Daratumumab and Ibrutinib for the Treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia, DIRECT Study

NCT04230304 | Terminated Phase 2 Results DMC FDA Drug

• 3 other identifiers: MC1784NCI-2020-0001019-001475
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies how well daratumumab and ibrutinib work in treating patients with chronic lymphocytic leukemia that has come back (relapsed) or has not responded to previous treatment (refractory). Daratumumab is a monoclonal antibody which works with the body's immune system to destroy cancer cells. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving daratumumab and ibrutinib may work better in treating patients with chronic lymphocytic leukemia compared to ibrutinib alone.

Conditions

Recurrent Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate by Cycle 7

  Will be evaluated in each cohort independently. A response is defined as an objective status of complete response (CR), CR with incomplete marrow recovery (CRi), complete clinical response (CCR), nodular partial response (nPR), or PR after 6 cycles of combination treatment. In each cohort, the proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent exact binomial confidence intervals for the true success proportion will be calculated.

  7 months

Secondary Outcomes (4)

• Overall Response Rate

  5 years

• Minimal Residual Disease (MRD) Response Rate

  Up to 5 years

• Progression-free Survival

  From registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 5 years

• Incidence of Adverse Events

  Up to 30 days after completion of study treatment

Study Arms (1)

Treatment (daratumumab, ibrutinib)

EXPERIMENTAL

Patients receive daratumumab IV on days 1, 8, 15, and 22 of cycles 1-2, on days 1 and 15 of cycles 3-6, and then on day 1 of subsequent cycles. Beginning in cycle 2, patients also receive ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Biological: Daratumumab; Drug: Ibrutinib

Interventions

Daratumumab BIOLOGICAL

Given IV

Also known as: Anti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414

Treatment (daratumumab, ibrutinib)

Ibrutinib DRUG

Given PO

Also known as: BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765

Treatment (daratumumab, ibrutinib)

Eligibility Criteria

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

You may qualify if:

• Diagnosis of B-CLL, confirmed by flow cytometry and as per the criteria outlined by the IWCLL/Hallek December 2008
• Patients must have relapse or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who have received at least 1 prior anti-CLL/SLL therapy. (Note: There is no upper limit of how many lines of therapy the patient may have received previously)
• Note: For the purpose of a particular therapy/regimen to be counted towards the number of prior treatments a patient must have received at least 2 cycles of the regimen e.g., a patient who change their treatment regimen after only 1 cycle (due to toxicity or any other reason) will not be considered to have "2" prior therapies
• Patients on low dose prednisone (≤ 10 mg) for treatment of conditions other than CLL are eligible
• Cohort 1 only: Exposed to previous bruton tyrosine kinase (BTK) inhibitor. Patients must meet one of the following criteria:
• They have been previously treated with a previous BTK inhibitor and were taken off for any reason (except grade 4 toxicity definitely attributed to BTK inhibitor) as long as deemed safe by the treatment physician to receive ibrutinib
• Currently on a BTK inhibitor and now have progressive disease (BTK inhibitor refractory)
• Currently on BTK inhibitor and have failed to achieve either a complete remission after at least 12 cycles of treatment with BTK or have suboptimal response (\< partial response \[PR\]) after being on BTK inhibitor treatment for 6 cycles
• Patients must have a measurable disease
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 at registration
• Absolute neutrophil count \>= 1000/mm\^3 (obtained =\< 14 days prior to registration)
• Hemoglobin \>= 7 g/dl (obtained =\< 14 days prior to registration)
• Platelets \>= 50,000/mm\^3 (obtained =\< 14 days prior to registration)
• Serum creatinine =\< 1.5 x upper limit of normal (ULN) \*OR\* creatinine clearance \> 25 ml/min) (obtained =\< 14 days prior to registration)
• Total bilirubin =\< 1.5 mg/dL or direct bilirubin =\< 1.0 mg/dL for patients with Gilbert's syndrome (obtained =\< 14 days prior to registration)

You may not qualify if:

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
• Patient is known to have chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) \< 50% of predicted normal (Note: FEV1 testing is required for subjects suspected of having chronic obstructive pulmonary disease and subjects must be excluded if FEV1 \< 50% of predicted normal)
• Patient is known to have moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification (Note: subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study)
• Since this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown, any of the following will deem the subject ineligible for the study:
• Pregnant women
• Nursing women
• Men or women of childbearing potential who are unwilling to employ adequate contraception
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
• Patients who have received no prior therapy for CLL
• Patients with history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix, unless in complete remission and off therapy for that disease for \> 3 years)
• Patients who have previously received daratumumab or any other anti-CD38 therapy on a clinical trial or for any other malignancy
• Prior or current exposure to any of the following:
• Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer.
• Focal radiation therapy within 14 days prior to randomization with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma
• Concomitant use of warfarin or other vitamin K antagonists

Sponsors & Collaborators

• Mayo Clinic: lead

Study Sites (1)

Mayo Clinic in Florida

Jacksonville, Florida, 32224-9980, United States

Location

Related Links

• Mayo Clinic Clinical Trials

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

daratumumab; ibrutinib

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Sikander Ailawadhi
• Organization: Mayo Clinic

Ailawadhi.Sikander@mayo.edu

904-953-2000

Study Officials

• Sikander Ailawadhi, M.D.

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: January 13, 2020
• First Posted: January 18, 2020
• Study Start: November 11, 2020
• Primary Completion: May 1, 2023
• Study Completion: February 13, 2025
• Last Updated: December 30, 2025
• Results First Posted: July 1, 2025

Record last verified: 2025-12

Locations

US (1)