Skip to main content

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

Trial Status: Active

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.

Inclusion Criteria

  • 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 CLL/SLL who have received at least 1 prior anti-CLL/small lymphocytic lymphoma (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
  • Cohort 1 only: Exposed to ibrutinib. Patients must meet one of the following criteria: * They have been previously treated with ibrutinib and were taken off for any reason (except grade 4 toxicity definitely attributed to ibrutinib) as long as deemed safe by the treatment physician to receive ibrutinib again * Currently on ibrutinib and now have progressive disease (ibrutinib refractory) * Currently on ibrutinib and have failed to achieve either a complete remission after at least 12 cycles of treatment with ibrutinib or have suboptimal response (< partial response [PR]) after being on ibrutinib 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)
  • Platelets >= 50,000/mm^3 (obtained =< 14 days prior to registration)
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) (minimal acceptable creatinine clearance [CLcr] > 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)

Exclusion Criteria

  • 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
  • Use of any other experimental drug or therapy =< 14 days prior to registration on this study * NOTE: Patients on low dose prednisone (=< 10 mg) for treatment of conditions other than CLL are eligible
  • 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 on a clinical trial or for any other malignancy
  • Concomitant use of warfarin or other vitamin K antagonists
  • Requires treatment with a strong cytochrome P450 modulators (CYP3A inhibitor and/or CYP3A inducers)
  • 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)

Florida

Jacksonville
Mayo Clinic in Florida
Status: ACTIVE
Contact: Sikander Ailawadhi
Phone: 904-953-2000

PRIMARY OBJECTIVES:

I. 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:

I. 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.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Mayo Clinic in Florida

Principal Investigator
Sikander Ailawadhi

  • Primary ID MC1784
  • Secondary IDs NCI-2020-00010
  • Clinicaltrials.gov ID NCT04230304