Description:
This phase II trial studies how well daratumumab works in treating transplant-eligible
participants with multiple myeloma. Monoclonal antibodies, such as daratumumab, may interfere
with the ability of cancer cells to grow and spread.
Title
- Brief Title: Daratumumab in Treating Transplant-Eligible Participants With Multiple Myeloma
- Official Title: Phase II Trial of Daratumumab for Transplant-Eligible Multiple Myeloma Patients
Clinical Trial IDs
- ORG STUDY ID:
MC1785
- SECONDARY ID:
NCI-2018-00332
- SECONDARY ID:
MC1785
- SECONDARY ID:
P30CA015083
- NCT ID:
NCT03477539
Conditions
- Minimal Residual Disease
- Plasma Cell Myeloma
Interventions
Drug | Synonyms | Arms |
---|
Daratumumab | Anti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414 | Treatment (daratumumab, ASCT, lenalidomide) |
Lenalidomide | CC-5013, CC5013, CDC 501, Revlimid | Treatment (daratumumab, ASCT, lenalidomide) |
Purpose
This phase II trial studies how well daratumumab works in treating transplant-eligible
participants with multiple myeloma. Monoclonal antibodies, such as daratumumab, may interfere
with the ability of cancer cells to grow and spread.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the percentage of patients achieving minimal residual disease (MRD)
negativity by multiparameter flow cytometry (MPF) after autologous stem cell transplant (SCT)
(at day 100) using pre-SCT daratumumab consolidation.
SECONDARY OBJECTIVES:
I. To determine percentage of patients achieving MRD negativity by MPF after 1 year of
daratumumab+lenalidomide-based maintenance therapy.
II. To determine progression-free survival (PFS) for peri-SCT treatment with daratumumab.
III. To determine percentage of MRD negativity by MPF after pre-SCT consolidation with
daratumumab.
IV. To determine safety profile of peri-SCT daratumumab with lenalidomide. V. To determine
the overall response rate (ORR) of patients receiving peri-SCT daratumumab for MM.
VI. To determine the overall survival (OS) for patients receiving peri-SCT daratumumab for
MM.
EXPLORATORY OBJECTIVES:
I. To correlate peripheral blood and bone marrow-based MRD testing using next generation
sequencing (NGS). II. To correlate the MRD assessment by MPF with that by NGS at all the time
points pre-specified for blood and bone marrow assessments.
III. To profile the immune repertoire of MM patients while receiving maintenance treatment
with daratumumab+lenalidomide.
IV. Correlate antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent
cell-mediated cytotoxicity (ADCC) with activity of daratumumab.
V. To determine daratumumab-induced immune reconstitution of the host through eradication of
immunosuppressive cellular elements.
VI. To assess pharmacokinetics (PK) of every 3-month dosing of daratumumab.
OUTLINE:
CONSOLIDATION I: Participants receive daratumumab intravenously (IV) on days 1, 8, 15, and
22. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression
or unacceptable toxicity.
CONSOLIDATION II: Beginning 8 weeks after completion of daratumumab course 2, participants
undergo autologous stem cell transplant (ASCT).
MAINTENANCE: Within 14 days after completion of day 100 visit post-SCT, participants receive
daratumumab IV on day 1 and lenalidomide orally (PO) daily on days 1-21. Treatment repeats
every 28 days for up to 12 courses in the absence of disease progression or unacceptable
toxicity. Participants who are still maintaining response continue to receive daratumumab IV
every 3 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 30 days and every 3-6
months for up to 3 years.
Trial Arms
Name | Type | Description | Interventions |
---|
Treatment (daratumumab, ASCT, lenalidomide) | Experimental | CONSOLIDATION I: Participants receive IV on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION II: Beginning 8 weeks after completion of daratumumab course 2, participants undergo ASCT.
