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Pomalidomide in Patients With Myeloproliferative Neoplasms in Fibrotic Stage

Primary Purpose

Myeloproliferative Neoplasms

Status

Completed

Phase

Phase 2

Locations

Germany

Study Type

Interventional

Intervention

Pomalidomide

About this trial

This is an interventional treatment trial for Myeloproliferative Neoplasms focused on measuring Myeloproliferative Neoplasms, Pomalidomide, Fibrotic Stage, Patients with Myeloproliferative Neoplasms in Fibrotic Stage

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Both female and male patients meeting the mentioned inclusion and exclusion criteria will be included in this clinical trial. The risk to get PMF or SMF does not depend on a patient's gender. Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:

Age ≥50 years at the time of voluntarily signing an IRB/IEC-approved informed consent
Diagnosis of Myeloproliferative Neoplasms (MPN) either de novo myelofibrosis according to WHO criteria (PMF) [20], secondary myelofibrosis (post-PV MF and post-ET MF according to the IWG-MRT consensus terminology) [21] or unclassifiable MPN with biopsy proven myelofibrosis
Anemia with hemoglobin level of <10 g/dl or transfusion-dependent anemia and/or thrombocytopenia <50 /nl or transfusion-dependent thrombocytopenia and/or neutropenia <1.0 /nl
Splenomegaly (>11 cm diameter) and/or leukoerythroblastosis
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
Subject must be willing to receive transfusion of blood products
ECOG performance status < 3
Female subjects with non-childbearing potential:
- Agree to have a pregnancy test at baseline
Male subjects:
- Agree to use condoms throughout study drug therapy, during any dose interruption and for four weeks after cessation of study therapy if their partner is of childbearing potential and has no contraception.
- Agree not to donate semen during study drug therapy and for four weeks after end of study drug therapy.
All Subjects:
- Will be counseled about potential teratogenic risks of the study medication.
- Agree to abstain from donating blood while taking study drug therapy and for one week following discontinuation of study drug therapy.
- Agree not to share study medication with another person and to return all unused study drug to the investigator
- No more than a 12-weeks-supply of study drug will be dispensed at a time.

Exclusion Criteria:

The presence of any of the following will exclude a patient from study enrollment:

Females of childbearing potentials°, pregnant or breast feeding females
BCR/ABL-positivity
Diagnosis of ET (according to WHO 2008 criteria)
Diagnosis of PV (according to WHO 2008 criteria)
>20% blasts in peripheral blood or bone marrow
Known positive status for HIV, HBV or HCV
Prior treatment with IMiDs (thalidomide, lenalidomide) or with Interferon-alpha within a 3 month time period before screening
History of thrombosis or pulmonary embolism
Peripheral neuropathy >grade 1 CTC
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.
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
Drug or alcohol abuse within the last 6 months
Patients with a "currently active" second malignancy other than nonmelanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year.

Criteria for women of non-childbearing potential:

A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria:

Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year. Amenorrhoea following cancer therapy does not rule out childbearing potential
Premature ovarian failure confirmed by a specialist gynecologist
Previous bilateral salpingo-oophorectomy, or hysterectomy
XY genotype, Turner syndrome, uterine agenesis

Sites / Locations

Universitätsklinikum Aachen
Charité Universitätsmedizin Berlin
Zentrum für Ambulante Hämatologie und Onkologie
BAG Freiberg-Richter, Jacobasch, Wolf, Illmer (Gemeinschaftspraxis)
Universitätsklinikum Düsseldorf
Klinikum der Johann Goethe-Universität Frankfurt
Universitätsklinikum Freiburg
Universitätsklinikum Hamburg Eppendorf
Universitätsklinikum Jena
Universitätsklinikum Magdeburg AöR
Universitätsmedizin Mannheim
Johannes Wesling Klinikum Minden
Stauferklinikum Schwäbisch Gmünd
Haematologisch-onkologische Praxis
Universitätsklinikum Ulm

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Pomalidomide

Arm Description

Every patient will remain on treatment until disease progression for at least 12 cycles, withdrawal of patient's informed consent or the occurrence of unacceptable toxicity. If a patient may benefit from treatment with pomalidomide the investigator together with the principle investigator will discuss the possibility of further treatment including maintenance treatment with pomalidomide on a case-by-case decision. This additional treatment will be performed within the follow-up period of the study, data will be collected and duration will be maximally 12 cycles.

