Refractory Multiple Myeloma
Conditions
Brief summary
This phase II trial is studying how well giving dinaciclib works in treating patients with relapsed or refractory multiple myeloma. Dinaciclib may stop the growth of cancer cells by clocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the efficacy (overall response rate) of single agent SCH 727965 in patients with relapsed or refractory multiple myeloma. SECONDARY OBJECTIVES: I. To evaluate the toxicities associated with use of single agent SCH 727965 in patients with relapsed or refractory multiple myeloma. II. To evaluate the response duration and progression free survival among patients with relapsed or refractory multiple myeloma undergoing treatment with single agent SCH 727965. III. To study the effect of SCH 727965 on myeloma cell proliferation, apoptotic rates and to assess the ability of the drug to inhibit drug targets (cyclin dependent kinases, cdk in the myeloma cell. OUTLINE: This is a multicenter, dose-escalation study. Patients receive dinaciclib IV over 2 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Blood and bone marrow samples are collected periodically for correlative studies. (US sites only) After completion of study treatment, patients are followed up for up to 3 years.
Interventions
DRUGdinaciclib
Given IV
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
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
* Relapsed or refractory multiple myeloma * Measurable disease as defined by at least ONE of the following: * Serum monoclonal protein \>= 1.0 g/dL * \> 200 mg of monoclonal protein in the urine on 24 hour electrophoresis * Serum immunoglobulin free light chain \>= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio * ≤ 5 prior therapies; stem cell transplantation and preceding induction therapy will be considered as one therapy; NOTE: Patients must not be candidates for stem cell transplantation or should have had stem cells collected previously * Life expectancy of ≥ 3 months * ECOG performance status of 0, 1 or 2 * Absolute neutrophil count \>= 1,000/mcL * Platelets \>= 75,000/mcL * Hemoglobin \>= 8 g/dL * Total serum bilirubin within normal institutional limits * AST (SGOT)/ALT(SGPT) =\< 2.5 X institutional ULN * Creatinine \< 2.5 mg/dL * Negative serum pregnancy test done ≤7 days prior to registration (for women of childbearing potential only); NOTE: Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * Ability to understand and the willingness to sign a written informed consent document * Willingness to provide blood and bone marrow samples for mandatory research component of this study; (US sites only)
Exclusion criteria
* Any of the following prior therapies: * Myelosuppressive therapy for myeloma ≤ 3 weeks prior to registration or those who have not recovered from acute reversible adverse events due to agents administered \> 3 weeks earlier * Non-myelosuppressive agents like thalidomide or high dose corticosteroids ≤ 2 weeks prior to registration * Receiving any other investigational agents * Concomitant high dose corticosteroids * NOTE: Concurrent use of corticosteroids, but patients may be on chronic steroids (maximum dose 20 mg/day prednisone equivalent) if they are being given for disorders other than amyloid, i.e., adrenal insufficiency, rheumatoid arthritis, etc. * NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment * Active malignancy with the exception of non melanoma skin cancer or in situ cervical or breast cancer * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infections or psychiatric illness/social situations that would limit compliance with study requirements * Pregnant or nursing women; NOTE: Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with SCH 727965, breastfeeding should be discontinued if the mother is treated with SCH 727965 * Currently taking inhibitors/inducers of CYP3A4; (SCH 727965 metabolizes via the CYP3A4 enzyme; there are potential drug interactions with concomitant use of CYP3A4 potent inhibitors/inducers; Principal Investigator should review each case and determine if patients on the CYP3A4 potent inhibitors/inducers are eligible and will make all effort to switch to alternative drugs; patients should not take grapefruit/ grapefruit juice or St. Johns' Wort) * Men or women of childbearing potential who are unwilling to employ adequate contraception
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Confirmed Responses, Defined to be an sCR, CR, VGPR, or PR Noted as the Objective Status on Two Consecutive Evaluations. | Up to 3 years | Complete Response (CR): Negative immunofixation of serum and urine Normalization of FLC ratio \< 5% plasma cells in bone marrow Disappearance of any soft tissue plasmacytomas Stringent Complete Response (sCR): CR, as above, with absence of clonal cells in bone marrow Partial Response (PR): One of the following: 1. A ≥ 50% reduction of measurable serum M-protein. 2. A reduction in 24h measurable urinary M-protein by ≥ 90% or to \<200 mg per 24h. 3. A ≥ 50% decrease in the difference between involved and uninvolved FLC levels. 4. ≥50% reduction in bone marrow plasma cells is required in place of Mprotein, provided baseline percentage was ≥ 30% 5. A ≥50% reduction in the size of soft tissue plasmacytomas. Very Good Partial Response (VGPR): PR as defined above in addition to having serum and urine M-component detectable by immunofixation but not on electrophoresis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Time from registration to progression or death due to any cause, assessed up to 3 years | The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. |
| Duration of Response | Date at which the patient's objective status is first noted to be either an sCR, CR, PR, or VGPR to the earliest date progression is documented, assessed up to 3 years | The distribution of duration of response will be estimated using the method of Kaplan-Meier. |
Countries
Singapore, United States
Participant flow
Recruitment details
From 7/2009 to 12/2011, 29 participants were accrued. The study opened at 50 mg/m\^2, accrued 2, and closed for safety review and protocol amendment. The study reopened with a dose escalation phase and accrued 4 at 30 mg/m\^2 dose, 7 at 40 mg/m\^2 dose, and 6 at 50 mg/m\^2 dose. The Phase II dose level was set at 50 mg/m\^2 and accrued 10 participants.
