Multiple Myeloma, Waldenstrom's Macroglobulinemia
Conditions
Keywords
Waldenstrom's Macroglobulinemia, Multiple Myeloma
Brief summary
To determine whether further study of single-agent enzastaurin is warranted in patients with previously treated Waldenstrom's Macroglobulinemia or Multiple Myeloma based on response.
Interventions
DRUGEnzastaurin
Enzastaurin: Cycle 1 Day 1 only: 3, 125-milligrams (mg) tablets three times on Day 1 (Day 1 total dose = 1125 mg) Day 2 onwards and subsequent Cycles: 2, 125-mg tablets orally twice a day (500 mg total per day). Cycle length (all cycles): 28 days. Patients may stay on drug past 8 cycles, (until the study is closed) or until disease progression.
Sponsors
Eli Lilly and Company
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
* At least 18 years of age. * Patients must have Waldenstrom's Macroglobulinemia (WM) or Multiple Myeloma (MM) previously treated with at least 1 and no more than 5 prior therapies. * Treatment with prior autologous transplant is permitted. If a transplant is used as consolidation following chemotherapy, without intervening disease progression, it will be considered 1 line of treatment with the preceding chemotherapy. * Patients with MM must have a monoclonal protein in the serum of greater than or equal to 1 gram per deciliter (g/dL) or monoclonal light chain in the urine protein electrophoresis of greater than or equal to 200 milligrams (mg)/ 24 hours, or measurable plasmacytoma. * Patients with WM must have an immunoglobulin M (IgM) paraprotein with a minimum IgM level of \> 2 times the upper limit of normal (ULN), have detectable lymphoplasmacytic (LPL) cells in the bone marrow, and be symptomatic for WM. * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2. * The following laboratory values obtained prior to registration: * Absolute neutrophil count (ANC) greater than or equal to 1000/microliter * Platelet (PLT) count greater than or equal to 75,000/microliter * Total bilirubin less than or equal to 1.5 x ULN (if total is elevated check direct and, if normal, patient is eligible) * Aspartate transaminase (AST) less than or equal to 3 x ULN * Creatinine less than or equal to 1.5 x ULN * Hemoglobin (Hgb) greater than or equal to 8.0 g/dL. * Expected survival of greater than 12 weeks. * The ability to provide informed consent. * Male and female patients with reproductive potential must use an approved contraceptive method, if appropriate (for example, intrauterine device \[IUD\], birth control pills, or barrier device) during and for 3 months after discontinuation of study treatment. Women with childbearing potential must have a negative serum pregnancy test less than or equal to 3 days prior to study enrollment
Exclusion criteria
* Prior allogeneic hematopoietic stem cell transplant. * Are unable to discontinue use of non-Enzyme-Inducing Anti-Epileptic Drugs (EIAEDs), for example carbamazepine, phenobarbital, and phenytoin. Patients on anti-coagulant therapy should be monitored. Ongoing treatment with therapeutic doses of Coumadin is prohibited. However, prophylactic, low dose (less than or equal to 2 mg daily) Coumadin for deep venous thrombosis (DVT) is allowed. In such cases, prothrombin time/ international normalized ratio (PT/INR) should be closely monitored. * Have electrocardiogram (ECG) abnormalities including baseline 12-lead ECG with QTc interval of greater than 450 milliseconds (msec) in males or greater than 470 msec in females, or QRS duration of greater than 100 msec. Patients who have a congenital long-QT-syndrome in their own or family medical history should be excluded at the investigator's discretion. * Have an uncontrolled infection. * Have prior treatment with Carmustine (BCNU) 6 weeks, alkylating agent 4 weeks, or other cytotoxic chemotherapy agents 4 weeks prior to registration in this trial. Have prior