol.

19. In the case of ruxolitinib pretreated patients, ruxolitinib primary
resistant patients defined as:
• No spleen reduction within the first 12 weeks after front line therapy
with ruxolitinib. AND
• No reduction in symptoms within the first 12 weeks after first-line
treatment with ruxolitinib

20. In the case of ruxolitinib pretreated patients, patients discontinuing ruxolitinib due to a Grade 4 AE related or suspected to be related to
ruxolitinib


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

Health Condition(s) or Problem(s) studied

Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PPV MF) or post essential thrombocythemia myelofibrosis (PET-MF)
MedDRA version: 19.0 Level: PT Classification code 10028537 Term: Myelofibrosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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: RUXOLITINIB PHOSPHATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

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: RUXOLITINIB PHOSPHATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

Primary end point(s): Safety:
- Safety and tolerability will be collected by monitoring the frequency, duration and severity of all grade AEs by the National Cancer Institute CTCAE v. 3 0, performing physical exams (PE), and evaluating changes in vital signs (VS), ECOG performance status (PS), electrocardiograms (ECGs) and serum chemistry and hematology results.
- Grade 3 and 4 AEs, Serious Adverse Events (SAEs).
- Change in laboratory values from Baseline to End of Treatment (serum chemistry and hematology).
- Changes in weight from Baseline to each assessment point and at end of treatment.
- Cardiac function as assessed by electrocardiograms (ECGs).
- Changes in vital signs.

Main Objective: to collect additional safety of INC424 in patients with PMF, PPV MF, or PET MF, who have either received prior treatment with commercially available agents, investigational drug or never received treatment

Timepoint(s) of evaluation of this end point: Monthly for the first 3 months, then every 3 months and at study discontinuation

Secondary Objective: To access the best overall response rate of INC424 in patients with PMF, PPV MF, or PET-MF as evaluated by the Investigator.

To collect (QoL) information in patients with PMF, PPV MF, or PET-MF treated with INC424.

To document MRU in patients with PMF, PPV MF, or PET-MF treated with INC424

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Monthly for the first 3 months, then every 3 months and at study discontinuation

Secondary end point(s): Quality of Life
- Change in ECOG PS from Baseline to each visit where measured.

- Change in Functional Assessment of Cancer Therapy for patients with Lymphoma (FACT-Lym) version 4 from Baseline to each visit where measured

- Change in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue from baseline to each visit where measured

Medical resource utilization (MRU)
Medical resource utilization (MRU) will be assessed as follows:

- Frequency and duration of hospitalization from Baseline up to week 48 of therapy

- Frequency of emergency room visits from Baseline up to week 48 of therapy.

- Frequency of general practitioner, specialist, and urgent care visits from Baseline up to week 48 of therapy.

- Number of transfusions and transfusion dependency status end of study.

- Splenectomy and use of splenic irradiation.

- Changes in use of concomitant medications for MPN symptom management

Efficacy
• Best overall response to treatment as assessed by spleen palpation (calculated as the percentage change in spleen length compared with baseline).
• Change in spleen length from Baseline to end of each visit.
• Change in WBC and platelet count from Baseline will be summarized to end of treatment.
• Shift in fibrosis in the bone marrow from Baseline to worst/best value on study (where bone marrow biopsies are performed - not mandatory).
• Progression free survival (PFS), acute myeloid leukemia free survival (LFS) and overall survival (OS).
• In patients without splenomegaly, patient reported outcomes measure symptoms of the disease.

Secondary ID(s)

CINC424A2401

2010-024473-39-AT

Source(s) of Monetary Support

Novartis Pharma Services AG