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

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT03187262
• Collaborator: Janssen, LP (Industry)
• Enrollment: 13
• Locations: 5
• Arm: 1
• Actual Duration (Months): 49.1
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This research study is studying Daratumumab as a possible treatment for Waldenström Macroglobulinemia.

Condition or Disease	Intervention/Treatment	Phase
Waldenström Macroglobulinemia	Drug: Daratumumab	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Daratumumab in Patients With Relapsed or Refractory Waldenström Macroglobulinemia
• Actual Study Start Date: Nov 27, 2017
• Actual Primary Completion Date: Jan 31, 2021
• Actual Study Completion Date: Dec 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Daratumumab Daratumumab will be administered in three phases: Induction, consolidation and maintenance During induction, participants will receive daratumumab on days 1, 8, 15 and 22 of each 28-day During consolidation, daratumumab will be administered on days 1 and 15 of each 28-day cycle During maintenance, daratumumab will be administered on day 1 of each 28-day cycle	Drug: Daratumumab; 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; Other Names: Darzalex

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Progression Free Survival [4 years]

   Amount of time following daratumumab administration until >25% increase in serum IgM

2. 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.

3. Number of Participants With Partial Response [2 years]

   Partial response (PR) is defined as achieving a ≥50% reduction in serum IgM levels.

4. 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.

5. Number of Participants With Minor Response [2 years]

   Minor Response (MR): A minor response (MR) is defined 25-49% reduction in serum IgM levels.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02214
2	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
3	Mayo Clinic	Rochester	Minnesota	United States	55905
4	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
5	University of Washington	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Janssen, LP

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 1, 2019

More Information

Publications

None provided.

• Responsible Party: Jorge J. Castillo, MD, MD, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03187262
• Other Study ID Numbers: 17-164
• First Posted: Jun 14, 2017
• Last Update Posted: Apr 28, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Jorge J. Castillo, MD, MD, Dana-Farber Cancer Institute: Waldenström Macroglobulinemia
• Additional relevant MeSH terms: Waldenstrom Macroglobulinemia; Daratumumab

Study Results

Participant Flow

Arm/Group Title	Daratumumab
Arm/Group Description	Daratumumab will be administered in three phases: Induction, consolidation and maintenance During induction, participants will receive daratumumab on days 1, 8, 15 and 22 of each 28-day During consolidation, daratumumab will be administered on days 1 and 15 of each 28-day cycle During maintenance, daratumumab will be administered on day 1 of each 28-day cycle Daratumumab: 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
Period Title: Induction
STARTED	13
COMPLETED	7
NOT COMPLETED	6
Period Title: Induction
STARTED	7
COMPLETED	2
NOT COMPLETED	5
Period Title: Induction
STARTED	2
COMPLETED	2
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Daratumumab
Arm/Group Description	Daratumumab will be administered in three phases: Induction, consolidation and maintenance During induction, participants will receive daratumumab on days 1, 8, 15 and 22 of each 28-day During consolidation, daratumumab will be administered on days 1 and 15 of each 28-day cycle During maintenance, daratumumab will be administered on day 1 of each 28-day cycle Daratumumab: 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
Overall Participants	13
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	3 23.1%
>=65 years	10 76.9%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	69
Sex: Female, Male (Count of Participants)
Female	3 23.1%
Male	10 76.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	13 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	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).
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Only participants who have measurable disease present at baseline, received at least one cycle of therapy, and had their disease re-evaluated were considered evaluable for response. 2 participants did not complete the first cycle of therapy and were unevaluable for the primary objective.

Arm/Group Title	Daratumumab
Arm/Group Description	Daratumumab will be administered in three phases: Induction, consolidation and maintenance During induction, participants will receive daratumumab on days 1, 8, 15 and 22 of each 28-day During consolidation, daratumumab will be administered on days 1 and 15 of each 28-day cycle During maintenance, daratumumab will be administered on day 1 of each 28-day cycle Daratumumab: 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
Measure Participants	11
Count of Participants [Participants]	3 23.1%

2. Secondary Outcome

Title	Progression Free Survival
Description	Amount of time following daratumumab administration until >25% increase in serum IgM
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.

