Escalation of Daratumumab Frequency Following Biochemical Progression in Relapsed/Refractory Multiple Myeloma

NCT04150692 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: 201910200
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

In a small case series, the investigators identified five patients who had an initial response to standard daratumumab (weekly for 2 cycles, every other week for 4 cycles, then monthly thereafter) either as mono- or combination therapy, who then had daratumumab frequency escalated when early biochemical progression was noted, an investigational endeavor. In this series, patients received a median of 5 additional cycles of daratumumab at an escalated frequency (range: 2-8). Additionally, the median change in involved paraprotein after one cycle of weekly-escalated dara was -40% (range: -67% to +5%), with most achieving prior partial response or stable disease. In patients who initially have at least a partial response (PR) to daratumumab, who then have biochemical progression following de-escalation, it is conceivable that CD38 saturation is not optimized at the every 4 weeks dosing interval. The investigators believe that escalating the frequency of daratumumab in patients with biochemical progression, in this investigational setting, may recapture the initial response, delay clinical progression, and/or delay treatment changes.

Conditions

Multiple Myeloma

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS)

  -Defined as the length of time between Cycle 1 Day 1 and progressive disease or death. Patients who are alive and progression-free or were lost to follow-up at the time of data analyses will be censored on the last known alive date.

  Up to 3 years following initiation of treatment (estimated to 3 years and 8 months)

Secondary Outcomes (5)

• Overall response rate (ORR)

  Up to 6 months following initiation of treatment

• Proportion of patients on treatment following 3 cycles

  Completion of cycle 3 by all enrolled patients (estimated to be 12 weeks)

• Paraprotein change between Cycle 1 and Cycle 2 of treatment

  From cycle 1 through cycle 2 (estimated to be 8 weeks)

• Overall survival

  Up to 2 years following treatment removal (estimated to be 2 years and 8 months)

• Duration of response (DOR)

  Up to 3 years following initiation of treatment (estimated to be 3 years and 8 months)

Study Arms (2)

Arm 1: Dara-SC Re-Escalation

EXPERIMENTAL

-Re-escalation will include weekly dosing for two 4-week cycles (8 doses, Days 1, 8, 15, and 22 of each 28-day cycle) followed by dosing every-other-week thereafter (Days 1 and 15 of each 28-day cycle). Patients will remain on study treatment until meeting clinical progression.

Biological: Dara-SC; Procedure: Blood for research assessments; Procedure: Bone marrow for research assessments

Arm 2: Dara-SC

ACTIVE COMPARATOR

-Continued subcutaneous daratumumab and and hyaluronidase-fihj (1,800mg/30,000U, \[Dara-SC\])

Biological: Dara-SC; Procedure: Blood for research assessments; Procedure: Bone marrow for research assessments

Interventions

Dara-SC BIOLOGICAL

-Subcutaneous daratumumab and hyaluronidase-fihj

Arm 1: Dara-SC Re-Escalation; Arm 2: Dara-SC

Blood for research assessments PROCEDURE

-Cycle 1 Day 1, Cycle 3 Day 1, and at progression or end of study (whichever is first)

Arm 1: Dara-SC Re-Escalation; Arm 2: Dara-SC

Bone marrow for research assessments PROCEDURE

-Cycle 1 Day 1, Cycle 3 Day 1, and at progression or end of study (whichever is first)

Arm 1: Dara-SC Re-Escalation; Arm 2: Dara-SC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 h)
• The difference between involved and uninvolved FLC levels (the absolute increase must be \> 10 mg/dL; only in patients without measurable serum and urine M-protein levels)
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Adequate bone marrow reserve, with ANC \>1500 and Platelets \>75k without transfusion or growth factors within 7 days prior to assessment
• Adequate hepatic function, with AST and ALT ≤ 3.5 times the upper limit of normal and bilirubin ≤ 2 mg/dL
• Creatinine clearance (CrCl) ≥ 15 mL/minute within 7 days prior to enrollment, either measured or calculated using a standard formula
• HBV DNA Tests: Subjects who are positive for Anti-HBc or Anti-HBs will undergo testing for hepatitis B DNA by PCR. 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. 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 as specified in the Time and Events Schedule. 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 IRB-approved written informed consent document

You may not qualify if:

• 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 Medicineas 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 with in the 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 as outlined in the ICF
• Concurrent malignancy other than MM requiring active treatment excluding skin cancer managed with local therapy
• Compromised cardiovascular function defined as any of the following:
• EKG evidence of acute ischemia;
• EKG evidence of medically significant conduction system abnormalities;

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Janssen, LP: collaborator

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Mark A Schroeder, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2019
• First Posted: November 5, 2019
• Study Start: January 8, 2021
• Primary Completion: March 31, 2026
• Study Completion: March 31, 2026
• Last Updated: January 24, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share