Pre-assignment details
Of the 10 participants accrued in the Phase II portion of the study, one was excluded for protocol violation. The 6 participants treated in the Safety Analysis Phase at the 50 mg/m\^2 dose level (after the protocol amendment) are included in the Phase II analysis. Therefore, this Phase II analysis is based on 15 evaluable participants.
Participants by arm
| Arm | Count |
|---|---|
| Phase II Participants were accrued at 50 mg/m\^2 dose level after December 30, 2009 addendum. Participants to receive 50 mg/m\^2 dinaciclib IV over 2 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Phase II |
|---|---|
| Age, Continuous | 64 years |
| Region of Enrollment Singapore | 3 participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 7 / 15 |
Outcome results
Primary
Number of Confirmed Responses, Defined to be an sCR, CR, VGPR, or PR Noted as the Objective Status on Two Consecutive Evaluations.
Complete Response (CR): Negative immunofixation of serum and urine Normalization of FLC ratio \< 5% plasma cells in bone marrow Disappearance of any soft tissue plasmacytomas Stringent Complete Response (sCR): CR, as above, with absence of clonal cells in bone marrow Partial Response (PR): One of the following: 1. A ≥ 50% reduction of measurable serum M-protein. 2. A reduction in 24h measurable urinary M-protein by ≥ 90% or to \<200 mg per 24h. 3. A ≥ 50% decrease in the difference between involved and uninvolved FLC levels. 4. ≥50% reduction in bone marrow plasma cells is required in place of Mprotein, provided baseline percentage was ≥ 30% 5. A ≥50% reduction in the size of soft tissue plasmacytomas. Very Good Partial Response (VGPR): PR as defined above in addition to having serum and urine M-component detectable by immunofixation but not on electrophoresis.
Time frame: Up to 3 years
Population: Fifteen of the 16 accrued Phase II participants were analyzed (1 participant was a protocol violation).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase II | Number of Confirmed Responses, Defined to be an sCR, CR, VGPR, or PR Noted as the Objective Status on Two Consecutive Evaluations. | Complete Response (CR) | 0 participants |
| Phase II | Number of Confirmed Responses, Defined to be an sCR, CR, VGPR, or PR Noted as the Objective Status on Two Consecutive Evaluations. | Stringent Complete Response (sCR) | 0 participants |
| Phase II | Number of Confirmed Responses, Defined to be an sCR, CR, VGPR, or PR Noted as the Objective Status on Two Consecutive Evaluations. | Very Good Partial Response (VGPR) | 0 participants |
| Phase II | Number of Confirmed Responses, Defined to be an sCR, CR, VGPR, or PR Noted as the Objective Status on Two Consecutive Evaluations. | Partial Response (PR) | 0 participants |
Secondary
Duration of Response
The distribution of duration of response will be estimated using the method of Kaplan-Meier.
Time frame: Date at which the patient's objective status is first noted to be either an sCR, CR, PR, or VGPR to the earliest date progression is documented, assessed up to 3 years
Population: Duration of Response was not analyzed due to lack of responses.
Secondary
Progression-free Survival
The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.
Time frame: Time from registration to progression or death due to any cause, assessed up to 3 years
Population: All 15 evaluable participants were analyzed for Progression-Free Survival.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II | Progression-free Survival | 2.73 months |