Chronic Myeloproliferative Disorders, Secondary Myelofibrosis
Conditions
Keywords
secondary myelofibrosis, polycythemia vera, essential thrombocythemia, primary myelofibrosis
Brief summary
RATIONALE: Biological therapies, such as CC-4047, may stimulate the immune system in different ways and stop cancer cells from growing. CC-4047 may also stop the growth of cancer cells by blocking blood flow to the cancer. PURPOSE: This trial is studying the side effects and best dose of CC-4047 and to see how well it works in treating patients with myelofibrosis.
Detailed description
OBJECTIVES: Phase I: Primary * To determine the Maximum Tolerated Dose of CC-4047 in the treatment of Primary, Post Polycythemia Vera, or Post Essential Thrombocythemia Myelofibrosis (PMF, post-PV MF, or post-ET MF). Phase II: Primary * Best overall response as determined by International Working Group Criteria over the first 6 cycles (168 days) of study treatment. Secondary * Safety (type, frequency, severity \[National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0\] of adverse events (AEs), and relationship of AEs to CC-4047. * Duration of response. * Time to response. * Best overall response as determined by International Working Group Criteria over the first 12 cycles (336 days) of study treatment. OUTLINE: Patients receive oral CC-4047. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 28 days and then every 6 months for up to 3 years.
Interventions
DRUGCC-4047
CC-4047: taken orally each day in a 28 day cycle.
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of primary and post essential thrombocythemia (ET) or post polycythemia vera (PV) myelofibrosis requiring therapy * De novo presentation (i.e., agnogenic myeloid metaplasia AND post ET or post PV myelofibrosis) * Developed after an antecedent history of PV (i.e., post polycythemic myeloid metaplasia) or essential polycythemia (i.e., post thrombocythemic myeloid metaplasia) * Total hemoglobin \< 10 g/dL OR transfusion dependent anemia (defined by a history of ≥ 2 units of red blood cell (RBC) transfusions within the past 28 days for hemoglobin \< 8.5 g/dL that was not associated with overt bleeding) OR marked splenomegaly (e.g., ≥ 10 cm below costal margin) PATIENT CHARACTERISTICS: * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Absolute neutrophil count (ANC) ≥ 500/μL * Platelet count ≥ 20,000/μL * Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3 times upper limit of normal (ULN) (≤ 5 times ULN if attributed to hepatic extramedullary hematopoiesis) * Total bilirubin ≤ 3 times ULN OR direct bilirubin ≤ 2 times ULN * Serum creatinine ≤ 2.0 mg/dL * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective double-method contraception for ≥ 28 days before, during, and for ≥ 28 days after completion of study treatment * Agrees to abstain from donating blood, semen, or sperm during and for ≥ 28 days after completion of study treatment * Willing to undergo transfusion of blood products (if applicable) * Able to complete questionnaire(s) alone or with assistance * No known HIV positivity, hepatitis B carrier, or active hepatitis C infection * No serious medical condition, psychiatric illness, or any other condition, including the presence of laboratory abnormalities, that (as judged by the treating physician) would preclude giving informed consent or participating in the study or confound the ability to interpret data from the study * No other active malignancies, except basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast * No active deep vein thrombosis or pulmonary embolism that has not been therapeutically anticoagulated PRIOR CONCURRENT THERAPY: * Recovered from all prior therapy * No prior CC-4047 * More than 28 days since prior growth factors, cytotoxic chemotherapeutic agents (e.g., hydroxyurea or anagrelide), corticosteroids, or experimental drugs or therapies * No other concurrent experimental drugs or therapies or cytotoxic chemotherapeutic agents (e.g., hydroxyurea or anagrelide) for myelofibrosis * No concurrent growth factors (including erythropoietin) for myelofibrosis, except G-CSF or pegfilgrastim * No concurrent chronic use (i.e., \> 2 weeks) of more than physiologic doses of corticosteroids (dose equivalent to \> 10 mg/day of prednisone)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine the Maximum Tolerated Dose of CC-4047 | The first 28-day cycle of treatment. | Starting at a dose level of 2.5 mg/d on days 1-21 in every 28 day cycle, participants were accrued in cohorts of three to assess dose limiting toxicities (DLT) and determine the maximum tolerated dose (MTD). Dose escalation at increments of 0.5 mg/d was done if no subject had a DLT (a grade 4 or higher hematologic toxicity or a grade 3 or higher febrile neutropenia or a grade 3 or higher non-hematologic toxicity) in cycle 1. Subsequent cohorts were treated until the maximum tolerated dose (MTD) was reached (dose level before that which results in a DLT in \>1 of 6 subjects). Subsequent participants were treated at the MTD, those without response at the MTD after 3 cycles were lowered to the minimal efficacious dose (MED) of 0.5 mg daily. Here, we are reporting the percentage of participants in Phase I with a DLT at each dose level. |
| Best Overall Response Over the First 6 Cycles of Treatment | Every cycle of treatment for 6 cycles. Each cycle is 28 days. | Response evaluation: Complete Remission (CR): Neutrophil count between 1 to 10 x 10\^9/L without peripheral blasts in blood or bone marrow. Partial Hematologic Response/Partial Remission (PR): Increase in neutrophil by 50% + above 10\^9/L for neutropenia) Clinical Improvement (CI): Increase in Neutrophil count, hemoglobin, platelet count or reduction in blood/marrow blasts. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Related Adverse Events. | During treatment and every 6 months until 3 years from registration or progression. | Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. The number of participants with grade 3 or higher adverse events at least possibly related to study treatment are reported here. |
| Duration of Response Time | Time from response to disease progression, intolerance of study drug, or death. | Duration of response is defined as the date at which the patient's objective status is first noted to be a CR, PR or CI to the date progression is documented (if one has occurred) or to the date of last follow-up(for those patients who have not progressed). |
| Time to Response | Time from registration to the first date of response within twelve 28-day cycles of treatment. | The time to response is defined as the time from study registration to the first date at which the patient's objective status was classified as a response (CR, PR or CI). In patients who do not achieve a response, time to response will be censored at the patient's last evaluation date. The distribution for each of these event-time variables (duration of response and time to response) will be estimated by Kaplan-Meier curves. |
Countries
United States
Participant flow
Recruitment details
This study opened June 2008 and accrued 12 Phase I participants and 65 Phase II participants before being closed in January 2010.
Pre-assignment details
Participants were accrued to the Phase I portion of this study in each of the 2.5, 3.0, and 3.5 mg dose cohorts. Dose Limiting Toxicities (DLT) were observed at the 3.5 mg level, and the 3 mg level was confirmed as the maximum tolerated dose. However, efficacy was not improved at higher doses and the most effective dose level was deemed 0.5 mg/day.
Participants by arm
| Arm | Count |
|---|---|
| Phase II All patients enrolled to this Phase II arm started treatment at 0.5mg/day with CC-4047 every day of each 28 day cycle. | 65 |
| Phase I Participants were accrued to the Phase I portion of this study in each of the 2.5, 3.0, and 3.5 mg dose cohorts to determine the Maximum Tolerated Dose (MTD). Dose limiting Toxicities (DLT) were observed at the 3.5 mg level, and the 3 mg level was confirmed as the maximum tolerated dose. For this study a DLT was defined as a grade 4 hematologic toxicity, a grade 3 or higher febrile neutropenia, or a grade 3 or higher non-hematologic toxicity. | 12 |
| Total | 77 |
Baseline characteristics
| Characteristic | Phase II | Phase I | Total |
|---|---|---|---|
| Age, Continuous | 68 years FULL_RANGE 9.7 | 66 years | 67 years |
| Region of Enrollment United States | 65 participants | 12 participants | 77 participants |
| Sex: Female, Male Female | 18 Participants | 7 Participants | 25 Participants |
| Sex: Female, Male Male | 47 Participants | 5 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 65 / 65 |
| serious Total, serious adverse events | 19 / 65 |
Outcome results
Primary
Best Overall Response Over the First 6 Cycles of Treatment
Response evaluation: Complete Remission (CR): Neutrophil count between 1 to 10 x 10\^9/L without peripheral blasts in blood or bone marrow. Partial Hematologic Response/Partial Remission (PR): Increase in neutrophil by 50% + above 10\^9/L for neutropenia) Clinical Improvement (CI): Increase in Neutrophil count, hemoglobin, platelet count or reduction in blood/marrow blasts.
