Lenalidomide for Myelodysplastic Syndrome Refractory to Hypomethylating Agents

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT01246076
• Collaborator: (none)
• Enrollment: 24
• Locations: 2
• Arm: 1
• Duration (Months): 50
• Patients Per Site: 12
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the proportion of confirmed responses (complete response, partial response, and hematologic improvement as defined by revised IWG criteria during the 12 months of treatment.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes	Drug: Lenalidomide	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of High Dose Lenalidomide in Patients With Myelodysplastic Syndrome Refractory to Hypomethylating Agents
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lenalidomide Lenalidomide 50 mg/day for two 28 day cycles. Patients who have bone marrow aplasia as defined by a cellularity of <10% will be observed till counts recover. If patients do not progress following 2 cycles of HD lenalidomide, they will receive low dose lenalidomide 10 mg daily for 12 cycles.	Drug: Lenalidomide; Other Names: Revlimid

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Confirmed Responses (Complete Remission, Partial Remission, or Hematologic Improvement) as Defined by the International Working Group Criteria [Up to 56 weeks (14 cycles of treatment)]

   Complete remission (CR): ≤5% myeloblasts bone marrow blasts, normal maturation in all cell lines (dysplasia will be noted), ≥11 g/dl peripheral blood hemoglobin, ≥100x10^9cells/μL peripheral blood platelets, ≥1000 cells/ μL peripheral blood absolute neutrophil count (ANC), and 0% peripheral blood blasts. Marrow complete remission (MCR): ≤5% myeloblasts and decreased by ≥50% compared to pre-treatment bone marrow blasts, bone marrow morphology not relevant, and peripheral blood (if hematological improvement they will be noted in addition to marrow CR). Partial remission (PR): previously had ≥5% myeloblasts and now have ≥5% myeloblasts but decreased by ≥50% compared to pre-treatment, bone marrow morphology not relevant, ≥11 g/dl peripheral blood hemoglobin, ≥100x109cells/μL peripheral blood platelets, ≥1000 cells/ μL peripheral blood ANC, and 0% peripheral blood blasts

Secondary Outcome Measures

1. Overall Survival Rate [6 months after end of treatment (up to 82 weeks from start of treatment)]

   -Overall survival rate is the percentage of participants who were alive 6 months after end of treatment.

2. Duration of Response [Until 6 months after end of treatment]

3. Time to Discontinuation of Treatment [Up to 56 weeks (14 cycles)]

4. Toxicity as Measured by Number of Participants Who Experienced Related Grade 3-5 Adverse Events Based on CTCAE Version 4 [30 days after end of treatment (up to 60 weeks)]

5. Time to Progression [Up to 6 months after completion of treatment (up to 82 weeks from start of treatment)]

   The time to progression is defined as the time from registration to the date of progression or last follow-up. Those who die will be considered to have had disease progression unless documented evidence clearly indicates no progression has occurred.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient must be able to understand and voluntarily sign an informed consent form.

• Patient must be ≥ 18 years old.

• Patient must be able to adhere to the study visit schedule and other protocol requirements.

• Patient must have histologically confirmed Myelodysplastic Syndrome as defined by FAB

Classification including CMML and secondary MDS which has either:

• progressed at any time during treatment with hypomethylating agents

• failed to achieve a response after 6 cycles

• progressed after treatment with hypomethylating agents had been discontinued Criteria for response and for progression as defined by revised IWG criteria

• Patient must have discontinued all previous cancer therapy, including radiation, hormonal therapy and surgery at least 4 weeks prior to treatment in this study.

• Patient must have an ECOG performance status of ≤ 2 at study entry

• Patient must have laboratory test results within these ranges:

• calculated creatinine clearance ≥ 30ml/min by Cockcroft-Gault formula

• total bilirubin ≤ 1.5 x ULN

• AST (SGOT) and ALT (SGPT) ≤ 3 x ULN

• Patient must be disease free of prior malignancies for at least 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.

• Patient must be registered into the mandatory Revlimid REMS® program and be willing and able to comply with the requirements of Revlimid REMS®.

• If a female of childbearing potential (FCBP), patient must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 to 14 days prior to initiation of therapy and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days).

Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program. A FCBP is defined as a sexually mature woman who:

1. has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

-If a FCBP, patient must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. The two methods of reliable contraception must include one highly effective method (i.e. intrauterine device (IUD), hormonal [birth control pills, injections, or implants], tubal ligation, partner's vasectomy) and one additional effective (barrier) method (i.e. latex condom, diaphragm, cervical cap). FCBP must be referred to a qualified provider of contraceptive methods if needed

Exclusion Criteria:

• Patient must not have any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.

• Patient must not be pregnant or breastfeeding.

• Patient must not have any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.

• Patient must not use any other experimental drug or therapy within 28 days of baseline.

• Patient must not have a known hypersensitivity to thalidomide.

• Patient must not have developed of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.

• Patient must not have any prior use of lenalidomide.

• Patient must not be concurrently using other anti-cancer agents or treatments.

• Patient must not have known seropositivity for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Scottsdale AZ	Scottsdale	Arizona	United States
2	Washington University School of Medicine	St. Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine

Investigators

• Principal Investigator: Ravi Vij, M.D., Washington University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01246076
• Other Study ID Numbers: 201011810
• First Posted: Nov 23, 2010
• Last Update Posted: Jan 5, 2016
• Last Verified: Nov 1, 2015

• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome; Lenalidomide

Study Results

Participant Flow

Recruitment Details	The study opened to participant enrollment on 06/30/2011 and closed to participant enrollment on 05/19/2014.

Arm/Group Title	Lenalidomide
Arm/Group Description	Lenalidomide 50 mg/day for two 28 day cycles. Patients who have bone marrow aplasia as defined by a cellularity of <10% will be observed till counts recover. If patients do not progress following 2 cycles of HD lenalidomide, they will receive low dose lenalidomide 10 mg daily for 12 cycles.
Period Title: Overall Study
STARTED	24
COMPLETED	24
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Lenalidomide
Arm/Group Description	Lenalidomide 50 mg/day for two 28 day cycles. Patients who have bone marrow aplasia as defined by a cellularity of <10% will be observed till counts recover. If patients do not progress following 2 cycles of HD lenalidomide, they will receive low dose lenalidomide 10 mg daily for 12 cycles.
Overall Participants	24
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	73
Sex: Female, Male (Count of Participants)
Female	5 20.8%
Male	19 79.2%
Region of Enrollment (participants) [Number]
United States	24 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Confirmed Responses (Complete Remission, Partial Remission, or Hematologic Improvement) as Defined by the International Working Group Criteria
Description	Complete remission (CR): ≤5% myeloblasts bone marrow blasts, normal maturation in all cell lines (dysplasia will be noted), ≥11 g/dl peripheral blood hemoglobin, ≥100x10^9cells/μL peripheral blood platelets, ≥1000 cells/ μL peripheral blood absolute neutrophil count (ANC), and 0% peripheral blood blasts. Marrow complete remission (MCR): ≤5% myeloblasts and decreased by ≥50% compared to pre-treatment bone marrow blasts, bone marrow morphology not relevant, and peripheral blood (if hematological improvement they will be noted in addition to marrow CR). Partial remission (PR): previously had ≥5% myeloblasts and now have ≥5% myeloblasts but decreased by ≥50% compared to pre-treatment, bone marrow morphology not relevant, ≥11 g/dl peripheral blood hemoglobin, ≥100x109cells/μL peripheral blood platelets, ≥1000 cells/ μL peripheral blood ANC, and 0% peripheral blood blasts
Time Frame	Up to 56 weeks (14 cycles of treatment)

Outcome Measure Data

Analysis Population Description

8 participants were not evaluable for this outcome measure because they did not complete at least one cycle of therapy.