Arm/Group Title	Daratumumab
Arm/Group Description	Daratumumab will be administered in three phases: Induction, consolidation and maintenance During induction, participants will receive daratumumab on days 1, 8, 15 and 22 of each 28-day During consolidation, daratumumab will be administered on days 1 and 15 of each 28-day cycle During maintenance, daratumumab will be administered on day 1 of each 28-day cycle Daratumumab: 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
Measure Participants	11
Median (Full Range) [months]	2

3. Secondary Outcome

Title	Number of Participants With Complete Response
Description	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.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.

Arm/Group Title	Daratumumab
Arm/Group Description	Daratumumab will be administered in three phases: Induction, consolidation and maintenance During induction, participants will receive daratumumab on days 1, 8, 15 and 22 of each 28-day During consolidation, daratumumab will be administered on days 1 and 15 of each 28-day cycle During maintenance, daratumumab will be administered on day 1 of each 28-day cycle Daratumumab: 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
Measure Participants	11
Count of Participants [Participants]	0 0%

4. Secondary Outcome

Title	Number of Participants With Partial Response
Description	Partial response (PR) is defined as achieving a ≥50% reduction in serum IgM levels.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.

Arm/Group Title	Daratumumab
Arm/Group Description	Daratumumab will be administered in three phases: Induction, consolidation and maintenance During induction, participants will receive daratumumab on days 1, 8, 15 and 22 of each 28-day During consolidation, daratumumab will be administered on days 1 and 15 of each 28-day cycle During maintenance, daratumumab will be administered on day 1 of each 28-day cycle Daratumumab: 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
Measure Participants	11
Count of Participants [Participants]	2 15.4%

5. Secondary Outcome

Title	Number of Participants With Very Good Partial Response
Description	Very Good Partial Response (VGPR): is defined as ≥90% reduction in serum IgM levels, or normalization of serum IgM levels.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.

Arm/Group Title	Daratumumab
Arm/Group Description	Daratumumab will be administered in three phases: Induction, consolidation and maintenance During induction, participants will receive daratumumab on days 1, 8, 15 and 22 of each 28-day During consolidation, daratumumab will be administered on days 1 and 15 of each 28-day cycle During maintenance, daratumumab will be administered on day 1 of each 28-day cycle Daratumumab: 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
Measure Participants	11
Count of Participants [Participants]	0 0%

6. Secondary Outcome

Title	Number of Participants With Minor Response
Description	Minor Response (MR): A minor response (MR) is defined 25-49% reduction in serum IgM levels.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.

Arm/Group Title	Daratumumab
Arm/Group Description	Daratumumab will be administered in three phases: Induction, consolidation and maintenance During induction, participants will receive daratumumab on days 1, 8, 15 and 22 of each 28-day During consolidation, daratumumab will be administered on days 1 and 15 of each 28-day cycle During maintenance, daratumumab will be administered on day 1 of each 28-day cycle Daratumumab: 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
Measure Participants	11
Count of Participants [Participants]	1 7.7%

