A Study of Daratumumab in Patients With Relapsed or Refractory Waldenström Macroglobulinemia

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved Daratumumab for this specific disease but it has been approved for other uses.

Daratumumab is a monoclonal human antibody. An antibody recognizes a specific protein and binds to it. Daratumumab binds to a protein called CD38 located on the surface of B cells like WM. Daratumumab has shown the ability to slow or stop the growth of cells that have CD38 on the cell surface when tested in laboratories.

In this research study, the investigators are evaluating the efficacy of Daratumumab as a single agent in participants with WM that has come back or has shown no response to previous treatment.

• Daratumumab (Drug), also known as Darzalex: Daratumumab is a monoclonal human antibody. Daratumumab has shown the ability to slow or stop the growth of cells that have CD38 on the cell surface when tested in laboratories

Primary outcomes

• Overall Response Rate [2 years]: Overall Response Rate= Minor response (>25%-50% reduction in serum IgM from baseline) + Partial Response (>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly).

Secondary outcomes

• Progression Free Survival [4 years]: Amount of time following daratumumab administration until >25% increase in serum IgM
• Number of Participants With Complete Response [2 years]: A complete response is defined as having resolution of WM related symptoms, normalization of serum IgM levels with complete disappearance of IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly.
• Number of Participants With Partial Response [2 years]: Partial response (PR) is defined as achieving a ≥50% reduction in serum IgM levels.
• Number of Participants With Very Good Partial Response [2 years]: Very Good Partial Response (VGPR): is defined as ≥90% reduction in serum IgM levels, or normalization of serum IgM levels.
• Number of Participants With Minor Response [2 years]: Minor Response (MR): A minor response (MR) is defined 25-49% reduction in serum IgM levels.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Clinicopathological diagnosis of Waldenström Macroglobulinemia (Owen et al. 2003), and meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenström macroglobulinemia (Kyle et al. 2003)
* At least one previous treatment for WM with either documented disease progression or no response (stable disease) to the most recent treatment regimen
* Measurable disease, defined as presence of serum immunoglobulin M (IgM) with a minimum IgM level of >2 times the upper limit of normal of each institution is required
* Participants with symptomatic hyperviscosity or serum IgM >5,000 mg/dL to undergo plasmapheresis prior to treatment initiation
* Age ≥18 years
* ECOG performance status ≤2 (see Appendix A)
* Participants must have preserved organ and marrow function as defined below:

  * Absolute neutrophil count ≥ 1,000/mcL
  * Platelets ≥ 50,000/mcL
  * Hemoglobin ≥ 8 g/dL
  * Total bilirubin ≤ 1.5 mg/dL or < 2 mg/dL if attributable to hepatic infiltration by neoplastic disease
  * AST/ALT ≤ 2.5 × institutional upper limit of normal
  * EGFR ≥ 30 ml/min
* Not on any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin.
* Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or have or will have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 90 days after discontinuation from the study. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test at screening.
* Able to adhere to the study visit schedule and other protocol requirements.
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Any serious medical condition, laboratory abnormality, uncontrolled intercurrent illness, or psychiatric illness/social condition that would prevent study participation.
* Concurrent use of any other anti-cancer agents or treatments or any other investigational agents.
* Any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
* Known CNS lymphoma.
* New York Heart Association classification III or IV heart failure.
* Known history of Human Immunodeficiency Virus (HIV), active infection with Hepatitis B Virus (HBV), and/or Hepatitis C Virus (HCV).
* Lactating or pregnant women.
* Grade >2 toxicity (other than alopecia) continuing from prior anti-cancer therapy.
* History of non-compliance to medical regimens.

Participant flow

Outcome results

• Overall Response Rate (Primary), Count of participants, Participants: Daratumumab 3
• Progression Free Survival (Secondary), Median, months: Daratumumab 2 (1 to 28)
• Number of Participants With Complete Response (Secondary), Count of participants, Participants: Daratumumab 0
• Number of Participants With Partial Response (Secondary), Count of participants, Participants: Daratumumab 2
• Number of Participants With Very Good Partial Response (Secondary), Count of participants, Participants: Daratumumab 0
• Number of Participants With Minor Response (Secondary), Count of participants, Participants: Daratumumab 1

Adverse events

Time frame: Adverse events were collected from baseline, throughout treatment with daratumumab, and for 30 days after last dose of daratumumab, up to 4 years

Serious adverse events by term

Other adverse events by term

19 more terms not shown.

• Study Protocol and Statistical Analysis Plan (PDF, 2019-02-01)

• Jorge J Castillo, MD, Principal investigator, Dana-Farber Cancer Institute