Arm/Group Title	Lenalidomide
Arm/Group Description	Lenalidomide 50 mg/day for two 28 day cycles. Patients who have bone marrow aplasia as defined by a cellularity of <10% will be observed till counts recover. If patients do not progress following 2 cycles of HD lenalidomide, they will receive low dose lenalidomide 10 mg daily for 12 cycles.
Measure Participants	16
CR	0 0%
MCR	8 33.3%
PR	0 0%
HI	2 8.3%

2. Secondary Outcome

Title	Overall Survival Rate
Description	-Overall survival rate is the percentage of participants who were alive 6 months after end of treatment.
Time Frame	6 months after end of treatment (up to 82 weeks from start of treatment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lenalidomide
Arm/Group Description	Lenalidomide 50 mg/day for two 28 day cycles. Patients who have bone marrow aplasia as defined by a cellularity of <10% will be observed till counts recover. If patients do not progress following 2 cycles of HD lenalidomide, they will receive low dose lenalidomide 10 mg daily for 12 cycles.
Measure Participants	24
Number [percentage of participants]	29 120.8%

3. Secondary Outcome

Title	Duration of Response
Time Frame	Until 6 months after end of treatment

Outcome Measure Data

Analysis Population Description

8 participants had a response -- all had MCR.

Arm/Group Title	Lenalidomide
Arm/Group Description	Lenalidomide 50 mg/day for two 28 day cycles. Patients who have bone marrow aplasia as defined by a cellularity of <10% will be observed till counts recover. If patients do not progress following 2 cycles of HD lenalidomide, they will receive low dose lenalidomide 10 mg daily for 12 cycles.
Measure Participants	8
Median (Full Range) [days]	70

4. Secondary Outcome

Title	Time to Discontinuation of Treatment
Time Frame	Up to 56 weeks (14 cycles)

Outcome Measure Data

Analysis Population Description

16 out of 24 participants were evaluable for this outcome measure as these 16 participants completed at least the first cycle of treatment.

Arm/Group Title	Lenalidomide
Arm/Group Description	Lenalidomide 50 mg/day for two 28 day cycles. Patients who have bone marrow aplasia as defined by a cellularity of <10% will be observed till counts recover. If patients do not progress following 2 cycles of HD lenalidomide, they will receive low dose lenalidomide 10 mg daily for 12 cycles.
Measure Participants	16
Median (Full Range) [cycles]	2

5. Secondary Outcome

Title	Toxicity as Measured by Number of Participants Who Experienced Related Grade 3-5 Adverse Events Based on CTCAE Version 4
Time Frame	30 days after end of treatment (up to 60 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lenalidomide
Arm/Group Description	Lenalidomide 50 mg/day for two 28 day cycles. Patients who have bone marrow aplasia as defined by a cellularity of <10% will be observed till counts recover. If patients do not progress following 2 cycles of HD lenalidomide, they will receive low dose lenalidomide 10 mg daily for 12 cycles.
Measure Participants	24
Pneumonia	12 50%
Sepsis	4 16.7%
Febrile neutropenia	8 33.3%
Rash	2 8.3%
Thromboembolic event	1 4.2%
Myocardial infarction	1 4.2%
New cancer - mammary analogue salivary carcinoma	1 4.2%

6. Secondary Outcome

Title	Time to Progression
Description	The time to progression is defined as the time from registration to the date of progression or last follow-up. Those who die will be considered to have had disease progression unless documented evidence clearly indicates no progression has occurred.
Time Frame	Up to 6 months after completion of treatment (up to 82 weeks from start of treatment)

Outcome Measure Data

Analysis Population Description

Time to progression was not analyzed. This was a prespecified secondary outcome but due to the early termination of the study time to progression was not followed.

Arm/Group Title	Lenalidomide
Arm/Group Description	Lenalidomide 50 mg/day for two 28 day cycles. Patients who have bone marrow aplasia as defined by a cellularity of <10% will be observed till counts recover. If patients do not progress following 2 cycles of HD lenalidomide, they will receive low dose lenalidomide 10 mg daily for 12 cycles.
Measure Participants	0

