Low to Intermediate-1 MDS, MDS, Myelodysplastic Syndrome, Non-deletion 5q
Conditions
Keywords
Myelodysplastic Syndrome, MDS, Low to Intermediate-1 MDS, Non-deletion 5q, Lenalidomide
Brief summary
Revlimid® (Lenalidomide) is indicated for a type of blood cancer, myelodysplastic syndrome (MDS), at 10mg for a specific type of myelodysplastic syndrome with a genetic abnormality called deletion 5q in Low and Intermediate-1 (INT-1) patients (staging system according to International Prognostic Scoring System (IPSS)). The purpose of this Phase I/II study is to determine the optimal dose of Revlimid® (Lenalidomide) in MDS Low and MDS INT-1 patients without deletion 5q by slowly increasing the dose while monitoring blood counts for safety evaluation as well as observe other adverse events. Efficacy will also be observed for the phase II portion of the study.
Detailed description
There are little options for non deletion 5q Low and INT-1 patients. This study aims to find an early clinical signal for higher activity and better response with lenalidomide in patients with non deletion 5q Low and INT-1 MDS patients. Lenalidomide is an immunomodulatory agent. Thalidomide, the parent compound, has both immunomodulatory and anti-angiogenic properties which could confer anti-tumor and anti-metastatic efforts. Lenalidomide has been demonstrated to possess anti-angiogenic activity through inhibition of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-alpha) induced endothelial cell migration (movement of cells in preparation to form new abnormal blood vessels for cancer cells), due at least in part to inhibition of Akt phosphorylation response to bFGF. In addition, lenalidomide has a variety of immunomodulatory effects. Lenalidomide stimulates T cell proliferation, and the production of interleukin-2 (IL-2), IL-10 and interferon-gamma (IFN-gamma), inhibits IL-1 beta and IL-6 and modulated IL-12 production. Although the exact anti-tumor mechanism of action of lenalidomide is unknown, a number of mechanisms are postulated for the activity of Lenalidomide in MDS.
Interventions
DRUGLenalidomide
Dose Level Lenalidomide Schedule 1. 15mg/day for d1-21 out of 28 days 2. 20mg/day for d1-21 out of 28 days 3. 25mg/day for d1-21 out of 28 days
Sponsors
Celgene Corporation
Sidney Kimmel Cancer Center at Thomas Jefferson University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Understand and voluntarily sign an informed consent form. 2. Age 18 years at the time of signing the informed consent form. 3. Able to adhere to the study visit schedule and other protocol requirements. 4. MDS patients who fulfill diagnostic criteria and classification by the IPSS Low or Int-1 categories according to cytogenetics, blood cytopenias and bone marrow blasts. See Appendix II. 5. All previous therapy such as azacitidine, decitabine, growth factors such as EPO (Procrit or Aranesp) and (Neupogen or Neulasta, Leukine, Neumega) or experimental therapy, must have been discontinued at least 4 weeks prior to treatment in this study. 6. ECOG performance status of 2 at study entry (see Appendix I). 7. Laboratory test results within these ranges: * Absolute neutrophil count 500/mm3 * Platelet count 50,000 /mm3 * Serum creatinine 2.0 mg/dL * Total bilirubin 1.5 mg/dL * AST (SGOT) and ALT (SGPT) 2 x ULN or 5 x ULN if hepatic metastases are present. 8. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. See Appendix V: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods, AND also Appendix VI: Education and Counseling Guidance Document. 9. Disease free of prior malignancies for 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma insitu of the cervix or breast * A female of childbearing potential is 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).
Exclusion criteria
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. 2. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide). 3. 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. 4. Use of any other experimental drug or therapy within 28 days of baseline. 5. Known hypersensitivity to thalidomide. 6. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. 7. Any prior use of lenalidomide. 8. Concurrent use of other anti-cancer agents or treatments. 9. Known positive for HIV or infectious hepatitis, type A, B or C. 10. Myocardial infarction within 6 months prior to enrollment, or New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active conduction system abnormalities. 11. History of thromboembolic disease within the past 6 months, regardless of anticoagulation \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine CR, PR, and Rate of Stable Disease in MDS Patients | 2 years | Determine CR, PR, and rate of stable disease in MDS patients, IPSS Score LOW or INT-1 who do not have the 5q- cytogenetic abnormality according to the IWG criteria for response in \>10mg doses of lenalidomide |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety With Dose Escalation | 2 years | Safety (type, frequency, severity, and relationship of adverse events to study treatment) with dose escalation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide (15mg) Lenalidomide will be given orally on day 1-21, followed by a 7day rest (28 day cycle). Cycles will be repeated every 28 days.
Lenalidomide: Dose Level Lenalidomide Schedule
1. 15mg/day for d1-21 out of 28 days
2. 20mg/day for d1-21 out of 28 days
3. 25mg/day for d1-21 out of 28 days | 3 |
| Lenalidomide (20mg) Lenalidomide will be given orally on day 1-21, followed by a 7day rest (28 day cycle). Cycles will be repeated every 28 days.
Lenalidomide: Dose Level Lenalidomide Schedule
1. 15mg/day for d1-21 out of 28 days
2. 20mg/day for d1-21 out of 28 days
3. 25mg/day for d1-21 out of 28 days | 5 |
| Lenalidomide (25mg) Lenalidomide will be given orally on day 1-21, followed by a 7day rest (28 day cycle). Cycles will be repeated every 28 days.
Lenalidomide: Dose Level Lenalidomide Schedule
1. 15mg/day for d1-21 out of 28 days
2. 20mg/day for d1-21 out of 28 days
3. 25mg/day for d1-21 out of 28 days | 0 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Lenalidomide (15mg) | Lenalidomide (20mg) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 5 Participants |
| Age, Continuous | 57.38 years STANDARD_DEVIATION 20.06 | 65.98 years STANDARD_DEVIATION 11.02 | 62.76 years STANDARD_DEVIATION 14.29 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 7 Participants |
| Region of Enrollment United States | 3 participants | 5 participants | 8 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 0 / 0 |
| serious Total, serious adverse events | 0 / 3 | 0 / 5 | 0 / 0 |
Outcome results
Primary
Determine CR, PR, and Rate of Stable Disease in MDS Patients
Determine CR, PR, and rate of stable disease in MDS patients, IPSS Score LOW or INT-1 who do not have the 5q- cytogenetic abnormality according to the IWG criteria for response in \>10mg doses of lenalidomide
Time frame: 2 years
Secondary
Safety With Dose Escalation
Safety (type, frequency, severity, and relationship of adverse events to study treatment) with dose escalation.
Time frame: 2 years