Clinical trial NCT01644110: Ruxolitinib and Pomalidomide Combination Therapy in Patients With Primary and Secondary MF
Official title: A Phase-Ib/II Study of Ruxolitinib and Pomalidomide Combination Therapy in Patients With Primary and Secondary Myelofibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Primary Myelofibrosis
Secondary Myelofibrosis
PMF
SMF
Post-PV MF
Post-ET MF
Lead sponsor: University of Ulm
Sponsor class: OTHER
First posted: 2012-07-18
Enrollment: 96
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Cohort 1 (Patient 1 - Patient 41): ruxolitinib treatment will be started at 10 mg twice daily up to 25 mg twice daily, whereas the dose of pomalidomide will be 0.5 mg once daily.

Cohort 2 (Patient 42 - Patient 90): ruxolitinib treatment will be started at 10 mg twice daily up to 25 mg twice daily, whereas the dose of pomalidomide will be started at 0.5 mg once daily up to 2 mg once daily.
Primary purpose: TREATMENT

Brief summary: The proposed study is an open-label, single-arm, Phase-Ib/II trial to assess the efficacy of oral drug combination ruxolitinib and pomalidomide in primary and secondary MF patients.

Detailed description: The proposed study is an open-label, single-arm, Phase-Ib/II trial to assess the efficacy of oral drug combination ruxolitinib and pomalidomide in primary and secondary MF patients. Dosages of the drugs are derived from previous Phase-I/II studies; ruxolitinib treatment will be started at 10 mg twice daily, whereas the dose of pomalidomide will be 0.5 mg once daily.

Dose reductions and discontinuations will be allowed in case of myelosuppressive effects.

Intra-patient dose escalation will be permitted for ruxolitinib to optimize efficacy of the therapeutic regimen; pomalidomide will be given in a permanent dosage of 0.5mg per day.

Treatment response will be evaluated continuously after each treatment cycle (1 cycle = 28 days) according to the IWG-MRT criteria expanded by the response criterion RCT-independency.

In case of progressive disease study therapy will be stopped; In patients showing response or stable disease, continuous therapy within the study is intended for a maximum of 12 treatment cycles; After completion of 12 treatment cycles, therapy can be continued if a measurable benefit of treatment is evident. This extension has to be discussed between the local and the principle investigator. Conditions leading to patient withdrawal from the study are detailed in the protocol "PATIENT WITHDRAWAL FROM STUDY PARTICIPATION".

Eligibility criteria: 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) (Appendix I)
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 could have a potential teratogenic risk.
    * be counseled about pregnancy precautions and risks of fetal exposure.
    * agree to abstain from donating blood while taking investigational product.
    * agree not to share study medication with another person and to return all unused study drug to the investigator.

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.

Primary outcomes:
measure: Best response rate within 12 treatment cycles according to the IWG-MRT criteria (including CR, PR, CI) and red cell transfusion (RCT) independency according to Gale et al 2010 and 2011).
timeFrame: one year
Secondary outcomes:
measure: Overall safety profile of ruxolitinib and pomalidomide combination observed during treatment, as well as cumulative incidence of leukemic transformation
timeFrame: one year
measure: Progression-free survival
timeFrame: three years
measure: duration of response
timeFrame: three years
measure: overall survival
timeFrame: three years
measure: Quality of life assessed by the Myeloproliferative Neoplasm Symptom
timeFrame: three years
measure: Clinical Benefit - Assessment of each patient
timeFrame: three years
measure: Monthly Response assessment
timeFrame: three years
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen - Med. Klinik IV
city: Augsburg
country: Germany
facility: Hämatologisch onkologische Praxis
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow
city: Dresden
country: Germany
facility: BAG Freiberg-Richter, Jacobasch, Wolf, Illmer
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Freiburg
country: Germany
facility: Uniklinikum Freiburg
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Köln
country: Germany
facility: Klinik für Innere Medizin Uniklinik Köln
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg AöR
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
city: Mannheim
country: Germany
facility: Universitätsklinikum Mannheim
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: Mutlangen
country: Germany
facility: Stauferklinikum Schwäbisch Gmünd
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: University of Ulm
Study officials:
affiliation: University of Ulm
name: Konstanz Doehner, MD
role: PRINCIPAL_INVESTIGATOR
References: