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Recurrent Chronic Lymphocytic LeukemiaPhase 2NCT04230304

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

A Phase 2 study testing Daratumumab and Ibrutinib in people with Recurrent Chronic Lymphocytic Leukemia and Recurrent Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, run by Mayo Clinic at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Daratumumab and Ibrutinib
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
8 participants
Where
1 siteUnited States
Study dates
11 Nov 2020to 13 Feb 2025
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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)
  • Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN (obtained =< 14 days prior to registration)
  • Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 3 months after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug
  • Negative pregnancy test done =< 14 days prior to registration, for persons of childbearing potential only
  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Provide written informed consent
  • Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)

Who cannot join

  • 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
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  • 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
  • Requires treatment with a strong cytochrome P450 modulators (CYP3A inhibitor and/or CYP3A inducers). NOTE: A comprehensive list of inhibitors, inducers, and substrates may be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/.
  • Major surgery =< 4 weeks prior to registration
  • Patients who are:
  • 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) deoxyribonucleic acid (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)
  • Clinically significant cardiac disease, including:
  • Myocardial infarction within 6 months before randomization, or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
  • Uncontrolled cardiac arrhythmia
  • Screening 12-lead ECG showing a baseline corrected QT interval (QTc) >40 msec.
  • Known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human proteins, Dara SC or its excipients (refer to the IB) or known sensitivity to mammalian-derived products
  • Have received vaccination with live attenuated vaccines within 4 weeks of first study agent administration
  • Patients with inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease, etc.)

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Mayo Clinic in Florida

    Jacksonville, Florida, 32224-9980

Other trials in United States

About this study

Official title: A Phase II Study of Daratumumab and Ibrutinib for Relapsed / Refractory Chronic Lymphocytic Leukemia Treatment (DIRECT)

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. Determine the overall response rate after 6 cycles of treatment with daratumumab in combination with ibrutinib in patients who are on /or are previously treated with ibrutinib. (Cohort 1) II. Determine the overall response rate after 6 cycles of treatment with daratumumab in combination with ibrutinib in patients who are naive to ibrutinib treatment. (Cohort 2)

SECONDARY OBJECTIVES:

  1. Determine the best overall response rate to treatment with daratumumab plus ibrutinib at any time during the course of the therapy. (Cohort 1) II. The overall incidence of MRD (minimal residual disease) negative state and the time to achieving MRD negativity at any time during this therapy. (Cohort 1) III. Progression free survival (as determined by the International Workshop on Chronic Lymphocytic Leukemia [IWCLL] criteria) among all patients. (Cohort 1) IV. The overall toxicity profile of daratumumab/ibrutinib treatment in this group of patients. (Cohort 1) V. Determine the best overall response rate to treatment with daratumumab plus ibrutinib at any time during the course of the therapy. (Cohort 2) VI. The overall incidence of MRD (minimal residual disease) negative state and the time to achieving MRD negativity at any time during this therapy. (Cohort 2) VII. The overall toxicity profile of daratumumab/ibrutinib treatment in this group of patients. (Cohort 2)

OUTLINE:

Patients receive daratumumab intravenously (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 orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study registration, patients are followed up periodically for up to 5 years.

Being tested
Daratumumab, Ibrutinib
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DaratumumabBiological

    Also called Anti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414

    Given IV

  • IbrutinibDrug

    Also called BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765

    Given PO

Study groups in NCT04230304
Study groupRoleWhat they receive
Treatment (daratumumab, ibrutinib)ExperimentalPatients 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.
Receives: Biological: Daratumumab; Drug: Ibrutinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 7 months

Secondary outcomes (4)

  1. Overall Response Rate

    Will be evaluated in each cohort independently. Will be estimated by the number of patients who achieve a CR, CRi, CCR, nPR, or PR at any time during combination treatment divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success rate will be calculated.

    Measured: 5 years

  2. Minimal Residual Disease (MRD) Response Rate

    Will be evaluated in each cohort independently. Will be estimated by the number of patients who achieve MRD negative response in both blood and bone marrow at any time during combination treatment divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success rate will be calculated. In patients who achieve MRD negative response, time to achieve MRD negative response will be summarized descriptively (median, range). Time to achieve MRD negative response is defined as time from registration to the earliest date of documentation of MRD negative response in both blood and bone marrow.

    Measured: Up to 5 years

  3. Progression-free Survival

    Will be evaluated in each cohort independently. The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.

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

  4. Incidence of Adverse Events

    Will be evaluated in each cohort independently. Platelets and hemoglobin will be graded according to the Grading Scale for Hematologic Adverse Events in Chronic Lymphocytic Leukemia (CLL) Studies. The maximum grade for each type of adverse event, regardless of causality, will be recorded and reported for each patient, and frequency tables will be reviewed to determine adverse event patterns.

    Measured: Up to 30 days after completion of study treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Jan 2020
  2. Study start11 Nov 2020
  3. Primary completion1 May 2023
  4. Study completion13 Feb 2025

Why it stopped: Slow accrual

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
8 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04230304
Sponsor's protocol ID
MC1784
Other IDs
NCI-2020-00010, MC1784, 19-001475
Status last verified
Dec 2025
First submitted
13 Jan 2020
Last updated
30 Dec 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Daratumumab and Ibrutinib in people with Recurrent Chronic Lymphocytic Leukemia and Recurrent Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, run by Mayo Clinic at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 30 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 1 Jul 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Response Rate by Cycle 7 (time frame: 7 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04230304.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Dec 2025.

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