treatment with biologic therapy less than or equal to 12 weeks or corticosteroids less than or equal to 2 weeks prior to registration in this trial. However, treatment with less than or equal to 10 mg of prednisone as a chronic therapy is allowed. * Have radiation therapy less than or equal to 2 weeks prior to treatment in this trial. * Are pregnant or breast-feeding. * Are being treated with concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational. * Are known to be human immunodeficiency virus (HIV) positive. * Were previously treated with enzastaurin. * Patients who are unable to swallow tablets. * Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. * Concurrent malignancy that could complicate interpretation of response or safety evaluation. Non-melanoma skin cancer and carcinoma in situ of the cervix are not exclusions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response (CR), Partial Response (PR) and Minimal Response (MR) or Minor Response (MinR): (Response Rate) | Baseline to measured progressive disease up to 40.51 months | European Group for Blood and Bone Marrow Transplant (EBMT) Response Criteria (RC) used for MM. CR: no serum/urine M protein for 6 weeks (wk), \<5% plasma cells in bone marrow (PCBM), no lytic bone lesions (LBL) size/number increase, no soft tissue plasmacytomas (STPC); PR: met some CR criteria plus maintain for 6 wk ≥50% serum monoclonal paraprotein (SPEP) and PCBM decrease, either decrease of ≥90% or \<200 mg light chain excretion (LCE), ≥50% STPC size decrease; MR: met some PR criteria plus maintain for 6 wk, a decrease of: 25-49% SPEP, 50-89% 24 hour urinary LCE, 25-49% PCBM, 25-49% STPC size. International Workshop on WM (IWWM) RC used for WM. CR: no serum M protein, malignant cells in BM, or lymphadenopathy/organomegaly; PR: ≥50% immunoglobulin M (IgM) and adenopathy/organomegaly (A/O) decrease; no new symptoms of WM. MinR: ≥25% to \<50% IgM decrease, no A/O progression; no cytopenias or clinical symptoms of WM. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Time of response to time of measured progressive disease up to 38.37 months | DOR is defined as elapsed time from the first evidence of CR, PR, MR or MinR until date of progression of disease (PD). EBMT RC used for MM. CR: no serum/urine M protein for 6 wk, \<5% PCBM, no LBL size/number increase, no STPC; PR: met some CR criteria plus maintain for 6 wk ≥50% SPEP and PCBM decrease, either decrease of ≥90% or \<200 mg LCE, ≥50% STPC size decrease; MR: met some PR criteria plus maintain for 6 wk decrease of: 25-49% SPEP, 50-89% 24 hour urinary LCE, 25-49% PCBM, 25-49% STPC size. PD: \>25% increase in SPEP, 24 hour urinary LCE, PCBM, STPC size increase, new bone lesion or STPC. IWWM RC used for WM. CR: no serum M protein, malignant cells in BM, or lymphadenopathy/organomegaly; PR: ≥50% IgM and A/O decrease; no new WM symptoms. MinR: ≥25% to \<50% IgM decrease, no A/O progression; no cytopenias or clinical of WM symptoms. PD: \>25% IgM increase, progression of clinical findings or symptoms. For participants who had no PD, DOR was censored at their last contact. |
| Time to Progressive Disease | Baseline to measured progressive disease up to 40.51 months | Time to progression is defined as the elapsed time from the date of study enrollment to the date of objectively determined progressive disease (PD). European Group for Blood and Bone Marrow Transplant (EBMT) Response Criteria was used for MM. PD: \>25% increase in serum monoclonal paraprotein (SPEP), 24 hour urinary light chain excretion (LCE), plasma cells in bone marrow (PCBM), soft tissue plasmacytomas (STPC) size increase, new bone lesion or STPC. International Workshop on WM (IWWM) Response Criteria was used for WM. PD: \>25% immunoglobulin M (IgM) increase, progression of clinical findings or symptoms. For participants who had no PD, time to PD was censored at their last contact. |
