Escalation of Daratumumab Frequency for the Treatment of Relapsed or Refractory Multiple Myeloma
This phase II trial studies how well escalation of daratumumab frequency works for the treatment of multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Daratumumab is an antibody designed to specifically target and eliminate a specific harmful object in the body, in this case cancerous plasma cells.
Inclusion Criteria
- Multiple myeloma diagnosis according to IMWG criteria
- Prior achievement of PR or better on standard daratumumab (single-agent or combination therapy)
- On daratumumab for at least 7 months, currently on once-monthly dosing
- Evidence of biochemical progression only, confirmed via two consecutive assessments. The interval between labs would generally be 1 to 4 weeks, and the second set of labs may be the screening assessment. Biochemical progression is defined as an increase of > 25% from lowest response value in any one or more of the following: * Serum M-component (the absolute increase must be > 0.5 g/dL) * Urine M-component (the absolute increase must be > 200 mg/24 hours [h]) * The difference between involved and uninvolved free light chain (FLC) levels (the absolute increase must be > 10 mg/dL; only in patients without measurable serum and urine M-protein levels)
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Absolute neutrophil count (ANC) > 1000 without transfusion or growth factors within 7 days prior to assessment
- Platelets > 75 k without transfusion or growth factors within 7 days prior to assessment
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.5 times the upper limit of normal
- Bilirubin =< 2 mg/dL
- Creatinine clearance (CrCl) >= 15 mL/minute within 7 days prior to enrollment, either measured or calculated using a standard formula
- Subjects who are positive for anti-hepatitis B core antigen (HBc) or anti-hepatitis B surface antibody (HBs) will undergo testing for hepatitis B deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR). Subjects with serologic findings suggestive of hepatitis B virus (HBV) vaccination (anti-HBs positivity as the only serologic marker) and a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. During and following study treatment, subjects who have history of HBV infection will be closely monitored for clinical and laboratory signs of reactivation of HBV. Where required by local law, the results of HBV testing may be reported to the local health authorities
- Able to understand and willing to sign an Institutional Review Board (IRB-approved written informed consent document
Exclusion Criteria
- Evidence of clinical progression/relapse over the 3 months prior to confirmed eligibility, based on centralized laboratory data performed at Washington University School of Medicine or radiographic data independently reviewed at Washington University School of Medicine defined as: * Development of new soft tissue plasmacytomas or bone lesions * Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion * Hypercalcemia (> 11.5 mg/dL) (2.65 mmol/L) * Decrease in hemoglobin of > 2 g/dL (1.25 mmol/L) not attributable to another cause as determined by investigator * Rise in serum creatinine by 2 mg/dL or more (177 mmol/L or more) not attributable to another cause as determined by investigator
- Evidence of myeloma within the central nervous system (CNS)
- Diagnosis of plasma cell leukemia
- Prior allergic reaction to daratumumab or medications used in the treatment backbone
- Interruption in daratumumab therapy for any reason in the preceding 6 months longer than 8 weeks
- Pregnant or lactating females – woman and men of childbearing potential are required to employ an effective contraceptive method
- Concurrent malignancy other than multiple myeloma (MM) requiring active treatment excluding skin cancer managed with local therapy
- Compromised cardiovascular function defined as any of the following: * Electrocardiogram (EKG) evidence of acute ischemia * EKG evidence of medically significant conduction system abnormalities * History of myocardial infarction within the last 6 months * Unstable angina pectoris or cardiac arrhythmia * History of class 3 or class 4 New York Heart Association congestive heart failure
- Severe persistent asthma (forced expiratory volume in 1 second [FEV1] < 60% and/or daily symptoms) or severe chronic obstructive pulmonary disease (COPD) defined clinically or by historical pulmonary function tests with an FEV1 < 50% predicted
- Seropositive for human immunodeficiency virus (HIV)
- Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
- Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
- Any other clinically significant medical disease or condition that, in the judgement of the investigator, would prevent the participant from safely participating in the trials
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04150692.
PRIMARY OBJECTIVE:
I. To determine if escalation of daratumumab delays progression and/or death.
SECONDARY OBJECTIVES:
I. To determine the overall response rate (ORR), defined as the proportion of patients with a partial response (PR) or better following T0, as defined by International Myeloma Working Group (IMWG) criteria.
II. To determine the proportion of patients remaining on treatment following 3 cycles of treatment with daratumumab.
III. To evaluate paraprotein change between cycle 1 and cycle 2 of treatment.
IV. To determine overall survival (OS), defined as the length of time between T0 and date of death.
V. To determine the duration of response (DOR), defined as the length of time between initial response and progressive disease (in responders).
EXPLORATORY OBJECTIVES:
I. Daratumumab trough level at screening/before T0.
Ia. Attempt to draw correlation between drug trough while on the monthly dosing schedule and response to escalation of daratumumab frequency.
Ib. Correlate daratumumab trough level prior to escalation with known pharmacokinetic (PK)/pharmacodynamic (PD) data on expected CD38 saturation (i.e. is the target still saturated toward the end of the monthly dosing schedule).
II. Flow cytometry (FC) – based CD38 saturation assessment on marrow aspirate and/or core samples at screening, end of study, and potentially at switch to biweekly dosing.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I (RE-ESCALATION): Patients receive daratumumab subcutaneously (SC) over 3-5 minutes on days 1, 8, 15 and 22 of cycles 1 and 2 and days 1 and 15 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM II (STANDARD OF CARE [SOC]): Patients receive daratumumab SC over 3-5 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up within 30 days then annually for 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationSiteman Cancer Center at Washington University
Principal InvestigatorMark Andrew Schroeder
- Primary ID201910200
- Secondary IDsNCI-2020-00270
- ClinicalTrials.gov IDNCT04150692