Adverse Events

Arm/Group Title	Lenalidomide
Arm/Group Description	Lenalidomide 50 mg/day for two 28 day cycles. Patients who have bone marrow aplasia as defined by a cellularity of <10% will be observed till counts recover. If patients do not progress following 2 cycles of HD lenalidomide, they will receive low dose lenalidomide 10 mg daily for 12 cycles.
All Cause Mortality
	Lenalidomide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Lenalidomide
	Affected / at Risk (%)	# Events
Total	19/24 (79.2%)
Blood and lymphatic system disorders
Anemia	1/24 (4.2%)
Cardiac disorders
Cardiac arrest	1/24 (4.2%)
Gastrointestinal disorders
Abdominal pain	1/24 (4.2%)
General disorders
Death	1/24 (4.2%)
Infections and infestations
Febrile neutropenia	5/24 (20.8%)
Lung infection	8/24 (33.3%)
Sepsis	3/24 (12.5%)
Skin infection	1/24 (4.2%)
Injury, poisoning and procedural complications
Fall	1/24 (4.2%)
Investigations
Platelet count decreased	1/24 (4.2%)
White blood cell decreased	1/24 (4.2%)
Metabolism and nutrition disorders
Dehydration	1/24 (4.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
High grade adenocarcinoma	1/24 (4.2%)
Renal and urinary disorders
Hematuria	1/24 (4.2%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/24 (4.2%)
Vascular disorders
Hematoma	1/24 (4.2%)
Thromboembolic event: pulmonary embolism	1/24 (4.2%)
Other (Not Including Serious) Adverse Events
	Lenalidomide
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Blood and lymphatic system disorders
Anemia	8/24 (33.3%)
Cardiac disorders
Atrial fibrillation	4/24 (16.7%)
Chest pain	1/24 (4.2%)
Diastolic dysfunction	1/24 (4.2%)
Ejection fraction decreased	1/24 (4.2%)
Myocardial infarction	1/24 (4.2%)
Non-cardiac chest pain	3/24 (12.5%)
Pericardial effusion	1/24 (4.2%)
Sinus bradycardia	3/24 (12.5%)
Sinus tachycardia	2/24 (8.3%)
Ear and labyrinth disorders
Ear pain	1/24 (4.2%)
Hearing impaired	1/24 (4.2%)
Vertigo	1/24 (4.2%)
Eye disorders
Blurred vision	2/24 (8.3%)
Gastrointestinal disorders
Abdominal pain	3/24 (12.5%)
Constipation	9/24 (37.5%)
Dental carries	2/24 (8.3%)
Diarrhea	10/24 (41.7%)
Dry mouth	1/24 (4.2%)
Dyspepsia	3/24 (12.5%)
Dysphagia	3/24 (12.5%)
Gastrointestinal pain	1/24 (4.2%)
Mucositis oral	8/24 (33.3%)
Nausea	10/24 (41.7%)
Periodontal disease	1/24 (4.2%)
Stomach pain	1/24 (4.2%)
Stomatitis	1/24 (4.2%)
Vomiting	7/24 (29.2%)
General disorders
Edema face	1/24 (4.2%)
Edema limbs	1/24 (4.2%)
Fatigue	17/24 (70.8%)
Fever	6/24 (25%)
Fluid overload	1/24 (4.2%)
Localized edema	1/24 (4.2%)
Neck edema	1/24 (4.2%)
Pain	3/24 (12.5%)
Immune system disorders
Allergic reaction	1/24 (4.2%)
Autoimmune hemolytic anemia	1/24 (4.2%)
Transfusion reaction	2/24 (8.3%)
Infections and infestations
Blood-Enterococcus faecium	1/24 (4.2%)
Clostridium difficile infection	2/24 (8.3%)
Febrile neutropenia	3/24 (12.5%)
Herpes stomatitis	1/24 (4.2%)
Lung infection	4/24 (16.7%)
Sepsis	1/24 (4.2%)
Sinusitis	1/24 (4.2%)
Skin infection	1/24 (4.2%)
Splenic infarction	1/24 (4.2%)