| Number of Participants With Adverse Events (Safety and Adverse Events) | Treatment start to 30 days after discontinuation of study treatment up to 23.40 months | Data are presented as number of participants who experienced serious adverse events or all other nonserious adverse events during the study including the 30-day follow-up period. A summary of serious adverse events and other nonserious adverse events is located in the Reported Adverse Event section. Safety data were collected up to 24 cycles plus 30 days of follow-up for a total up to 23.40 months. |
Other
| Measure | Time frame |
|---|---|
| Number of Participants Who Died Due to Progressive Disease During the 30 Days Following Discontinuation From Study Treatment | Study treatment discontinuation up to 30 days post study treatment discontinuation |
Countries
France, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Multiple Myeloma (MM) Participants diagnosed with MM received: Three 125-milligrams (mg) Enzastaurin tablets three times on Day 1 of Cycle 1 (Day 1 total dose = 1125 mg). Day 2 onwards and subsequent Cycles: Two 125-mg tablets orally twice a day (500 mg total per day). Cycle length (all cycles): 28 days. | 14 |
| Waldenstrom's Macroglobulinemia (WM) Participants diagnosed with WM received: Three 125-milligrams (mg) Enzastaurin tablets three times on Day 1 of Cycle 1 (Day 1 total dose = 1125 mg). Day 2 onwards and subsequent Cycles: Two 125-mg tablets orally twice a day (500 mg total per day). Cycle length (all cycles): 28 days. | 42 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Death Due to Adverse Events | 1 | 0 |
| Overall Study | Death Due to Progressive Disease | 2 | 0 |
| Overall Study | Death Due to Study Drug Related | 0 | 1 |
| Overall Study | Physician Decision | 1 | 6 |
| Overall Study | Progressive Disease | 7 | 25 |
| Overall Study | Sponsor decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 5 |
Baseline characteristics
| Characteristic | Multiple Myeloma (MM) | Waldenstrom's Macroglobulinemia (WM) | Total |
|---|---|---|---|
| Age, Continuous | 73.28 years STANDARD_DEVIATION 7.51 | 64.57 years STANDARD_DEVIATION 8.53 | 66.7 years STANDARD_DEVIATION 9.06 |
| Race/Ethnicity, Customized African | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 14 Participants | 41 Participants | 55 Participants |
| Region of Enrollment France | 14 Participants | 5 Participants | 19 Participants |
| Region of Enrollment United States | 0 Participants | 37 Participants | 37 Participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 8 Participants | 35 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 14 | 42 / 42 |
| serious Total, serious adverse events | 4 / 14 | 9 / 42 |
Outcome results
Primary
Percentage of Participants With Complete Response (CR), Partial Response (PR) and Minimal Response (MR) or Minor Response (MinR): (Response Rate)
European Group for Blood and Bone Marrow Transplant (EBMT) Response Criteria (RC) used for MM. CR: no serum/urine M protein for 6 weeks (wk), \<5% plasma cells in bone marrow (PCBM), no lytic bone lesions (LBL) size/number increase, no soft tissue plasmacytomas (STPC); PR: met some CR criteria plus maintain for 6 wk ≥50% serum monoclonal paraprotein (SPEP) and PCBM decrease, either decrease of ≥90% or \<200 mg light chain excretion (LCE), ≥50% STPC size decrease; MR: met some PR criteria plus maintain for 6 wk, a decrease of: 25-49% SPEP, 50-89% 24 hour urinary LCE, 25-49% PCBM, 25-49% STPC size. International Workshop on WM (IWWM) RC used for WM. CR: no serum M protein, malignant cells in BM, or lymphadenopathy/organomegaly; PR: ≥50% immunoglobulin M (IgM) and adenopathy/organomegaly (A/O) decrease; no new symptoms of WM. MinR: ≥25% to \<50% IgM decrease, no A/O progression; no cytopenias or clinical symptoms of WM.
