Multiple Myeloma
Conditions
Keywords
Relapsed
Brief summary
The study drug elotuzumab, has been clinically shown to be effective in treating relapsed/refractory MM in combination with either bortezomib, or lenalidomide and dexamethasone. Elotuzumab in combination with lenalidomide and dexamethasone is currently approved by the Food and Drug Administration (FDA) for the treatment of patients with multiple myeloma. Carfilzomib is also FDA approved for treating multiple myeloma and frequently given in combination with lenalidomide and dexamethasone for treatment of relapsed/refractory MM. Based on these findings, this study will look at how subjects with relapsed/refractory MM respond to a combination treatment with the following drugs: elotuzumab, carfilzomib, lenalidomide and dexamethasone. The combination of these four drugs is not FDA approved and is experimental.
Detailed description
This single arm, open-label phase II study is designed with the primary objective of evaluating the efficacy of induction therapy comprised of 4 cycles of carfilzomib, lenalidomide, dexamethasone and elotuzumab (KRd+elotuzumab) in terms of very good partial response or better (VGPR+) in subjects with relapsed and/or refractory MM, and comparing to relevant historical controls. Post induction, all subjects will undergo disease evaluation for assessment of the primary endpoint. Maintenance therapy comprised of elotuzumab and lenalidomide (R+elotuzumab) will start directly after induction and continue until relapse or progression.
Interventions
DRUGElotuzumab
Experimental
Sponsors
Wake Forest University Health Sciences
Bristol-Myers Squibb
Atrium Health Levine Cancer Institute
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 meet all of the following applicable inclusion criteria to participate in this study: 1. Written informed consent and HIPAA authorization for release of personal health information signed by the subject or his/her legally authorized representative. 2. Age \>= 18 years at the time of consent. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 (see Appendix A, Section 18.1). 4. Documented history of relapsed and/or refractory multiple myeloma per IMWG 2016 criteria \[22\] as defined below (biochemical and/or clinical relapse per IMWG criteria); (NOTE: subjects refractory to bortezomib and/or lenalidomide are eligible; subjects who previously received carfilzomib are eligible provided they experienced a minimal response or better and relapsed \>60 days after completion of treatment \[see
Exclusion criteria
#2\]): 1. Relapse is defined as progression of disease after an initial response to previous treatment, more than 6 months after discontinuation of treatment. 2. Refractory is defined as lack of response to previous treatment, progression of disease during treatment, or progression of disease within 6 months of discontinuation of treatment. 5. Prior treatment with one line (and no more than one line) of systemic therapy for MM; NOTE: A new line of therapy is considered to start when a planned course of therapy is modified to include other treatment agents (alone or in combination) as a result of progressive disease (PD), relapse, or toxicity or when a planned period of observation off therapy is interrupted by a need for additional treatment for the disease. Induction therapy and stem cell transplant followed by planned maintenance therapy (provided there is no intervening PD) are considered to be a single line. 6. Subject must have recovered from any treatment-induced toxicities to ≤ grade 1 or baseline 7. Adequate washout from previous therapy: 1. Prior chemotherapy is completed \>3 weeks prior to day 1 of treatment (6 weeks for melphalan, nitrosoureas or monoclonal antibodies). 2. Autologous transplant completed (referring to day of stem cell infusion) \>12 weeks prior to day 1 of treatment; allogeneic transplant \>16 weeks prior to day 1 of treatment. 3. Prior radiotherapy completed at least 2 weeks prior to day 1 of treatment. 4. Corticosteroid therapy at a dose equivalent to dexamethasone \>4mg/day has been completed at least 2 weeks prior to day 1 of treatment. 8. Measurable disease defined as: 1. Serum M-protein \> 0.5 g/dL OR 2. Urine M-protein ≥200 mg/24 h OR 3. Involved free light chain (FLC) level ≥10 mg/dL provided serum FLC ratio is abnormal. 9. Demonstrate adequate organ function within 1 week of day 1 of treatment as defined in the table in Sec.tion 3.2 of protocol (#8) 10. Adequate cardiac function as defined by ≥45% Left Ventricular Ejection Fraction (LVEF) by ECHO or MUGA within 28 days prior to day 1 of treatment. 11. Females of childbearing potential (FCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to day 1 of treatment, and be willing to undergo serial serum or urine pregnancy testing. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (at least 12 consecutive months with no menses without an alternative medical cause). 12. FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a failure rate of \<1% per year when used consistently and correctly) plus a second contraceptive method (considered acceptable \[failure rate of \>1% per year\] or highly effective) from the time of informed consent until 6 months after the last protocol prescribed therapy has been discontinued. NOTE: estrogens may further increase the risk of thrombosis (beyond that associated with lenalidomide) and their use should be based on a benefit-risk decision. For the highly effective contraceptive method, a method with low user dependency is preferable but not required (see tables, adapted from: http://www.hma.eu/fileadmin/dateien/Human\_Medicines/01-About\_HMA/Working\_Groups/CTFG/2014\_09\_HMA\_CTFG\_Contraception.pdf). 13. Male subjects (even those who have had a vasectomy) who are sexually active with a FCBP must be willing to use latex or synthetic condoms from the time of informed consent until 180 days after the last protocol prescribed therapy has been discontinued. The FCBP partner should also consider contraception recommendations (see inclusion #11). 14. As determined by the enrolling physician, ability of the subject to understand and comply with study procedures for the entire length of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With VGPR or Better Response to Induction | From enrollment to the disease response determined at the end of the induction part of regimen (4 cycles of KRd-Elo was planned, but some subjects progressed before the end of induction). The median length of induction was 16 weeks. | The primary endpoint is a binary variable determined for each subject indicating whether the subject achieved a very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) to induction treatment with KRd-Elo, as defined by the IMWG 2016 response criteria. Per IMWG 2016 criteria, VGPR is defined as serum/urine M-protein detectable by immunofixation but not electrophoresis OR \>= 90% reduction in serum M protein plus urine M-protein \<100 mg/24 h. CR is defined as negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow aspirates. sCR is defined as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With an Objective Response | From enrollment to best response while on study treatment; subjects remained on treatment until disease progression or death or unacceptable toxicity. Subjects were on treatment for a median of 12 months. | Objective response was determined for each subject as a binary variable indicating whether the subject achieved a best overall response of partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) at any time on study treatment as determined by IMWG 2016 response criteria. Per IMWG 2016 criteria, PR is defined as at least 50% reduction of serum M-protein plus reduction in 24 hour urinary M-protein by 90% or to \<200 mg/24h. VGPR is defined as serum/urine M-protein detectable by immunofixation but not electrophoresis OR \>= 90% reduction in serum M protein plus urine M-protein \<100 mg/24 h. CR is defined as negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow aspirates. sCR is defined as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry. |
| Overall Survival (OS) | From date of treatment start to date of death, or censored as described; assessed for approximately 5 years. | OS is defined as the duration from treatment start date to the date of death from any cause. Subjects who are alive or lost to follow up at the time of the analysis will be censored at the last known date they were alive. |
| Progression Free Survival (PFS) | From treatment start date to date of progression/death, or censored as described; assessed for approximately 3 years. | PFS is defined as the duration of time from treatment start date to first occurrence of either progressive disease (PD) or death. PD must be objectively determined per IMWG 2016 criteria, where progression date is date of last assessment that identified PD. If subject died without documented PD, progression date will be death date. For surviving subjects who do not have PD, PFS will be censored at the date of last disease assessment. For subjects who received subsequent anti-cancer therapy prior to documented PD, PFS will be censored at the date of last disease assessment prior to commencement of subsequent therapy. Subjects who have an initial PFS event immediately following 2 or more consecutive missed assessments will be censored at date of last assessment prior to missed assessments. |
| Time to Disease Progression (TTP) | From treatment start date to date of progression/death, or censored as described; assessed for approximately 3 years. | TTP is defined as the duration of time from treatment start date to first occurrence of either progressive disease (PD) or death related to disease progression. PD must be objectively determined per IMWG 2016 criteria, where progression date is date of last assessment that identified PD. If a subject died for causes related to disease progression then progression date will be date of death. If a subject died for causes other than disease progression, TTP will be censored at the date of other cause mortality. For surviving subjects who do not have PD, TTP will be censored at the date of last disease assessment. For subjects who received subsequent anti-cancer therapy prior to documented PD, TTP will be censored at the date of last disease assessment prior to commencement of subsequent therapy. Subjects who have an initial TTP event immediately following 2 or more consecutive missed assessments will be censored at date of last assessment prior to missed assessments. |
| Duration of Response (DoR) | From time of first response to date of progression/death, or censored as described; assessed for approximately 3 years. | DoR will be calculated for each subject with a partial response, very good partial response, complete response, or stringent complete response on study treatment. The DoR intervals will be calculated from the time of the first assessment that identified response until disease progression or death. The censoring mechanism for DoR will be the same as described for PFS. |
| Time to Next Treatment (TTNT) | From treatment start date to date of next treatment, or censored as described; assessed for approximately 3 years. | TTNT will be calculated from the time of treatment start until the start of the first subsequent anti-cancer therapy after all protocol directed therapy is completed. For surviving subjects who do not receiving subsequent therapy, TTNT will be censored at the last contact date. For subjects who die before beginning subsequent anti-cancer therapy, TTNT will be censored at the date of death |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORManisha Bhutani, MD
Wake Forest University Health Sciences
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| KRd-Elotuzumab Induction (4 28-day cycles):
Carfilzomib (IV) @ 20 mg/m\^2, Day 1 of Cycle 1; @ 56 mg/m\^2, Day 8,15 of Cycle 1; @ 56 mg/m\^2, Day 1,8,15 of Cycles 2-4
Lenalidomide (Oral) @ 25 mg, once daily at bedtime on Days 1-21 of each cycle (Cycles 1-4)
Dexamethasone @ 28 mg orally OR 8 mg IV, once weekly on Day 1,8,15,22 of Cycles 1-2; @28 mg orally OR 8 mg IV on Day 1 of Cycles 3-4
Elotuzumab (IV) @ 10 mg/kg, once weekly on Day 1,8,15,22 of Cycles 1-2; @ 20 mg/kg on Day 1 of Cycles 3-4
Maintenance (28-day cycles):
Elotuzumab (IV) @ 20 mg/kg, Day 1 of each cycle (Cycles 1-n)
Lenalidomide (Oral) @ 15 mg (or last tolerated dose if \<15 mg), once daily at bedtime on Days 1-21 of each cycle (Cycles 1-n) | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | KRd-Elotuzumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 64 years |
| Baseline ISS Stage Stage I | 7 Participants |
| Baseline ISS Stage Stage II | 3 Participants |
| Baseline ISS Stage Stage III | 5 Participants |
| Baseline R-ISS Stage Stage I | 5 Participants |
| Baseline R-ISS Stage Stage II | 5 Participants |
| Baseline R-ISS Stage Stage III | 5 Participants |
| ECOG at Baseline 0 | 6 Participants |
| ECOG at Baseline 1 | 8 Participants |
| ECOG at Baseline 2 | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Prior ASCT No Prior ASCT | 3 Participants |
| Prior ASCT Prior ASCT | 12 Participants |
| Prior Bortezomib Exposure No Prior Bortezomib | 1 Participants |
| Prior Bortezomib Exposure Prior Bortezomib | 14 Participants |
| Prior Lenalidomide Exposure No prior lenalidomide | 2 Participants |
| Prior Lenalidomide Exposure Prior lenalidomide | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 15 |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 8 / 15 |
Outcome results
Primary
Number of Participants With VGPR or Better Response to Induction
The primary endpoint is a binary variable determined for each subject indicating whether the subject achieved a very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) to induction treatment with KRd-Elo, as defined by the IMWG 2016 response criteria. Per IMWG 2016 criteria, VGPR is defined as serum/urine M-protein detectable by immunofixation but not electrophoresis OR \>= 90% reduction in serum M protein plus urine M-protein \<100 mg/24 h. CR is defined as negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow aspirates. sCR is defined as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry.
Time frame: From enrollment to the disease response determined at the end of the induction part of regimen (4 cycles of KRd-Elo was planned, but some subjects progressed before the end of induction). The median length of induction was 16 weeks.
Population: The response evaluable population is defined as all subjects who initiate treatment with elotuzumab and who have measurable disease at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KRd-Elotuzumab | Number of Participants With VGPR or Better Response to Induction | 7 Participants |
p-value: 0.3995% CI: [0.213, 0.734]Fisher Exact
Secondary
Duration of Response (DoR)
DoR will be calculated for each subject with response for the VGPR+ and overall response endpoints. The DoR intervals will be calculated from the time of the first assessment that identified response until disease progression or death. The censoring mechanism for DoR will be the same as described for PFS.
Time frame: From time of first response to date of progression/death, or censored as described; assessed for approximately 3 years.
Secondary
Number of Subjects With an Objective Response
Objective response was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR) or partial response (PR) as determined by IMWG 2016 response criteria.
Time frame: From enrollment to best response while on study treatment; subjects remained on treatment until disease progression or death or unacceptable toxicity.
Secondary
Overall Survival (OS)
OS is defined as the duration from treatment start date to the date of death from any cause. Subjects who are alive or lost to follow up at the time of the analysis will be censored at the last known date they were alive.
Time frame: From date of treatment start to date of death, or censored as described; assessed for approximately 5 years.
Secondary
Progression Free Survival (PFS)
PFS is defined as the duration of time from treatment start date to first occurrence of either progressive disease (PD) or death. PD must be objectively determined per IMWG 2016 criteria, where progression date is date of last assessment that identified PD. If subject died without documented PD, progression date will be death date. For surviving subjects who do not have PD, PFS will be censored at the date of last disease assessment. For subjects who received subsequent anti-cancer therapy prior to documented PD, PFS will be censored at the date of last disease assessment prior to commencement of subsequent therapy. Subjects who have an initial PFS event immediately following 2 or more consecutive missed assessments will be censored at date of last assessment prior to missed assessments.
Time frame: From treatment start date to date of progression/death, or censored as described; assessed for approximately 3 years.
Secondary
Time to Disease Progression (TTP)
TTP is defined as the duration of time from treatment start date to first occurrence of either progressive disease (PD) or death related to disease progression. PD must be objectively determined per IMWG 2016 criteria, where progression date is date of last assessment that identified PD. If a subject died for causes related to disease progression then progression date will be date of death. If a subject died for causes other than disease progression, TTP will be censored at the date of other cause mortality. For surviving subjects who do not have PD, TTP will be censored at the date of last disease assessment. For subjects who received subsequent anti-cancer therapy prior to documented PD, TTP will be censored at the date of last disease assessment prior to commencement of subsequent therapy. Subjects who have an initial TTP event immediately following 2 or more consecutive missed assessments will be censored at date of last assessment prior to missed assessments.
Time frame: From treatment start date to date of progression/death, or censored as described; assessed for approximately 3 years.
Secondary
Time to Next Treatment (TTNT)
TTNT will be calculated from the time of treatment start until the start of the first subsequent anti-cancer therapy after all protocol directed therapy is completed. For surviving subjects who do not receiving subsequent therapy, TTNT will be censored at the last contact date. For subjects who die before beginning subsequent anti-cancer therapy, TTNT will be censored at the date of death
Time frame: From treatment start date to date of next treatment, or censored as described; assessed for approximately 3 years.