Staphylococcus epidermidis	1/24 (4.2%)
Tooth infection	1/24 (4.2%)
Urinary tract infection	1/24 (4.2%)
VRE stool	4/24 (16.7%)
Injury, poisoning and procedural complications
Bruising	11/24 (45.8%)
Fall	2/24 (8.3%)
Hip fracture	1/24 (4.2%)
Investigations
Activated partial thromboplastin time prolonged	7/24 (29.2%)
Alanine aminotransferase increased	13/24 (54.2%)
Alkaline phosphatase increased	8/24 (33.3%)
Aspartate aminotransferase increased	11/24 (45.8%)
BUN increased	1/24 (4.2%)
Blood bilirubin increased	10/24 (41.7%)
Cardiac troponin I increased	2/24 (8.3%)
Chills	5/24 (20.8%)
Creatinine increased	7/24 (29.2%)
Ejection fraction decreased	1/24 (4.2%)
INR increased	8/24 (33.3%)
Lymphocyte count decreased	13/24 (54.2%)
Neutrophil count decreased	9/24 (37.5%)
Platelet count decreased	12/24 (50%)
Splenomegaly	1/24 (4.2%)
Weight loss	5/24 (20.8%)
White blood cell decreased	13/24 (54.2%)
Metabolism and nutrition disorders
Anorexia	7/24 (29.2%)
Dehydration	5/24 (20.8%)
Hyperglycemia	3/24 (12.5%)
Hyperkalemia	4/24 (16.7%)
Hypermagnesemia	1/24 (4.2%)
Hypernatremia	3/24 (12.5%)
Hyperuricemia	3/24 (12.5%)
Hypoalbuminemia	17/24 (70.8%)
Hypocalcemia	16/24 (66.7%)
Hypoglycemia	1/24 (4.2%)
Hypokalemia	8/24 (33.3%)
Hypomagnesemia	2/24 (8.3%)
Hyponatremia	10/24 (41.7%)
Hypophosphatemia	7/24 (29.2%)
Iron overload	1/24 (4.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/24 (4.2%)
Back pain	6/24 (25%)
Bone pain	3/24 (12.5%)
Flank pain	1/24 (4.2%)
Generalized aches and pains	1/24 (4.2%)
Generalized muscle weakness	7/24 (29.2%)
Hand cramps	1/24 (4.2%)
Muscle cramps	2/24 (8.3%)
Myalgia	1/24 (4.2%)
Pain in extremity	6/24 (25%)
Nervous system disorders
Akathisia	1/24 (4.2%)
Dizziness	10/24 (41.7%)
Dysgeusia	2/24 (8.3%)
Headache	7/24 (29.2%)
Lethargy	2/24 (8.3%)
Psychiatric disorders
Anxiety	5/24 (20.8%)
Confusion	4/24 (16.7%)
Depression	1/24 (4.2%)
Hallucinations	1/24 (4.2%)
Insomnia	2/24 (8.3%)
Renal and urinary disorders
Acute kidney injury	4/24 (16.7%)
Hematuria	1/24 (4.2%)
Proteinuria	8/24 (33.3%)
Urinary frequency	2/24 (8.3%)
Urinary incontinence	1/24 (4.2%)
Urinary tract pain	1/24 (4.2%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/24 (4.2%)
Aspiration	1/24 (4.2%)
Atelectasis	3/24 (12.5%)
Cough	10/24 (41.7%)
Dyspnea	15/24 (62.5%)
Epistaxis	8/24 (33.3%)
Hoarseness	3/24 (12.5%)
Hypoxia	6/24 (25%)
Pleural effusion	4/24 (16.7%)
Productive cough	5/24 (20.8%)
Pulmonary edema	4/24 (16.7%)
Respiratory failure	1/24 (4.2%)
Sore throat	3/24 (12.5%)
Wheezing	3/24 (12.5%)
Skin and subcutaneous tissue disorders
Alopecia	2/24 (8.3%)
Bullous dermatitis	1/24 (4.2%)
Dry skin	4/24 (16.7%)
Pruritus	6/24 (25%)
Purpura	5/24 (20.8%)
Rash maculo-papular	16/24 (66.7%)
Scalp pain	1/24 (4.2%)
Skin hyperpigmentation	1/24 (4.2%)
Skin ulceration	3/24 (12.5%)
Vascular disorders
Hematoma	2/24 (8.3%)
Hot flashes	1/24 (4.2%)
Hypertension	3/24 (12.5%)
Hypotension	6/24 (25%)
Thromboembolic event - DVT	2/24 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.