Outcomes

Primary Outcome Measures

Objective disease response, as defined by the IWG-MRT criteria for response in MF patients extended by the criterion RBC-transfusion independence (TI)

Secondary Outcome Measures

Overall safety profile of pomalidomide characterized by type, frequency, severity, timing and relatedness of adverse events (AEs) and laboratory abnormalities observed during treatment

Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 3.0

Event-free survival

Relapse-free survival

Overall survival

Full Information

NCT ID

NCT00949364

First Posted

July 28, 2009

Last Updated

September 21, 2017

Sponsor

University of Ulm

1. Study Identification

Unique Protocol Identification Number

NCT00949364

Brief Title

Pomalidomide in Patients With Myeloproliferative Neoplasms in Fibrotic Stage

Official Title

Multi-Center Phase II Study With Pomalidomide in Patients With Myeloproliferative Neoplasms in Fibrotic Stage

Study Type

Interventional

2. Study Status

Record Verification Date

September 2017

Overall Recruitment Status

Completed

Study Start Date

December 2009 (undefined)

Primary Completion Date

December 14, 2016 (Actual)

Study Completion Date

December 14, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Ulm

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This is a phase II, multi-center study of pomalidomide in adult patients with PMF, SMF, and unclassifiable MPN showing at least grade 1 bone marrow fibrosis and requiring therapy. All patients will receive per oral pomalidomide on a daily basis. First cohort (Before Amendment No. 1 ID 1-41): Treatment starts with a phase of pomalidomide therapy with 2 mg per day. Individual dose reduction as outlined in the safety section is allowed. If no response was achieved (no complete remission (CR), partial response (PR), clinical improvement (CI) and no progressive disease according to the IWG-MRT criteria) after 3 months, prednisolone is added in a starting dose of 30 mg per day. In the absence of progressive disease, at least 6 months of treatment with pomalidomide is intended. In patients without disease progression after 6 months and those with response to treatment are intended to receive pomalidomide for at least 12 months. Additional antiproliferative treatment with hydroxyurea for leukocytosis (>20 x 109/l) and/or thrombocytosis (>750 x 109/l) and/or symptomatic splenomegaly in a starting dose of 2g/day with individual dose adjustment is allowed. Second cohort (After Amendment No. 1 ID > 41): To evaluate the relative impact of prednisolone to the objective response rate, a randomization has been integrated into the study concept. The addition of prednisolone is up-front randomized for the start of prednisolone either after 3 or 6 cycles of treatment with pomalidomide as single agent if no response occurred during this period. This results in the following treatment arms: Treatment Arm A) Pomalidomide 0.5 mg per day + additional prednisolone at start of cycle 4 (day 85), in case no response was achieved until end of cycle 3. Treatment Arm B) Pomalidomide 0.5 mg per day + additional prednisolone at start of cycle 7 (day 169), if no response was achieved until end of cycle 6. Treatment for all patients starts with pomalidomide as single agent at a dose of 0.5mg per day. The addition of prednisolone will be initiated as randomized either at start of cycle 4 or start of cycle 7 (starting dose 30 mg per day). In the absence of progressive disease, at least 12 cycles of treatment with pomalidomide are intended. Additional antiproliferative treatment with hydroxyurea for leukocytosis (>20 x 109/l) and/or thrombocytosis (>750 x 109/l) and/or symptomatic splenomegaly in a starting dose of 2g/day with individual dose adjustment is allowed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myeloproliferative Neoplasms

Keywords

Myeloproliferative Neoplasms, Pomalidomide, Fibrotic Stage, Patients with Myeloproliferative Neoplasms in Fibrotic Stage

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

103 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Pomalidomide

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Pomalidomide

Intervention Description

Treatment starts with pomalidomide as single agent therapy: 0.5 mg/day. Prednisolone will be started in the absence of PD as randomized either at start of cycle 4 or start of cycle 7 (starting dose: 30 mg/day for 28 days followed by 15 mg/day and 10 mg/day for 28 days), if no response acc. to IWG-MRT (no CR, PR, CI, TI) was achieved. If PD: treatment is stopped. Otherwise, continuous treatment at least until end of cycle 12 is intended. For patients responding to the combination treatment (pomalidomide/prednisolone) a concom. treatment after cycle 6 or 9 (depending on the randomization result) with prednisolone in doses equal or below 7.5 mg/day are allowed. If a patient may benefit from treatment with pomalidomide the invest. and the PI will discuss the possibility of further treatment including maintenance treatment with pomalidomide on a case-by-case decision (max. duration: 12 cycles).

Primary Outcome Measure Information:

Title

Objective disease response, as defined by the IWG-MRT criteria for response in MF patients extended by the criterion RBC-transfusion independence (TI)

Time Frame

one year

Secondary Outcome Measure Information:

Title

Overall safety profile of pomalidomide characterized by type, frequency, severity, timing and relatedness of adverse events (AEs) and laboratory abnormalities observed during treatment

