Rev-CLL: Study of Lenalidomide in Previously Untreated, Symptomatic Chronic Lymphocytic Leukemia (CLL)
Study Details
Study Description
Brief Summary
This study will assess the
-
efficacy (response rate) of oral lenalidomide in the treatment of patients with symptomatic, previously untreated, chronic lymphocytic leukemia (CLL),
-
toxicity of lenalidomide in patients with CLL as well as time to progression, stable disease duration and, if responses are observed, response duration.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
This is a phase II, nonrandomized, single institution study in symptomatic, previously untreated CLL patients. Subjects will receive the study drug, lenalidomide, starting at 2.5 mg daily x 3 weeks (days 1-21) and escalating up to a target dose of 10 mg daily X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28 day cycle. Although a maximal dose of 10 mg daily (days 1-21) will be targeted, if a patient is felt by the investigator to be benefiting from doses less than the target dose (i.e. 2.5 mg or 5 mg daily), the investigator may at his discretion choose to hold the patient at that dose without further escalation. For those patients who have progressive disease after cycle 3, further dose escalations as assessed by response and toxicity at the end of each escalated dose cycle to a maximum of 25 mg (days 1-21) will be allowed. Patients will be treated with lenalidomide until disease progression or 2 cycles past CR. (no maximum of cycles).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Lenalidiomide Lenalidomide target dose of 10 mg PO OD X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28-day cycle. |
Drug: Lenalidomide
Subjects will receive lenalidomide, starting at 2.5 mg daily x 3 weeks (days 1-21) and escalating up to a target dose of 10 mg daily X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28 day cycle.Patients will be treated with lenalidomide until disease progression or 2 cycles past CR. (no maximum of cycles).
Other Names:
|
Outcome Measures
Primary Outcome Measures
- To Assess the Efficacy (Response Rate) of Oral Lenalidomide in the Treatment of Patients With Symptomatic, Previously Untreated, Chronic Lymphocytic Leukemia (CLL) [Patients will be treated with lenalidomide until disease progression or 2 cycles past CR (no maximum of cycles). Participants were followed upto 53.2 months for the final data analysis.]
The primary endpoint was objective response to lenalidomide (Complete response +Partial response) evaluated as per the revised 1996 National Cancer Institute Working Group Guidelines. Complete response: absence of lymphadenopathy and organomegaly by physical exam and radiology, absence of constitutional symptoms, normal CBC. Bone marrow to be done 2 months after the above criteria are met, must be normocellular, with <30% lymphocytes. Partial Response: ≥ 50% decrease in the peripheral blood lymphocytes from pre-treatment value, ≥ 50% reduction in lymphadenopathy and organomegaly by physical exam or on CT scan. one or more of the following: neutrophils ≥ 1.5 x109/L, platelets > 100 x109/L or 50% improvement over baseline, hemoglobin > 110 g/L or 50% improvement over baseline (without transfusion).
Secondary Outcome Measures
- Percentage of Participants With Progression-free Survival (PFS) and Overall Survival (OS). [Patients will be treated with lenalidomide until disease progression or 2 cycles past CR (no maximum of cycles). Participants were followed upto 53.2 months for the final data analysis.]
Assess the time to disease progression and overall survival. (Progressive disease is defined as at least one of the following: more than or equal to 50% increase in the sum of the products of the greatest diameters of at least 2 lymph nodes on 2 consecutive determinations 2 weeks apart (at least one node must be ≥ 2 cm) or new palpable lymph nodes, more than or equal to 50% increase in the size of the liver and/or spleen as determined by measurement below the costal margin or appearance of palpable hepatomegaly or splenomegaly not previously present, more than or equal to 50% increase in the absolute number of circulating lymphocytes to at least 5.0 x109/L, OR transformation to a more aggressive histology (e.g. Richter's syndrome or prolymphocytic leukemia with >55% prolymphocytes)).
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Understand and voluntarily sign an informed consent form.
-
Age ≥18 years at the time of signing the informed consent form.
-
Able to adhere to the study visit schedule and other protocol requirements.
-
A confirmed diagnosis of B-cell CLL by NCI Working Group criteria
-
No prior systemic therapy for CLL. Steroid therapy alone for autoimmune cytopenias (anemia or thrombocytopenia) is NOT considered a prior systemic therapy.
-
Radiation: Patients may have received prior radiation therapy restricted to ≤ 25% of functioning bone marrow. Patients must be ≥ 4 weeks since last treatment with radiation therapy.
-
Surgery: previous surgery is permissible. Patient must be ≥ 4 weeks since any major surgery.
-
Patients must have symptomatic disease requiring therapy. One or more of the following must be present to be eligible:
-
Symptomatic lymphadenopathy
-
Hepatomegaly and/or splenomegaly
-
Anemia (Hb <110 g/L)
-
Thrombocytopenia (platelets <100)
-
Fatigue, weight loss, night sweats, fever (without infection) or other constitutional symptoms felt to require treatment as per treating physician discretion
-
Persistent rise in lymphocyte count with doubling time of < 12 months
-
ECOG performance status of ≤ 2 at study entry.
-
Laboratory Requirements: (must be done within 7 days prior to first study drug dose)
Hematology: Absolute granulocytes (AGC) ≥ 1.0 x 109/L Platelets ≥ 50 x 109/L Chemistry:
Serum creatinine ≤ 1.5 x UNL Bilirubin ≤ 1.5 x UNL AST (or ALT if AST ≤ 2.5 x UNL not available)
-
Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL 10 - 14 days prior to therapy and repeated within 24 hours of starting study drug and must either commit to continued abstinence from heterosexual sexual intercourse or begin TWO acceptable methods of birth control, one highly effective methods and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking lenalidomide. In addition, sexually active WCBP must agree to ongoing pregnancy testing. Men must agree not to father a child and agrees to use a condom if his partner is of child bearing potential.
-
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
Exclusion Criteria:
-
Patients who fulfill any of the following criteria are not eligible for admission to the study:
-
Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
-
Pregnant or lactating females. (Lactating females must agree not to breast feed while taking lenalidomide).
-
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.
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Use of any other experimental drug or therapy within 28 days of baseline.
-
Patients previously or currently receiving treatment with other anti-cancer therapy for CLL
-
Lymphoproliferative disease other than CLL (includes patients with prolymphocytic leukemia, mantle cell lymphoma, and those who have transformed to a more aggressive lymphoma, or Richter's syndrome).
-
Known hypersensitivity to thalidomide.
-
The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
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Any prior use of lenalidomide.
-
Concurrent use of other anti-cancer agents or treatments.
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Known positive for HIV or infectious hepatitis, type A, B or C.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University Health Network - Princess Margaret Cancer Centre | Toronto | Ontario | Canada | M5G 2M9 |
Sponsors and Collaborators
- University Health Network, Toronto
- Celgene
Investigators
- Principal Investigator: Christine I Chen, MD, University Health Network, Toronto
Study Documents (Full-Text)
None provided.More Information
Additional Information:
- Single-Agent Lenalidomide in the Treatment of Previously Untreated Chronic Lymphocytic Leukemia: JCO March 20, 2011 vol. 29 no. 9 1175-1181.
- 'Long-term follow-up of a phase 2 trial of single agent lenalidomide in previously untreated patients with chronic lymphocytic leukaemia,' British Journal of Haematology, 2014, 165, 722-740
Publications
None provided.- Rev-06-0099
- RV-CLL-PI-0099
Study Results
Participant Flow
| Recruitment Details | This was a single site, Investigator initiated study. Patients gave informed consent according to institutional and university human experimentation committee requirements. Previously untreated B-cell CLL patients >/= 18 years of age were eligible if they met the eligibility criteria. |
|---|---|
| Pre-assignment Detail | Study was halted and the protocol amended after severe toxicities were noted in the first 2 study patients when they were dosed as per the initial protocol dosing guidelines. Their data was not included in the analysis and additional 25 eligible patients were enrolled and their data was analyzed. |
| Arm/Group Title | Lenalidiomide |
|---|---|
| Arm/Group Description | Lenalidomide target dose of 10 mg PO OD X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28-day cycle. Lenalidomide: Subjects will receive lenalidomide, starting at 2.5 mg daily x 3 weeks (days 1-21) and escalating up to a target dose of 10 mg daily X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28 day cycle. Patients will be treated with lenalidomide until disease progression or 2 cycles past CR. (no maximum of cycles). Dose escalation beyond 10 mg daily to a maximum of 25 mgs daily was permitted for nonresponders. |
| Period Title: Overall Study | |
| STARTED | 27 |
| COMPLETED | 25 |
| NOT COMPLETED | 2 |
Baseline Characteristics
| Arm/Group Title | Lenalidiomide |
|---|---|
| Arm/Group Description | Lenalidomide target dose of 10 mg PO OD X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28-day cycle. Lenalidomide: Subjects will receive lenalidomide, starting at 2.5 mg daily x 3 weeks (days 1-21) and escalating up to a target dose of 10 mg daily X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28 day cycle. Patients will be treated with lenalidomide until disease progression or 2 cycles past CR. (no maximum of cycles). |
| Overall Participants | 25 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
17
68%
|
| >=65 years |
8
32%
|
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
60
|
| Sex: Female, Male (Count of Participants) | |
| Female |
9
36%
|
| Male |
16
64%
|
| Region of Enrollment (participants) [Number] | |
| Canada |
25
100%
|
Outcome Measures
| Title | To Assess the Efficacy (Response Rate) of Oral Lenalidomide in the Treatment of Patients With Symptomatic, Previously Untreated, Chronic Lymphocytic Leukemia (CLL) |
|---|---|
| Description | The primary endpoint was objective response to lenalidomide (Complete response +Partial response) evaluated as per the revised 1996 National Cancer Institute Working Group Guidelines. Complete response: absence of lymphadenopathy and organomegaly by physical exam and radiology, absence of constitutional symptoms, normal CBC. Bone marrow to be done 2 months after the above criteria are met, must be normocellular, with <30% lymphocytes. Partial Response: ≥ 50% decrease in the peripheral blood lymphocytes from pre-treatment value, ≥ 50% reduction in lymphadenopathy and organomegaly by physical exam or on CT scan. one or more of the following: neutrophils ≥ 1.5 x109/L, platelets > 100 x109/L or 50% improvement over baseline, hemoglobin > 110 g/L or 50% improvement over baseline (without transfusion). |
| Time Frame | Patients will be treated with lenalidomide until disease progression or 2 cycles past CR (no maximum of cycles). Participants were followed upto 53.2 months for the final data analysis. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Severe toxicities were seen in the first two patients enrolled on the initial protocol. The study was halted and the protocol amended to use a starting dose of lenalidomide 2.5 mg with monthly escalations to a target dose of 10 mg, extended tumor lysis prophylaxis and monitoring. 25 response evaluable patients were enrolled on the amended protocol. |
| Arm/Group Title | Lenalidiomide |
|---|---|
| Arm/Group Description | Lenalidomide target dose of 10 mg PO OD X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28-day cycle. Lenalidomide: Subjects will receive lenalidomide, starting at 2.5 mg daily x 3 weeks (days 1-21) and escalating up to a target dose of 10 mg daily X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28 day cycle. Patients will be treated with lenalidomide until disease progression or 2 cycles past CR. (no maximum of cycles). Dose escalation beyond 10 mg daily to a maximum of 25 mgs daily was permitted for nonresponders. |
| Measure Participants | 25 |
| Complete response |
5
20%
|
| Partial response |
13
52%
|
| Stable Disease |
6
24%
|
| Title | Percentage of Participants With Progression-free Survival (PFS) and Overall Survival (OS). |
|---|---|
| Description | Assess the time to disease progression and overall survival. (Progressive disease is defined as at least one of the following: more than or equal to 50% increase in the sum of the products of the greatest diameters of at least 2 lymph nodes on 2 consecutive determinations 2 weeks apart (at least one node must be ≥ 2 cm) or new palpable lymph nodes, more than or equal to 50% increase in the size of the liver and/or spleen as determined by measurement below the costal margin or appearance of palpable hepatomegaly or splenomegaly not previously present, more than or equal to 50% increase in the absolute number of circulating lymphocytes to at least 5.0 x109/L, OR transformation to a more aggressive histology (e.g. Richter's syndrome or prolymphocytic leukemia with >55% prolymphocytes)). |