MAINTENANCE: Within 14 days after completion of day 100 visit post-SCT, participants receive daratumumab IV on day 1 and lenalidomide PO daily on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Participants who are still maintaining response continue to receive daratumumab IV every 3 months in the absence of disease progression or unacceptable toxicity. | |
Eligibility Criteria
Inclusion Criteria:
- Pathologically confirmed diagnosis of multiple myeloma who are transplant eligible and
have received any prior induction therapy (with or without maintenance)
- Measurable MRD in bone marrow within 28 days prior to registration (MPF method)
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 at
registration
- Absolute neutrophil count (ANC) >= 1,000 cell/mm^3 without growth factor support,
obtained =< 14 days prior to registration
- Platelets >= 50,000 cells/mm^3 for patients who have bone marrow plasmacytosis < 50%
or >= 30,000 cells/mm^3 for patients who have bone marrow plasmacytosis of >= 50%,
obtained =< 14 days prior to registration
- Calculated or measured creatinine clearance >= 30 ml/min, obtained =< 14 days prior to
registration
- Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert?s syndrome,
in which case the direct bilirubin must be =< 1.5 X ULN, obtained =< 14 days prior to
registration
- Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) =< 3 x ULN,
obtained =< 14 days prior to registration
- Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 X ULN, obtained =<
14 days prior to registration
- Negative urine or serum pregnancy test for women of childbearing potential
- NOTE: females of reproductive potential must adhere to the scheduled pregnancy
testing as required in the Revlimid REMS program
- Provide informed written consent
- Willing to provide bone marrow aspirate and core, and blood samples for correlative
research purposes
- Measurable disease of multiple myeloma at the time of baseline values for disease
assessment 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 ? Bone marrow plasma cells
>= 30%
Exclusion Criteria:
- Any previous ASCT for multiple myeloma (MM)
- Any prior therapy with daratumumab
- Non-secretory MM or known amyloid light-chain (AL) amyloidosis
- Clinically significant active infection requiring intravenous antibiotics (=< 14 days
prior to registration)
- >= grade 3 neuropathy and/or polyneuropathy, organomegaly, endocrinopathy, monoclonal
protein, skin changes (POEMS syndrome)
- Other prior malignancy
- Exceptions:
- Adequately treated basal cell or squamous cell skin cancer
- Any in situ cancer
- Adequately treated stage I or II cancer from which the patient is currently
in complete remission, or
- Any other cancer from which the patient has been disease free for at least 3
years
- Concurrent therapy considered investigational
- NOTE: patients must not be planning to receive any radiation therapy (except
localized radiation for palliative care that must be completed prior to starting
cycle 1, day 1)
- Pregnant women
- Nursing women (lactating females are eligible provided that they agree not to breast
feed while taking lenalidomide)
- Men or women of childbearing potential who are unwilling to employ adequate
contraception
- Major surgery =< 4 weeks prior to registration
- History of stroke/intracranial hemorrhage =< 6 months prior to registration
- Clinically significant cardiac illness including New York Heart Association (NYHA)
class III or class IV heart failure, unstable angina pectoris, myocardial infarction
within the past 6 months, or >= grade 3 cardiac arrhythmias noted =< 14 days prior to
registration
- Known human immunodeficiency virus positive (HIV+) patients
- Known hepatitis B or hepatitis C infection
- Exhibiting clinical signs of meningeal involvement of multiple myeloma
- Known severe chronic obstructive pulmonary disease or asthma defined as forced
expiratory volume (FEV1) in 1 second less than < 60% of expected
Maximum Eligible Age: | 64 Years |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Rate of minimal residual disease (MRD) negative response after autologous stem cell transplantation (ASCT) |
Time Frame: | At day 100 post ASCT |
Safety Issue: | |
Description: | MRD negative response after ASCT is defined as achievement of MRD negative status in the bone marrow by flow cytometry (multiparameter flow cytometry [MPF]) at the day 100 post ASCT visit. |
Secondary Outcome Measures
Measure: | The rate of MRD negative response after pre-stem cell transplant (SCT) consolidation with daratumumab |
Time Frame: | Up to 3 years |
Safety Issue: | |
Description: | This will be estimated by the number of patients who achieve MRD negative status by flow cytometry (MPF) in the bone marrow after pre-SCT consolidation with daratumumab divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true rate of MRD negative response after pre-SCT consolidation with daratumumab will be calculated. |
Measure: | Rate of MRD negative response after 1 year (12 courses) of daratumumab and lenalidomide maintenance |
Time Frame: | At 1 year (12 courses) of daratumumab and lenalidomide maintenance |
Safety Issue: | |
Description: | This will be estimated by the number of patients who achieve MRD negative status by flow cytometry (MPF) in the bone marrow after 1 year of maintenance therapy divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true rate of MRD negative response after 1 year of maintenance will be calculated. |
Measure: | Progression-free survival |
Time Frame: | From registration up to 3 years |
Safety Issue: | |
Description: | The distribution of progression-free survival will be estimated using the Kaplan-Meier method. |
Measure: | Survival time |
Time Frame: | From registration up to 3 years |
Safety Issue: | |
Description: | The distribution of survival time will be estimated using the Kaplan-Meier method. |
Measure: | Overall response rate |
Time Frame: | At day 100 post ASCT |
Safety Issue: | |
Description: | This will be estimated by the number of patients with an objective status of stringent complete responses, complete response, very good partial response, or partial response at the day 100 post ASCT assessment divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true overall response rate at day 100 post ASCT will be calculated. |
Measure: | Incidence of adverse events |
Time Frame: | Up to 3 years |
Safety Issue: | |
Description: | The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Mayo Clinic |
Last Updated
May 1, 2019