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The Efficacy of Azacitidine +/- Lenalidomide in High-risk Myelodysplastic Syndrome (MDS)and Acute Myeloid Leukemia (AML) With Del(5q).

Primary Purpose

Myelodysplastic Syndrome, Acute Myelogenous Leukemia

Status

Unknown status

Phase

Phase 2

Locations

Sweden

Study Type

Interventional

Intervention

Azacitidine

azacitidine + lenalidomide

About this trial

This is an interventional treatment trial for Myelodysplastic Syndrome focused on measuring MDS, AML, Azacitidine, Lenalidomide, del5q

Eligibility Criteria

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

Inclusion Criteria:

18 years of age at the time of signing the informed consent form.
MDS with IPSS Int-2 or High with a karyotype including del(5q).
Acute myeloid leukaemia (AML) with multilineage dysplasia and 20-30 % blasts (former RAEB-t) with a karyotype including del(5q).
Subject has signed the informed consent form.
Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test prior to starting lenalidomide. In addition, sexually active WCBP must agree to use adequate contraceptive methods (oral, injectable, patches, or implantable hormonal contraceptive methods; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on lenalidomide. WCBP must agree to have pregnancy tests every 4 weeks while on lenalidomide.
Males (including those who have had a vasectomy) must use barrier contraception (latex condoms) when engaging in reproductive sexual activity with WCBP while on lenalidomide, when temporarily stopping lenalidomide and 28 days after the last dose of lenalidomide.

Note: Refractory and relapsed patients can be included as long as they fulfil the inclusion criteria.

Exclusion Criteria:

Eligible for upfront allogeneic SCT without prior induction chemotherapy or azacitidine
Pregnant or lactating females.
Prior therapy with azacitidine
Prior therapy with lenalidomide
Expected survival less than two months.
Acute promyelocytic leukemia (APL)
Central nervous system leukemia
Serum biochemical values as follows
1. Serum creatinine >2.0 mg/dL (177 mmol/L)
2. Serum aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transferase (ALT)/serum glutamate pyruvate transaminase (SGPT) >3.0 x upper limit of normal (ULN)
3. Serum total bilirubin >1.5 mg/dL
Prior allergic reaction to thalidomide
Uncontrolled systemic infection

Sites / Locations

Lars MöllgårdRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

azacitidine

azacitidine + lenalidomide

Arm Description

Outcomes

Primary Outcome Measures

Response according to IWG criteria for MDS and AML

Response according to IWG criteria include hematologic response (including transfusion independence), bone marrow response (blast count) and cytogenetic response (karyotype) after 6 cycles of azacytidine or azacytidine+lenalidomide. For patients who can keep the 4 week interval the Time Frame will be 25 weeks. The cycle interval can be extended up to 8 weeks which makes 44 weeks the maximum Time Frame.

Secondary Outcome Measures

Cytogenetic response after 3 cycles using Fluorescence In Situ Hybridization(FISH)

After 3 cycles the 5q- clone will be measured with FISH to see if there is a response already at that time. For patients who can keep the 4 week interval the Time Frame will be 25 weeks. The cycle interval can be extended up to 8 weeks which makes 44 weeks the maximum Time Frame.

Safety (number and types of adverse advents) in azacitidine vs azacitidine + lenalidomide groups

Heamtological adverse events will be monitored by checking Hemoglobin,Leucocyte count, Platelet and a Differential every week. Non-Hematological adverse events will be monitored and reported in the Case report form (CRF). For patients who can keep the 4 week interval the Time Frame will be 25 weeks. The cycle interval can be extended up to 8 weeks which makes 44 weeks the maximum Time Frame.

Azacitidine cycle interval between groups

For patients who can keep the 4 week interval the Time Frame will be 25 weeks. The cycle interval can be extended up to 8 weeks which makes 44 weeks the maximum Time Frame.

Survival in azacitidine vs azacitidine + lenalidomide groups

All patients will undergo follow-up once yearly from start of treatment; week 52, 104, and 156.

Relapse in azacitidine vs azacitidine + lenalidomide groups

All patients will undergo follow-up once yearly from start of treatment; week 52, 104, and 156.