Description

Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 3.0

Time Frame

one year

Title

Event-free survival

Time Frame

three years

Title

Relapse-free survival

Time Frame

three years

Title

Overall survival

Time Frame

three years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Both female and male patients meeting the mentioned inclusion and exclusion criteria will be included in this clinical trial. The risk to get PMF or SMF does not depend on a patient's gender. Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study: Age ≥50 years at the time of voluntarily signing an IRB/IEC-approved informed consent Diagnosis of Myeloproliferative Neoplasms (MPN) either de novo myelofibrosis according to WHO criteria (PMF) [20], secondary myelofibrosis (post-PV MF and post-ET MF according to the IWG-MRT consensus terminology) [21] or unclassifiable MPN with biopsy proven myelofibrosis Anemia with hemoglobin level of <10 g/dl or transfusion-dependent anemia and/or thrombocytopenia <50 /nl or transfusion-dependent thrombocytopenia and/or neutropenia <1.0 /nl Splenomegaly (>11 cm diameter) and/or leukoerythroblastosis 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 Subject must be willing to receive transfusion of blood products ECOG performance status < 3 Female subjects with non-childbearing potential: Agree to have a pregnancy test at baseline Male subjects: Agree to use condoms throughout study drug therapy, during any dose interruption and for four weeks after cessation of study therapy if their partner is of childbearing potential and has no contraception. Agree not to donate semen during study drug therapy and for four weeks after end of study drug therapy. All Subjects: Will be counseled about potential teratogenic risks of the study medication. Agree to abstain from donating blood while taking study drug therapy and for one week following discontinuation of study drug therapy. Agree not to share study medication with another person and to return all unused study drug to the investigator No more than a 12-weeks-supply of study drug will be dispensed at a time. Exclusion Criteria: The presence of any of the following will exclude a patient from study enrollment: Females of childbearing potentials°, pregnant or breast feeding females BCR/ABL-positivity Diagnosis of ET (according to WHO 2008 criteria) Diagnosis of PV (according to WHO 2008 criteria) >20% blasts in peripheral blood or bone marrow Known positive status for HIV, HBV or HCV Prior treatment with IMiDs (thalidomide, lenalidomide) or with Interferon-alpha within a 3 month time period before screening History of thrombosis or pulmonary embolism Peripheral neuropathy >grade 1 CTC 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. 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 Drug or alcohol abuse within the last 6 months Patients with a "currently active" second malignancy other than nonmelanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. Criteria for women of non-childbearing potential: A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria: Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year. Amenorrhoea following cancer therapy does not rule out childbearing potential Premature ovarian failure confirmed by a specialist gynecologist Previous bilateral salpingo-oophorectomy, or hysterectomy XY genotype, Turner syndrome, uterine agenesis

Facility Information:

Facility Name

Universitätsklinikum Aachen

City

Aachen

ZIP/Postal Code

52074

Country

Germany

Facility Name

Charité Universitätsmedizin Berlin

City

Berlin

ZIP/Postal Code

13353

Country

Germany

Facility Name

Zentrum für Ambulante Hämatologie und Onkologie

City

Bonn

ZIP/Postal Code

53119

Country

Germany

Facility Name

BAG Freiberg-Richter, Jacobasch, Wolf, Illmer (Gemeinschaftspraxis)

City

Dresden

ZIP/Postal Code

01307

Country

Germany

Facility Name

Universitätsklinikum Düsseldorf

City

Düsseldorf

ZIP/Postal Code

40225

Country

Germany

Facility Name

Klinikum der Johann Goethe-Universität Frankfurt

City

Frankfurt

ZIP/Postal Code

60590

Country

Germany

Facility Name

Universitätsklinikum Freiburg

City

Freiburg

ZIP/Postal Code

79106

Country

Germany

Facility Name

Universitätsklinikum Hamburg Eppendorf

City

Hamburg Eppendorf

ZIP/Postal Code

20246

Country

Germany

Facility Name

Universitätsklinikum Jena

City

Jena

ZIP/Postal Code

07740

Country

Germany

Facility Name

Universitätsklinikum Magdeburg AöR

City

Magdeburg

ZIP/Postal Code

39120

Country

Germany

Facility Name

Universitätsmedizin Mannheim

City

Mannheim

ZIP/Postal Code

68167

Country

Germany

Facility Name

Johannes Wesling Klinikum Minden

City

Minden

ZIP/Postal Code

32429

Country

Germany

Facility Name

Stauferklinikum Schwäbisch Gmünd

City

Mutlangen

ZIP/Postal Code

73557

Country

Germany

Facility Name

Haematologisch-onkologische Praxis

City

München

ZIP/Postal Code

80331

Country

Germany

Facility Name

Universitätsklinikum Ulm

City

Ulm

ZIP/Postal Code

89081

Country

Germany

12. IPD Sharing Statement

Citations:

PubMed Identifier

27774990

Citation

Schlenk RF, Stegelmann F, Reiter A, Jost E, Gattermann N, Hebart H, Waller C, Hochhaus A, Platzbecker U, Schafhausen P, Blau IW, Verbeek W, Heidel FH, Werner M, Kreipe H, Teleanu V, Benner A, Dohner H, Griesshammer M, Dohner K. Pomalidomide in myeloproliferative neoplasm-associated myelofibrosis. Leukemia. 2017 Apr;31(4):889-895. doi: 10.1038/leu.2016.299. Epub 2016 Oct 24.

Results Reference

result

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Pomalidomide in Patients With Myeloproliferative Neoplasms in Fibrotic Stage

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