| Time Frame | Patients will be treated with lenalidomide until disease progression or 2 cycles past CR (no maximum of cycles). Participants were followed upto 53.2 months for the final data analysis. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Lenalidiomide |
|---|---|
| Arm/Group Description | Lenalidomide target dose of 10 mg PO OD X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28-day cycle. Lenalidomide: Subjects will receive lenalidomide, starting at 2.5 mg daily x 3 weeks (days 1-21) and escalating up to a target dose of 10 mg daily X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28 day cycle. Patients will be treated with lenalidomide until disease progression or 2 cycles past CR. (no maximum of cycles). Dose escalation beyond 10 mg daily to a maximum of 25 mgs daily was permitted for nonresponders. |
| Measure Participants | 25 |
| Overall survival |
85.3
341.2%
|
| Progression free survival |
64.6
258.4%
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | CTCAE Version 3.0 was used for adverse event grading and categorizing | |
| Arm/Group Title | Lenalidiomide | |
| Arm/Group Description | Lenalidomide target dose of 10 mg PO OD X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28-day cycle. Lenalidomide: Subjects will receive lenalidomide, starting at 2.5 mg daily x 3 weeks (days 1-21) and escalating up to a target dose of 10 mg daily X 3 weeks (days 1-21) followed by 1 week off therapy (days 22-28) on a 28 day cycle. Patients will be treated with lenalidomide until disease progression or 2 cycles past CR. (no maximum of cycles). Dose escalation beyond 10 mg daily to a maximum of 25 mgs daily was permitted for nonresponders. | |
All Cause Mortality |
||
| Lenalidiomide | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Lenalidiomide | ||
| Affected / at Risk (%) | # Events | |
| Total | 17/25 (68%) | |
| Blood and lymphatic system disorders | ||
| Febrile Neutropenia | 4/25 (16%) | 4 |
| Cardiac disorders | ||
| Coronary Artery disease | 1/25 (4%) | 1 |
| Atrial Fibrillation | 1/25 (4%) | 1 |
| General disorders | ||
| Fever | 1/25 (4%) | 1 |
| Infections and infestations | ||
| Disseminated Zoster | 1/25 (4%) | 1 |
| Community Acquired pneumonia | 1/25 (4%) | 1 |
| Ear infection | 1/25 (4%) | 1 |
| Bacteremia | 1/25 (4%) | 1 |
| Injury, poisoning and procedural complications | ||
| Fracture | 1/25 (4%) | 1 |
| Investigations | ||
| Thrombocytopenia | 2/25 (8%) | 2 |
| Cytopenias | 1/25 (4%) | 1 |
| Metabolism and nutrition disorders | ||
| Diabetic Ketoacidosis | 1/25 (4%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| In-situ Squamous cell carcinoma | 2/25 (8%) | 2 |
| Relapse of lung cancer | 1/25 (4%) | 1 |
| Basal Cell Carcinoma | 1/25 (4%) | 1 |
| Endometrial adenocarcinoma | 1/25 (4%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 1/25 (4%) | 1 |
| Skin and subcutaneous tissue disorders | ||
| Skin Rash | 1/25 (4%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Lenalidiomide | ||
| Affected / at Risk (%) | # Events | |
| Total | 25/25 (100%) | |
| Blood and lymphatic system disorders | ||
| Tumor Flare | 22/25 (88%) | |
| Leg edema | 3/25 (12%) | |
| Febrile Neutropenia | 1/25 (4%) | |
| Anemia | 6/25 (24%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 8/25 (32%) | |
| Constipation | 6/25 (24%) | |
| General disorders | ||
| Fatigue | 18/25 (72%) | |
| Infections and infestations | ||
| Skin infection | 4/25 (16%) | |
| Upper Respiratory/Sinus infection | 2/25 (8%) | |
| Investigations | ||
| Elevated Creatinine | 11/25 (44%) | |
| Hypocalcemia | 11/25 (44%) | |
| Hypokalemia | 10/25 (40%) | |
| Hypophosphatemia | 10/25 (40%) | |
| Elevated AST or ALT | 9/25 (36%) | |
| Hypernatremia | 5/25 (20%) | |
| Hyponatremia | 4/25 (16%) | |
| Neutropenia | 18/25 (72%) | |
| Thrombocytopenia | 7/25 (28%) | |
| Musculoskeletal and connective tissue disorders | ||
| Myalgia | 10/25 (40%) | |
| Generalized Muscle weakness | 3/25 (12%) | |
| Nervous system disorders | ||
| Sensory neuropathy | 4/25 (16%) | |
| Dizziness | 3/25 (12%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea | 3/25 (12%) | |
| Skin and subcutaneous tissue disorders | ||
| Rash | 15/25 (60%) | |
| Pruritus | 8/25 (32%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Dr. Christine Chen |
|---|---|
| Organization | University Health Network - Princess Margaret Cancer Centre |
| Phone | 416-946-2827 |
| Christine.Chen@uhn.ca |
- Rev-06-0099
- RV-CLL-PI-0099