Analysis of a broad spectrum of molecular and cellular events which previously have been identified as related to MDS with del(5q).

Bone marrow will be biobanked at inclusion and after 6 cycles of treatment or or at end of study if this occurs at an earlier time point. For patients who can keep the 4 week interval the Time Frame will be 25 weeks. The cycle interval can be extended up to 8 weeks which makes 44 weeks the maximum Time Frame.

Full Information

NCT ID

NCT01556477

First Posted

March 12, 2012

Last Updated

March 14, 2012

Sponsor

Nordic MDS Group

1. Study Identification

Unique Protocol Identification Number

NCT01556477

Brief Title

The Efficacy of Azacitidine +/- Lenalidomide in High-risk Myelodysplastic Syndrome (MDS)and Acute Myeloid Leukemia (AML) With Del(5q).

Official Title

A Multicentre Open Randomized Phase II Study of the Efficacy and Safety of Azacitidine Alone or in Combination With Lenalidomide in High-risk Myeloid Disease (High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia) With a Karyotype Including Del(5q)

Study Type

Interventional

2. Study Status

Record Verification Date

March 2012

Overall Recruitment Status

Unknown status

Study Start Date

March 2012 (undefined)

Primary Completion Date

July 2014 (Anticipated)

Study Completion Date

November 2014 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Nordic MDS Group

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The proposed phase II trial is a multicenter, randomized, open-label study that will evaluate the efficacy and safety of azacitidine alone or in combination with lenalidomide in high-risk Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML) with a karyotype including del(5q). The primary objective will be to evaluate the efficacy in terms of response according to International Working Group (IWG) criteria for MDS and AML after 6 cycles of azacitidine or azacitidine + lenalidomide treatment, or at end of study if this occurs at an earlier time point.

Detailed Description

This is an prospective open multi-center randomized phase II study of standard dose azacytidine with or without the addition of lenalidomide in high-risk myeloid disease (high-risk MDS and AML) with a karyotype including del(5q). Seventy-two patients, eligible for treatment with azacytidine (Intermedium/INT-2 and High-risk MDS and AML with 20-30 % marrow blasts according to label) will be included. Azacytidine will be given in a modified standard dose, azacytidine 5+2 (75 mg/m2/ d subcutaneously for 5 days, followed by a 2-day weekend break, followed by azacytidine 75 mg/m2/ d for 2 days every 28 days, no individual dose exceeding 200 mg) for 6 cycles. Cycle interval may be prolonged if toxicity according to predefined criteria occurs. Patients will be randomized to azacytidine (Arm A) or azacytidine + lenalidomide (Arm B). The initial dose of lenalidomide is 10 mg 21/28 days, starting day 1 in each azacytidine cycle and leaving the last week before start of next azacytidine cycle free. The dose should be increased to 20 mg day 1 in cycle 4 if no toxicity according to predefined criteria occurs. The total study period is 24 weeks + additional weeks caused by prolonged cycle interval. Patients, who following a response may be eligible for allo-SCT may exit the study after cycle 3, 4 or 5 and then be subject to end-of-study assessment. Patients who at start of treatment, or any time during study have a neutrophil count <0,5 x 109/l will be treated with Granulocyte-ColonyStimulatingFactor (G-CSF).

6. Conditions and Keywords

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

Myelodysplastic Syndrome, Acute Myelogenous Leukemia

Keywords

MDS, AML, Azacitidine, Lenalidomide, del5q

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

72 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

azacitidine

Arm Type

Active Comparator

Arm Title

azacitidine + lenalidomide

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Azacitidine

Other Intervention Name(s)

Vidaza

Intervention Description

Intervention Type

Drug

Intervention Name(s)

azacitidine + lenalidomide

Other Intervention Name(s)

Vidaza and Revlimid

Intervention Description

Azacitidine 5-2-2 (75 mg/m2/day subcutaneously for 5 days, followed by a 2-day weekend break, followed by azacitidine 75 mg/m2/ day for 2 days every 28 days, no individual dose exceeding 200 mg) for 6 cycles. Initial dose of lenalidomide is 10 mg 21/28 days, starting day 1 in each azacitidine cycle and leaving the last week before start of next azacitidine cycle free. The dose should increased to 25 mg day 1 in cycle 4 if no toxicity according to predefined criteria occurs. Total treatment period is 24 weeks.

