Multiple Myeloma
Conditions
Keywords
Multiple Myeloma
Brief summary
The purpose of this study is to evaluate the safety and effectiveness of an investigational new drug called carfilzomib, in combination with dexamethasone in subjects with newly diagnosed multiple myeloma followed by treatment with a combination of drugs clarithromycin (Biaxin®), lenalidomide (Revlimid®) and dexamethasone (Decadron®) \[BiRD\] then lenalidomide alone.
Detailed description
While new anti-myeloma therapies such as bortezomib and immunomodulatory drugs have been developed, multiple myeloma remains an incurable malignancy. Given that obtaining a complete remission (CR) with therapy will allow patients with newly diagnosed multiple myeloma to enjoy a higher quality of life and longer duration of freedom from disease symptoms, finding an optimally effective and well-tolerated regimen is imperative. The robust overall response rate of 91% with the BiRD regimen for patients with newly diagnosed multiple myeloma is encouraging and we believe that by adding carfilzomib the overall response rate and CR rate can be improved. As carfilzomib has proven efficacy in myeloma and in patient's who have relapsed on bortezomib, we anticipate that it will synergize with the previous BiRD regimen to induce greater reduction of tumor burden overall. The primary endpoints include best response rate, toxicities, progression free survival, event free survival, and overall survival. In those patients who are eligible for autologous stem cell transplantation, we will also study the effect of carfilzomib on CD 34+ stem cell yield following mobilization.
Interventions
DRUGcarfilzomib
45 mg/m2 IV on days 1, 2, 8, 9, 15 and 16 of each 28 day cycles.
DRUGDexamethasone
20 mg orally on days 1, 2, 8, 9, 15 and 16 of a 28 day cycle, while receiving carfilzomib.
DRUGClarithromycin
500 mg twice a day for each 28 day cycle of BiRD treatment. BiRD begins after carfilzomib treatment has been completed.
DRUGLenalidomide
25 mg orally days 1-21 for each 28 day cycle of BiRD treatment. BiRD begins after carfilzomib treatment has been completed.
Sponsors
Weill Medical College of Cornell University
Onyx Therapeutics, Inc.
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
* Subject must voluntarily sign and understand written informed consent. * Subject is ≥ 18 years at the time of signing the consent form. * Subject has histologically confirmed multiple myeloma that has never before been treated. * Subject had no anti-myeloma therapy within 14 days prior to initiation of study treatment except for corticosteroids with a maximum allowed dosage equivalent to three pulses of dexamethasone (40mg daily for 4 days equals one pulse). Patients may have received prior adjuvant antiresorptive therapy (i.e., pamidronate or zoledronic acid) as routine care, or radiation therapy as palliation for pain and/or spinal cord compression. * Subject has measurable disease as defined by \> 0.5 g/dL serum monoclonal protein, \> 10 mg/dL involved serum free light chain (either kappa or lambda) provided that the serum free light chain ratio is abnormal, \> 0.2 g/24 hrs urinary M-protein excretion, and/or measurable plasmacytoma(s) of at least 1cm in greatest dimension as measured by either CT scanning or MRI. * Subject has a Karnofsky performance status ≥ 60% (\> 50% if due to bony involvement of myeloma (see Appendix VI). * Subject is able to take prophylactic anticoagulation as detailed in section 9.1 (patients intolerant to aspirin may use warfarin or low molecular weight heparin). * Subject is registered into the mandatory RevAssist® program, and is willing and able to comply with the requirements of RevAssist® program. * If subject is a female of childbearing potential (FCBP),† she must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) 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 females of child bearing potential even if they have had a successful vasectomy. * Subjects must meet the following laboratory parameters: * Absolute neutrophil count (ANC) ≥750 cells/mm3 (1.0 x 109/L) * Hemoglobin ≥ 7 g/dL * Platelet count ≥ 30,000/mm3 (75 x 109/L) * Serum SGOT/AST \< 3.0 x upper limits of normal (ULN) * Serum SGPT/ALT \< 3.0 x upper limits of normal (ULN) * Serum creatinine \< 2.5 mg/dL (221 µmol/L) * Serum total bilirubin \< 2.0 mg/dL (34 µmol/L)
Exclusion criteria
