| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Primary and Secondary Myelofibrosis |
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| E.1.1.1 | Medical condition in easily understood language |
| Diagnosis of Myeloproliferative Neoplasms (MPN) either de novo myelofibrosis according to current WHO criteria (PMF), secondary myelofibrosis (post-PV MF & post-ET MF) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To evaluate the clinical efficacy of ruxolitinib and pomalidomide combination therapy in primary and secondary MF patients based on the consensus criteria of the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) (Tefferi A et al, 2006), extended by the criterion RBC-transfusion independence (RBC-TI) (Gale RP et al, 2011; Gale RP et al, 2012). |
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
• To evaluate progression-free survival, response duration and overall survival
• To assess quality of life ((MPN-SAF Protocol 5/25/11)
• To evaluate clinical benefit (defined as prolongation of RBC transfusion intervals by ≥50% compared to baseline in transfusion dependent patients or ≥1 g/dL Hb increase in the absence of RBC transfusion dependency and/or improvement of at least one MF-associated symptom according by a minimum of 50% and/or improvement of ≥2 MF-associated symptoms by a minimum of 25%) treatment continuation is intended until disease progression or other reasons for withdrawal.
Safety Objective
• To evaluate the safety of combination therapy with both IMPs (ruxolitinib and pomalidomide) in patients with primary and secondary MF
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥18 years at the time of voluntarily signing an IRB/IEC-approved informed consent
2. Diagnosis of Myeloproliferative Neoplasms (MPN) either de novo myelofibrosis according to current WHO criteria (PMF), secondary myelofibrosis (post-PV MF and post-ET MF) according to the IWG-MRT consensus terminology)
3. Anemia with hemoglobin level of <10 g/dl or transfusion-dependent anemia
4. Splenomegaly (>11 cm total diameter) and/or leukoerythroblastosis
5. Adequate organ function, i.e. ALT and/or AST <3 x upper limit of normal (ULN), total bilirubin <3 x ULN, and serum creatinine <2 mg/dl
6. Subject must be willing to receive transfusion of blood products
7. ECOG performance status <3
8. Females of childbearing potential (FCBP) must undergo repetitive pregnancy testing (serum or urine) and pregnancy results must be negative.
9. Reliable contraception should be maintained throughout the study and for 28 days after study treatment discontinuation
10. Unless practicing complete abstinence from heterosexual intercourse, sexually active FCBP must agree to use adequate contraceptive methods
11. Males (including those who have had a vasectomy) must use barrier contraception (condoms) when engaging in sexual activity with FCBP. Males must agree not to donate semen or sperm
12. All subjects must:
-understand that the investigational product (in particular Pomalidomide) could have a potential teratogenic risk.
-be regulary counseled about pregnancy precautions and risks of fetal exposure.
-agree to abstain from donating blood while receiving investigational product during dose interruptions and for at least 28 days after last dose.
agree not to share study medication with another person and to return all unused study drug to the investigator.
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|
| E.4 | Principal exclusion criteria |
1. Patients eligible for hematopoietic stem cell transplantation (suitable candidate and suitable donor is available)
2. Patients with response to standard therapy as recommended by the Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie (DGHO/Onkopedia)
3. Pregnant or breast feeding females
4. BCR/ABL-positivity
5. Diagnosis of ET (according to WHO 2016 criteria)
6. Diagnosis of PV (according to WHO 2016 criteria)
7. >20% blasts in peripheral blood or bone marrow
8. thrombocytopenia <100 /nl or transfusion-dependent thrombocytopenia
9. neutropenia <0.5 /nl
10. Known positive status for HIV, HBV or HCV
11. Prior treatment with IMiDs (thalidomide, lenalidomide, pomalidomide) or with Interferon-alpha within a 3 month time period before Screening-phase
12. Patient treatment with Ruxolitinib within a 14 days time period before Screening-phase
13. History of thrombosis or pulmonary embolism within 6 months prior to study entry
14. Peripheral neuropathy >grade 1 CTC
15. No consent for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician about study participation.
16. Presence of any medical/psychiatric condition or laboratory abnormalities which may limit full compliance with the study, increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study
17. Drug or alcohol abuse within the last 6 months
18. History of malignancy except for i) adequately treated local basal cell or squamous cell carcinoma of the skin, ii) asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to randomization, or iii) any other cancer that has been in complete remission for ≥ 5 years
19. Patients undergoing treatment with hematopoietic growth factor receptor agonists (i.e., erythropoietin [Epo], granulocyte colony stimulating factor (GCSF [Neupogen; Neulasta], romiplostim, eltrombopag) within a 4 weeks period prior to screening-phase.
20. Patients receiving any medication listed in the Appendix V “Prohibited Medications” (within 7 days prior to the first dose of study drug).
21. 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.
22. Patients under ongoing treatment with another investigational medication or having been treated with an investigational medication within 28 days of screening.
23. No consent for biobanking.
24. Patients who cannot adhere to Pregnancy Prevention Plan |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Best response rate within 12 treatment cycles according to the IWG-MRT criteria (including complete remission, CR, partial remission, PR, clinical improvement, CI), stable disease, SD (Tefferi A et al, 2006), and red cell transfusion (RCT) independency according to Gale et al 2010 and 2011). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Overall safety profile of ruxolitinib and pomalidomide combination characterized by type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 3.0), timing and relatedness of adverse events (AEs) and laboratory abnormalities observed during treatment, as well as cumulative incidence of leukemic transformation
• Monthly Response assessment, clinical benefit, Progression-free survival, duration of response and overall survival
• Quality of life assessed by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF Protocol 5/25/11), change in ECOG performance status (s. Appendix IV) from study entry to each visit where the variable is measured.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
A first safety assessment was performed after treatment of 6 patients. Safety assessment was based on an observation period of each patient of least one cycle (28 days). The safety profile was favourably evaluated by the Data Safety Monitoring Board.
Thereafter, a continuous safety assessment will be performed once a year during the study.
All deaths during the study, including the post treatment follow up period, will be documented in patients’ data listings.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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