Time frame: Baseline to measured progressive disease up to 40.51 months
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Multiple Myeloma (MM) | Percentage of Participants With Complete Response (CR), Partial Response (PR) and Minimal Response (MR) or Minor Response (MinR): (Response Rate) | 7.1 percentage of participants |
| Waldenstrom's Macroglobulinemia (WM) | Percentage of Participants With Complete Response (CR), Partial Response (PR) and Minimal Response (MR) or Minor Response (MinR): (Response Rate) | 38.1 percentage of participants |
Secondary
Duration of Response (DOR)
DOR is defined as elapsed time from the first evidence of CR, PR, MR or MinR until date of progression of disease (PD). EBMT RC used for MM. CR: no serum/urine M protein for 6 wk, \<5% PCBM, no LBL size/number increase, no STPC; PR: met some CR criteria plus maintain for 6 wk ≥50% SPEP and PCBM decrease, either decrease of ≥90% or \<200 mg LCE, ≥50% STPC size decrease; MR: met some PR criteria plus maintain for 6 wk decrease of: 25-49% SPEP, 50-89% 24 hour urinary LCE, 25-49% PCBM, 25-49% STPC size. PD: \>25% increase in SPEP, 24 hour urinary LCE, PCBM, STPC size increase, new bone lesion or STPC. IWWM RC used for WM. CR: no serum M protein, malignant cells in BM, or lymphadenopathy/organomegaly; PR: ≥50% IgM and A/O decrease; no new WM symptoms. MinR: ≥25% to \<50% IgM decrease, no A/O progression; no cytopenias or clinical of WM symptoms. PD: \>25% IgM increase, progression of clinical findings or symptoms. For participants who had no PD, DOR was censored at their last contact.
Time frame: Time of response to time of measured progressive disease up to 38.37 months
Population: All participants who received at least one dose of the study drug and had complete response (CR) or partial response (PR) or minimal response (MR) or minor response (MinR). The numbers of participants censored are 1 (MM) and 13 (WM).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Multiple Myeloma (MM) | Duration of Response (DOR) | NA months |
| Waldenstrom's Macroglobulinemia (WM) | Duration of Response (DOR) | NA months |
Secondary
Number of Participants With Adverse Events (Safety and Adverse Events)
Data are presented as number of participants who experienced serious adverse events or all other nonserious adverse events during the study including the 30-day follow-up period. A summary of serious adverse events and other nonserious adverse events is located in the Reported Adverse Event section. Safety data were collected up to 24 cycles plus 30 days of follow-up for a total up to 23.40 months.
Time frame: Treatment start to 30 days after discontinuation of study treatment up to 23.40 months
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Multiple Myeloma (MM) | Number of Participants With Adverse Events (Safety and Adverse Events) | Serious Adverse Events | 4 Participants |
| Multiple Myeloma (MM) | Number of Participants With Adverse Events (Safety and Adverse Events) | Other Nonserious Adverse Events | 12 Participants |
| Waldenstrom's Macroglobulinemia (WM) | Number of Participants With Adverse Events (Safety and Adverse Events) | Serious Adverse Events | 9 Participants |
| Waldenstrom's Macroglobulinemia (WM) | Number of Participants With Adverse Events (Safety and Adverse Events) | Other Nonserious Adverse Events | 42 Participants |
Secondary
Time to Progressive Disease
Time to progression is defined as the elapsed time from the date of study enrollment to the date of objectively determined progressive disease (PD). European Group for Blood and Bone Marrow Transplant (EBMT) Response Criteria was used for MM. PD: \>25% increase in serum monoclonal paraprotein (SPEP), 24 hour urinary light chain excretion (LCE), plasma cells in bone marrow (PCBM), soft tissue plasmacytomas (STPC) size increase, new bone lesion or STPC. International Workshop on WM (IWWM) Response Criteria was used for WM. PD: \>25% immunoglobulin M (IgM) increase, progression of clinical findings or symptoms. For participants who had no PD, time to PD was censored at their last contact.
Time frame: Baseline to measured progressive disease up to 40.51 months
Population: All participants who had at least one dose of the study drug. The numbers of participants censored are 7 (MM) and 33 (WM).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Multiple Myeloma (MM) | Time to Progressive Disease | 5.11 months |
| Waldenstrom's Macroglobulinemia (WM) | Time to Progressive Disease | 27.73 months |
Other Pre-specified
Number of Participants Who Died Due to Progressive Disease During the 30 Days Following Discontinuation From Study Treatment
Time frame: Study treatment discontinuation up to 30 days post study treatment discontinuation
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Multiple Myeloma (MM) | Number of Participants Who Died Due to Progressive Disease During the 30 Days Following Discontinuation From Study Treatment | 0 Participants |
| Waldenstrom's Macroglobulinemia (WM) | Number of Participants Who Died Due to Progressive Disease During the 30 Days Following Discontinuation From Study Treatment | 1 Participants |