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.
Title
- Brief Title: 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
Clinical Trial IDs
- ORG STUDY ID:
POMINC(MPNSG02-12)
- SECONDARY ID:
2012-002431-29
- NCT ID:
NCT01644110
Conditions
- Primary Myelofibrosis
- Secondary Myelofibrosis
- PMF
- SMF
- Post-PV MF
- Post-ET MF
Interventions
Drug | Synonyms | Arms |
---|
INCB018424/CC-4047 | | ruxolitinib/pomalidomide |
Purpose
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".
Trial Arms
Name | Type | Description | Interventions |
---|
ruxolitinib/pomalidomide | Experimental | 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. | |
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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
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). |
Time Frame: | one year |
Safety Issue: | |
Description: | Best response rate within 12 treatment cycles according to the IWG-MRT |
Secondary Outcome Measures
Measure: | Overall safety profile of ruxolitinib and pomalidomide combination observed during treatment, as well as cumulative incidence of leukemic transformation |
Time Frame: | one year |
Safety Issue: | |
Description: | 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 |
Measure: | Progression-free survival |
Time Frame: | three years |
Safety Issue: | |
Description: | Progression-free survival |
Measure: | duration of response |
Time Frame: | three years |
Safety Issue: | |
Description: | duration of response |
Measure: | overall survival |
Time Frame: | three years |
Safety Issue: | |
Description: | overall survival |
Measure: | Quality of life assessed by the Myeloproliferative Neoplasm Symptom |
Time Frame: | three years |
Safety Issue: | |
Description: | Quality of life assessed by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF Protocol 5/25/11), change in ECOG performance status from study entry to each visit where the variable is measured. |
Measure: | Clinical Benefit - Assessment of each patient |
Time Frame: | three years |
Safety Issue: | |
Description: | Clinical Benefit:
Lab / Clinical data: Stable disease (SD) plus hematologic improvement: 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
Questionaire: Stable disease (SD) plus improvement of MF-associated symptoms: SD plus improvement of at least one MF-associated symptom according to the MPN-SAF / EORTC QLQ-C30 or FACT-Lym by a minimum of 50% and/or SD plus improvement of ≥ two MF-associated symptoms according the MPN-SAF / EORTC QLQ-C30 or FACT-Lym by a minimum of 25% each. |
Measure: | Monthly Response assessment |
Time Frame: | three years |
Safety Issue: | |
Description: | Response criteria:
Assessment according to the IWG-MRT (based on lab, clinical data): CR / PR / CI / PD / SD / RD/ RBC-TD / RBC-TI |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | University of Ulm |
Last Updated
December 23, 2019