Trial Outcomes & Findings for Daratumumab and Ibrutinib for the Treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia, DIRECT Study (NCT NCT04230304)

Last Updated: 2025-12-30

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

8 participants

Primary outcome timeframe

7 months

Results posted on

2025-12-30

Participant Flow

Participant milestones

Participant milestones
Measure	Cohort 1 (Previous BTK Inihibitor Exposed) 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.	Cohort 2 (BTK Inihibitor naïve) 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.
Overall Study STARTED	6	2
Overall Study COMPLETED	6	2
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 (Previous BTK Inihibitor Exposed) n=6 Participants 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.	Cohort 2 (BTK Inihibitor naïve) n=2 Participants 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.	Total n=8 Participants Total of all reporting groups
Age, Continuous	68.7 years STANDARD_DEVIATION 4.68 • n=174 Participants	60.5 years STANDARD_DEVIATION 0.71 • n=166 Participants	66.6 years STANDARD_DEVIATION 5.48 • n=167 Participants
Sex: Female, Male Female	1 Participants n=174 Participants	2 Participants n=166 Participants	3 Participants n=167 Participants
Sex: Female, Male Male	5 Participants n=174 Participants	0 Participants n=166 Participants	5 Participants n=167 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=174 Participants	0 Participants n=166 Participants	0 Participants n=167 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=174 Participants	2 Participants n=166 Participants	8 Participants n=167 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=174 Participants	0 Participants n=166 Participants	0 Participants n=167 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=174 Participants	0 Participants n=166 Participants	0 Participants n=167 Participants
Race (NIH/OMB) Asian	0 Participants n=174 Participants	0 Participants n=166 Participants	0 Participants n=167 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=174 Participants	0 Participants n=166 Participants	0 Participants n=167 Participants
Race (NIH/OMB) Black or African American	1 Participants n=174 Participants	0 Participants n=166 Participants	1 Participants n=167 Participants
Race (NIH/OMB) White	5 Participants n=174 Participants	2 Participants n=166 Participants	7 Participants n=167 Participants
Race (NIH/OMB) More than one race	0 Participants n=174 Participants	0 Participants n=166 Participants	0 Participants n=167 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=174 Participants	0 Participants n=166 Participants	0 Participants n=167 Participants

PRIMARY outcome

Timeframe: 7 months

Population: Both cohorts are analyzed together to avoid deidentifying the outcome for individual patents. Neither arm has enough patients to represent a valid estimate for overall response rate. These results should not be used to compare this treatment to any other treatment or to compare patient cohorts. These results are only reported for regulation purposes. Both cohorts are analyzed together to avoid deidentifying the outcome for the two cohort B patents.

Outcome measures

Outcome measures
Measure	Treatment (Daratumumab, Ibrutinib) n=8 Participants 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.
Overall Response Rate by Cycle 7	0.375 proportion of participants

SECONDARY outcome

Timeframe: 5 years

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 5 years

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

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

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 30 days after completion of study treatment

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.

Outcome measures

Outcome data not reported

Adverse Events

Treatment (Daratumumab, Ibrutinib)

Serious events: 2 serious events

Other events: 8 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Treatment (Daratumumab, Ibrutinib) n=8 participants at risk 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.
Infections and infestations Sepsis	12.5% 1/8 • Number of events 1 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Infections and infestations Skin infection	12.5% 1/8 • Number of events 2 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Respiratory, thoracic and mediastinal disorders Pneumonitis	12.5% 1/8 • Number of events 1 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.

Other adverse events

Other adverse events
Measure	Treatment (Daratumumab, Ibrutinib) n=8 participants at risk 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.
Blood and lymphatic system disorders Anemia	75.0% 6/8 • Number of events 50 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Cardiac disorders Atrial fibrillation	12.5% 1/8 • Number of events 5 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
General disorders Fatigue	62.5% 5/8 • Number of events 61 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Injury, poisoning and procedural complications Bruising	75.0% 6/8 • Number of events 133 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Investigations Creatinine increased	12.5% 1/8 • Number of events 1 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Investigations Lymphocyte count decreased	12.5% 1/8 • Number of events 3 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Investigations Lymphocyte count increased	37.5% 3/8 • Number of events 44 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Investigations Neutrophil count decreased	12.5% 1/8 • Number of events 1 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Investigations Platelet count decreased	50.0% 4/8 • Number of events 43 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Investigations White blood cell decreased	12.5% 1/8 • Number of events 1 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Musculoskeletal and connective tissue disorders Arthralgia	12.5% 1/8 • Number of events 19 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Musculoskeletal and connective tissue disorders Muscle cramp	12.5% 1/8 • Number of events 13 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Musculoskeletal and connective tissue disorders Myalgia	12.5% 1/8 • Number of events 1 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Respiratory, thoracic and mediastinal disorders Epistaxis	12.5% 1/8 • Number of events 1 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Skin and subcutaneous tissue disorders Rash maculo-papular	37.5% 3/8 • Number of events 4 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Skin and subcutaneous tissue disorders Skin and subcut tissue disord - Oth spec	12.5% 1/8 • Number of events 1 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.
Vascular disorders Hypertension	37.5% 3/8 • Number of events 65 • Adverse events were followed for 3 years and mortality is still being followed. Due to lack of accrual, adverse events and morality is reported by treatment group and not cohort. With only two patients accrued to cohort B, it would be unethical to report their isolated adverse events and mortality.

Additional Information

Sikander Ailawadhi

Mayo Clinic

Phone: 904-953-2000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place