Time frame: Every cycle of treatment for 6 cycles. Each cycle is 28 days.
Population: None of the participants from the Phase I cohort were analyzed for this endpoint. All 65 Phase II participants were evaluable for this endpoint and included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Best Overall Response Over the First 6 Cycles of Treatment | Complete Remission | 0 participants |
| Phase I | Best Overall Response Over the First 6 Cycles of Treatment | Partial Remission | 0 participants |
| Phase I | Best Overall Response Over the First 6 Cycles of Treatment | Clinical Improvement | 9 participants |
Primary
Determine the Maximum Tolerated Dose of CC-4047
Starting at a dose level of 2.5 mg/d on days 1-21 in every 28 day cycle, participants were accrued in cohorts of three to assess dose limiting toxicities (DLT) and determine the maximum tolerated dose (MTD). Dose escalation at increments of 0.5 mg/d was done if no subject had a DLT (a grade 4 or higher hematologic toxicity or a grade 3 or higher febrile neutropenia or a grade 3 or higher non-hematologic toxicity) in cycle 1. Subsequent cohorts were treated until the maximum tolerated dose (MTD) was reached (dose level before that which results in a DLT in \>1 of 6 subjects). Subsequent participants were treated at the MTD, those without response at the MTD after 3 cycles were lowered to the minimal efficacious dose (MED) of 0.5 mg daily. Here, we are reporting the percentage of participants in Phase I with a DLT at each dose level.
Time frame: The first 28-day cycle of treatment.
Population: None of the Phase II participants were evaluable for this endpoint. For the Phase I portion of this study, three participants were accrued at a 2.5 mg/day dose level, six at the 3.0 mg/day dose level, and three at the 3.5 mg/day dose level.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Determine the Maximum Tolerated Dose of CC-4047 | 2.5 mg/day | 0 percentage of participants with DLT |
| Phase I | Determine the Maximum Tolerated Dose of CC-4047 | 3.0 mg/day | 0 percentage of participants with DLT |
| Phase I | Determine the Maximum Tolerated Dose of CC-4047 | 3.5 mg/day | 66 percentage of participants with DLT |
Secondary
Duration of Response Time
Duration of response is defined as the date at which the patient's objective status is first noted to be a CR, PR or CI to the date progression is documented (if one has occurred) or to the date of last follow-up(for those patients who have not progressed).
Time frame: Time from response to disease progression, intolerance of study drug, or death.
Population: None of the Phase I participants were evaluable for this endpoint. Sixty-five (65) participants were recruited for the Phase II portion. Results presented here are on the 9 Phase II patients who responded to treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I | Duration of Response Time | 5.6 Months |
Secondary
Number of Participants With Treatment Related Adverse Events.
Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. The number of participants with grade 3 or higher adverse events at least possibly related to study treatment are reported here.
Time frame: During treatment and every 6 months until 3 years from registration or progression.
Population: None of the Phase I participants were used for this primary endpoint. All 65 Phase II participants were evaluable for this endpoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Number of Participants With Treatment Related Adverse Events. | Grade 3 or Higher | 6 participants |
| Phase I | Number of Participants With Treatment Related Adverse Events. | Grade 4 or Higher | 3 participants |
| Phase I | Number of Participants With Treatment Related Adverse Events. | Grade 5 | 0 participants |
Secondary
Time to Response
The time to response is defined as the time from study registration to the first date at which the patient's objective status was classified as a response (CR, PR or CI). In patients who do not achieve a response, time to response will be censored at the patient's last evaluation date. The distribution for each of these event-time variables (duration of response and time to response) will be estimated by Kaplan-Meier curves.
Time frame: Time from registration to the first date of response within twelve 28-day cycles of treatment.
Population: None of the Phase I participants were evaluable for this endpoint. Sixty-five (65) patients were recruited for the Phase II portion. Only 9 of the 65 patients achieved a response. Thus, the median of time to response and the upper limit of 95% confidence interval are not attainable.