Clinical Trials /

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

NCT04230304

Description:

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Daratumumab and Ibrutinib for the Treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia, DIRECT Study
  • Official Title: A Phase II Study of Daratumumab and Ibrutinib for Relapsed / Refractory Chronic Lymphocytic Leukemia Treatment (DIRECT)

Clinical Trial IDs

  • ORG STUDY ID: MC1784
  • SECONDARY ID: NCI-2020-00010
  • SECONDARY ID: MC1784
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT04230304

Conditions

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

Interventions

DrugSynonymsArms
DaratumumabAnti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414Treatment (daratumumab, ibrutinib)
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Treatment (daratumumab, ibrutinib)

Purpose

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.

Detailed Description

      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)

      CORRELATIVE RESEARCH OBJECTIVES:

      I. To conduct correlative studies for further understanding of the biological relevance of
      CD38 as a therapeutic target and its impact on response to treatment with daratumumab.

      II. To determine the incidence of ibrutinib induced lymphocytosis and if pre-treatment with
      daratumumab prevent the development of this flare reaction.

      III. Determine the number of patients who show clinical evidence of anti-chronic lymphocytic
      leukemia (CLL) response after 4 weeks of treatment of Daratumumab alone and correlation with
      their baseline CD38 MFI determined by flow cytometry.

      IV. Durability of the MRD negative (-) state (determined from the time of first documentation
      of MRD- until the first documentation of MRD positive (+) (or last date shown to be MRD- for
      a censor).

      V. Establish the progression free survival (PFS) for patients who have achieved MRD (minimal
      residual disease) negative state in comparison to those who did not achieve MRD negativity
      post cycle 12.

      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 Arms

NameTypeDescriptionInterventions
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.
  • Daratumumab
  • Ibrutinib

Eligibility Criteria

        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 (or other BTK inhibitors and have relapse or
             refractory disease and require treatment (as outlined in IWCLL/Hallek December 2008).
             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 1 month 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

          -  Willingness to provide mandatory blood specimens for correlative research

          -  Willingness to provide mandatory tissue specimens for correlative research

          -  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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:At the End of cycle 7 (each cycle is 28 days)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Minimal residual disease (MRD) response rate
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Progression-free survival
Time Frame:From registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 5 years
Safety Issue:
Description:Will be evaluated in each cohort independently. The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.
Measure:Incidence of adverse events
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Mayo Clinic

Last Updated

January 14, 2020