Primary Outcome Measure Information:

Title

Response according to IWG criteria for MDS and AML

Description

Time Frame

25-44 weeks (after 6 cycles of azacitidine or azacitidine+lenalidomide)

Secondary Outcome Measure Information:

Title

Cytogenetic response after 3 cycles using Fluorescence In Situ Hybridization(FISH)

Description

Time Frame

25-44 weeks

Title

Safety (number and types of adverse advents) in azacitidine vs azacitidine + lenalidomide groups

Description

Time Frame

25-44 weeks

Title

Azacitidine cycle interval between groups

Description

For patients who can keep the 4 week interval the Time Frame will be 25 weeks. The cycle interval can be extended up to 8 weeks which makes 44 weeks the maximum Time Frame.

Time Frame

25-44 weeks

Title

Survival in azacitidine vs azacitidine + lenalidomide groups

Description

All patients will undergo follow-up once yearly from start of treatment; week 52, 104, and 156.

Time Frame

Up to week 156

Title

Relapse in azacitidine vs azacitidine + lenalidomide groups

Description

All patients will undergo follow-up once yearly from start of treatment; week 52, 104, and 156.

Time Frame

Up to week 156

Title

Analysis of a broad spectrum of molecular and cellular events which previously have been identified as related to MDS with del(5q).

Description

Time Frame

25-44 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 18 years of age at the time of signing the informed consent form. MDS with IPSS Int-2 or High with a karyotype including del(5q). Acute myeloid leukaemia (AML) with multilineage dysplasia and 20-30 % blasts (former RAEB-t) with a karyotype including del(5q). Subject has signed the informed consent form. Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test prior to starting lenalidomide. In addition, sexually active WCBP must agree to use adequate contraceptive methods (oral, injectable, patches, or implantable hormonal contraceptive methods; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on lenalidomide. WCBP must agree to have pregnancy tests every 4 weeks while on lenalidomide. Males (including those who have had a vasectomy) must use barrier contraception (latex condoms) when engaging in reproductive sexual activity with WCBP while on lenalidomide, when temporarily stopping lenalidomide and 28 days after the last dose of lenalidomide. Note: Refractory and relapsed patients can be included as long as they fulfil the inclusion criteria. Exclusion Criteria: Eligible for upfront allogeneic SCT without prior induction chemotherapy or azacitidine Pregnant or lactating females. Prior therapy with azacitidine Prior therapy with lenalidomide Expected survival less than two months. Acute promyelocytic leukemia (APL) Central nervous system leukemia Serum biochemical values as follows Serum creatinine >2.0 mg/dL (177 mmol/L) Serum aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transferase (ALT)/serum glutamate pyruvate transaminase (SGPT) >3.0 x upper limit of normal (ULN) Serum total bilirubin >1.5 mg/dL Prior allergic reaction to thalidomide Uncontrolled systemic infection

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Lars Möllgård, MD, PhD

Phone

+46 8 5858 0000

lars.mollgard@karolinska.se

First Name & Middle Initial & Last Name or Official Title & Degree

Bengt Rasmussen, MD

Phone

+46 19 6021111

bengt.rasmussen@orebroll.se

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Lars Möllgård, MD, PhD

Organizational Affiliation

Nordic MDS Group

Official's Role

Principal Investigator

Facility Information:

Facility Name

Lars Möllgård

City

Stockholm

ZIP/Postal Code

141 86

Country

Sweden

Individual Site Status

Recruiting

12. IPD Sharing Statement

Links:

URL

http://www.nmds.org

Description

Nordic MDS Group website

Learn more about this trial

The Efficacy of Azacitidine +/- Lenalidomide in High-risk Myelodysplastic Syndrome (MDS)and Acute Myeloid Leukemia (AML) With Del(5q).

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