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
Arm/Group Title	Daratumumab
Arm/Group Description	Daratumumab will be administered in three phases: Induction, consolidation and maintenance During induction, participants will receive daratumumab on days 1, 8, 15 and 22 of each 28-day During consolidation, daratumumab will be administered on days 1 and 15 of each 28-day cycle During maintenance, daratumumab will be administered on day 1 of each 28-day cycle Daratumumab: 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
All Cause Mortality
	Daratumumab
	Affected / at Risk (%)	# Events
Total	1/13 (7.7%)
Serious Adverse Events
	Daratumumab
	Affected / at Risk (%)	# Events
Total	6/13 (46.2%)
Blood and lymphatic system disorders
Anemia	1/13 (7.7%)	1
Febrile neutropenia	1/13 (7.7%)	1
General disorders
Infusion reaction	1/13 (7.7%)	1
Fever	1/13 (7.7%)	1
Infections and infestations
Sepsis	2/13 (15.4%)	2
Strep salvarius bacteremia	1/13 (7.7%)	1
Investigations
Thrombocytopenia	2/13 (15.4%)	2
Neutropenia	1/13 (7.7%)	1
Musculoskeletal and connective tissue disorders
Leg weakness	1/13 (7.7%)	1
Nervous system disorders
Transient Ischemic Attack	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	Daratumumab
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Blood and lymphatic system disorders
Anemia	4/13 (30.8%)	4
Cardiac disorders
Atrial Fibrillation	1/13 (7.7%)	1
Tachycardia	1/13 (7.7%)	1
Chest pain	1/13 (7.7%)	1
Palpitations	2/13 (15.4%)	2
Ear and labyrinth disorders
Ear pain	2/13 (15.4%)	2
Decreased Hearting	1/13 (7.7%)	1
Vertigo	1/13 (7.7%)	1
Eye disorders
Floaters	1/13 (7.7%)	1
Gastrointestinal disorders
Abdominal distention	1/13 (7.7%)	1
Abdominal pain	1/13 (7.7%)	1
Constipation	1/13 (7.7%)	1
Dry mouth	1/13 (7.7%)	1
GERD	1/13 (7.7%)	1
Increased appetite	1/13 (7.7%)	1
Nausea	3/13 (23.1%)	3
Vomiting	1/13 (7.7%)	1
General disorders
Chills	2/13 (15.4%)	2
Peripheral edema	2/13 (15.4%)	2
Fatigue	9/13 (69.2%)	9
Fever	4/13 (30.8%)	4
Infusion related reaction	5/13 (38.5%)	5
Infections and infestations
Thrush	1/13 (7.7%)	1
Otitis media	1/13 (7.7%)	1
Sinusitis	2/13 (15.4%)	2
Upper respiratory infection	3/13 (23.1%)	3
Injury, poisoning and procedural complications
Fall	1/13 (7.7%)	1
Fracture	1/13 (7.7%)	1
Investigations
Alanine aminotransferase increased	1/13 (7.7%)	1
Alkaline pohosphatase increased	2/13 (15.4%)	2
Aspartate aminotransferase increased	1/13 (7.7%)	1
Blood bilirubin increased	1/13 (7.7%)	1
Lymphocyte count decreased	2/13 (15.4%)	2
Neutrophil count decreased	3/13 (23.1%)	3
Platelet count decreased	1/13 (7.7%)	1
Weight loss	2/13 (15.4%)	2
White blood cell decreased	1/13 (7.7%)	1
Metabolism and nutrition disorders
Anorexia	3/13 (23.1%)	3
Hyperkalemia	1/13 (7.7%)	1
Hypernatremia	1/13 (7.7%)	1
Hypoalbuminemia	2/13 (15.4%)	2
Hyponatremia	4/13 (30.8%)	4
Musculoskeletal and connective tissue disorders
Arthralgia	1/13 (7.7%)	1
Arthritis	1/13 (7.7%)	1
Back pain	2/13 (15.4%)	2
Generalized muscle weakness	2/13 (15.4%)	2
AC joint separation	1/13 (7.7%)	1
Body aches	1/13 (7.7%)	1
Muscle cramping	1/13 (7.7%)	1
Myalgia	2/13 (15.4%)	2
Pain in extremity	1/13 (7.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ganglion cyst	1/13 (7.7%)	1
Nervous system disorders
Ataxia	1/13 (7.7%)	1
Dysgeusia	2/13 (15.4%)	2
Headache	3/13 (23.1%)	3
Memory loss	1/13 (7.7%)	1
Peripheral sensory neuropathy	2/13 (15.4%)	2
Presyncope	1/13 (7.7%)	1
Sinus pain	1/13 (7.7%)	1
Psychiatric disorders
Agitation	1/13 (7.7%)	1
Anxiety	1/13 (7.7%)	1
Confusion	4/13 (30.8%)	4
Insomnia	2/13 (15.4%)	2
Restlessness	1/13 (7.7%)	1
Renal and urinary disorders
Painful urination	1/13 (7.7%)	1
Urinary frequency	1/13 (7.7%)	1
Reproductive system and breast disorders
PSA elevation	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/13 (15.4%)	2
Dyspnea	2/13 (15.4%)	2
Epistaxis	2/13 (15.4%)	2
Postnasal drip	1/13 (7.7%)	1
Sore throat	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis	3/13 (23.1%)	3
Rash	1/13 (7.7%)	1
Tender feeling on skin	1/13 (7.7%)	1
Toe blister	1/13 (7.7%)	1
Vascular disorders
Flushing	1/13 (7.7%)	1
Hot flashes	1/13 (7.7%)	1
Hypotension	1/13 (7.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.