* Subject has immeasurable MM (no measurable monoclonal protein, free light chains in blood or urine, or measureable plasmacytoma on radiologic scanning). * Subject has a prior history of other malignancies unless disease free for ≥ 5 years, except for basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or localized prostate cancer with Gleason score \< 7 with stable prostate specific antigen (PSA) levels. * Subject has had myocardial infarction within 6 months prior to enrollment , or NYHA(New York Hospital Association) Class III or IV heart failure, Ejection Fraction \< 35%, uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active conduction system abnormalities. * Female subject who is pregnant or lactating. * Subject has known HIV infection * Subject has known active hepatitis B or hepatitis C infection. * Subject has active viral or bacterial infections or any coexisting medical problem that would significantly increase the risks of this treatment program. * Subject has known hypersensitivity to dexamethasone, clarithromycin, lenalidomide, thalidomide, allopurinol, or carfilzomib. * Subject has a history of thromboembolic event within the past 4 weeks prior to enrollment. * Subject has any clinically significant medical or psychiatric disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response to Car-BiRD Treatment. | From baseline to best response, up to 116 weeks. | The best response for all patients who had at least one dose of drug was measured. Response categories: Stringent Complete Response (sCR), Complete Remission(CR), Very Good Partial Remission(VGPR), Partial Remission (PR), Progressive Disease (PD), Stable Disease (SD). The response is evaluated based on the IMWG criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival | From date of study enrollment until the date of removal of study due to progression of disease, toxicity or withdrawal of consent, up to 1222 days. | an event is defined by coming off protocol for any reason, including progression of disease, lack of disease response, regimen intolerability, withdrawal of consent or death. |
| MRD Negativity Following CarBiRD Regimen | From start of study up to Revlimid Maintenance Cycle 4. | Minimal Residual Disease (MRD) was assessed for all participants as soon as they achieved CR/sCR, regardless of what phase they were on. MRD negativity is defined as the complete absence of plasma cells on bone marrow biopsy. MRD positivity is defined as the presence of residual plasma cells (\<5%) on bone marrow biopsy. The IMWG criteria were used to determine CR and sCR. |
| Progression Free Survival | From start of study drug until first incidence of progression, up to 1222 days. | Progression was defined using the IMWG criteria. |
| Stem Cells Collection | At the end of the Car Phase, prior to the start of the BiRD Phase, on average after 162 days. | At the end of the Car Phase, all participants underwent stem cell collection. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRuben Niesvizky, M.D.
Weill Medical College of Cornell University
Participant flow
Pre-assignment details
Two subjects were ineligible and therefore never started treatment.
Participants by arm
| Arm | Count |
|---|---|
| Car-BiRD Therapy Carfilzomib, Clarithromycin (Biaxin®), Lenalidomide (Revlimid®), and Dexamethasone (Decadron®) \[Car-BiRD\]
Car Phase:
carfilzomib: 45 mg/m2 IV on days 1, 2, 8, 9, 15 and 16 of each 28 day cycles. Dexamethasone: 20 mg orally on days 1, 2, 8, 9, 15 and 16 of a 28 day cycle, while receiving carfilzomib.
BiRD Phase:
Clarithromycin: 500 mg twice a day for each 28 day cycle of BiRD treatment. BiRD begins after carfilzomib treatment has been completed.
Lenalidomide: 25 mg orally days 1-21 for each 28 day cycle of BiRD treatment. BiRD begins after carfilzomib treatment has been completed.
Dexamethasone: 40 mg orally on days 1, 8, 15 and 22 of each 28 day cycle of BiRD treatment. BiRD begins after carfilzomib treatment has been completed.
Maintenance Phase:
Lenalidomide: 10 mg orally on days 1-21 or each 28 day cycle of maintenance. Maintenance begins after BiRD treatment has been completed. | 72 |
| Total | 72 |
Baseline characteristics
| Characteristic | Car-BiRD Therapy |
|---|---|
| Age, Customized BiRD Phase | 59.6 years |
| Age, Customized Car Phase | 60.4 years |
| Age, Customized Maintenance Phase | 59.2 years |
| Ethnicity (NIH/OMB) BiRD Phase Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) BiRD Phase Not Hispanic or Latino | 48 Participants |
| Ethnicity (NIH/OMB) BiRD Phase Unknown or Not Reported | 7 Participants |
| Ethnicity (NIH/OMB) Car Phase Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Car Phase Not Hispanic or Latino | 61 Participants |
| Ethnicity (NIH/OMB) Car Phase Unknown or Not Reported | 8 Participants |
| Ethnicity (NIH/OMB) Maintenance Phase Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Maintenance Phase Not Hispanic or Latino | 45 Participants |
| Ethnicity (NIH/OMB) Maintenance Phase Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) BiRD Phase American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) BiRD Phase Asian | 0 Participants |
| Race (NIH/OMB) BiRD Phase Black or African American | 4 Participants |
| Race (NIH/OMB) BiRD Phase More than one race | 5 Participants |
| Race (NIH/OMB) BiRD Phase Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) BiRD Phase Unknown or Not Reported | 27 Participants |
| Race (NIH/OMB) BiRD Phase White | 22 Participants |
| Race (NIH/OMB) Car Phase American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Car Phase Asian | 0 Participants |
| Race (NIH/OMB) Car Phase Black or African American | 5 Participants |
| Race (NIH/OMB) Car Phase More than one race | 6 Participants |
| Race (NIH/OMB) Car Phase Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Car Phase Unknown or Not Reported | 32 Participants |
| Race (NIH/OMB) Car Phase White | 29 Participants |
| Race (NIH/OMB) Maintenance Phase American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Maintenance Phase Asian | 0 Participants |
| Race (NIH/OMB) Maintenance Phase Black or African American | 3 Participants |
| Race (NIH/OMB) Maintenance Phase More than one race | 5 Participants |
| Race (NIH/OMB) Maintenance Phase Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Maintenance Phase Unknown or Not Reported | 26 Participants |
| Race (NIH/OMB) Maintenance Phase White | 20 Participants |
| Sex: Female, Male BiRD Phase Female | 26 Participants |
| Sex: Female, Male BiRD Phase Male | 32 Participants |
| Sex: Female, Male Car Phase Female | 29 Participants |
| Sex: Female, Male Car Phase Male | 43 Participants |
| Sex: Female, Male Maintenance Phase Female | 23 Participants |
| Sex: Female, Male Maintenance Phase Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 72 |
| other Total, other adverse events | 72 / 72 |
| serious Total, serious adverse events | 26 / 72 |
Outcome results
Primary
Response to Car-BiRD Treatment.
The best response for all patients who had at least one dose of drug was measured. Response categories: Stringent Complete Response (sCR), Complete Remission(CR), Very Good Partial Remission(VGPR), Partial Remission (PR), Progressive Disease (PD), Stable Disease (SD). The response is evaluated based on the IMWG criteria.
Time frame: From baseline to best response, up to 116 weeks.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Car-BiRD Therapy | Response to Car-BiRD Treatment. | PR | 11 Participants |
| Car-BiRD Therapy | Response to Car-BiRD Treatment. | sCR/CR | 28 Participants |
| Car-BiRD Therapy | Response to Car-BiRD Treatment. | VGPR | 31 Participants |
| Car-BiRD Therapy | Response to Car-BiRD Treatment. | SD | 1 Participants |
| Car-BiRD Therapy | Response to Car-BiRD Treatment. | PD | 0 Participants |
| Car-BiRD Therapy | Response to Car-BiRD Treatment. | Not Evaluable | 1 Participants |
Secondary
Event Free Survival
an event is defined by coming off protocol for any reason, including progression of disease, lack of disease response, regimen intolerability, withdrawal of consent or death.
Time frame: From date of study enrollment until the date of removal of study due to progression of disease, toxicity or withdrawal of consent, up to 1222 days.
Population: 44 participants analyzed out of the 72 participants initially enrolled in the study. 28 participants are active and therefore have not experienced any events leading to removal from study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Car-BiRD Therapy | Event Free Survival | 401.5 Days |
Secondary
MRD Negativity Following CarBiRD Regimen
Minimal Residual Disease (MRD) was assessed for all participants as soon as they achieved CR/sCR, regardless of what phase they were on. MRD negativity is defined as the complete absence of plasma cells on bone marrow biopsy. MRD positivity is defined as the presence of residual plasma cells (\<5%) on bone marrow biopsy. The IMWG criteria were used to determine CR and sCR.
Time frame: From start of study up to Revlimid Maintenance Cycle 4.
Population: 28 participants achieved CR or sCR.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Car-BiRD Therapy | MRD Negativity Following CarBiRD Regimen | MRD positive | 10 Participants |
| Car-BiRD Therapy | MRD Negativity Following CarBiRD Regimen | MRD negative | 17 Participants |
| Car-BiRD Therapy | MRD Negativity Following CarBiRD Regimen | Not Evaluable | 1 Participants |
Secondary
Progression Free Survival
Progression was defined using the IMWG criteria.
Time frame: From start of study drug until first incidence of progression, up to 1222 days.
Population: 21 participants had an incidence of progression.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Car-BiRD Therapy | Progression Free Survival | 18.3 months |
Secondary
Stem Cells Collection
At the end of the Car Phase, all participants underwent stem cell collection.
Time frame: At the end of the Car Phase, prior to the start of the BiRD Phase, on average after 162 days.
Population: 58 participants reached the end of the Car Phase. From those 58 participants, 52 were collected, 5 participants declined stem cell collection and 1 participant's results were not evaluable.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Car-BiRD Therapy | Stem Cells Collection | 12854635 Number of stem cells collected per Kg | Standard Deviation 5388946.9 |