Clinical Trials /

A Combination of Acalabrutinib With R-CHOP for Patient Diffuse Large B-cell Lymphoma (DLBCL)

NCT03571308

Description:

Previously untreated CD20 positive diffuse large B-cell lymphoma (DLBCL) requiring full course chemoimmunotherapy.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Combination of Acalabrutinib With R-CHOP for Patient Diffuse Large B-cell Lymphoma (DLBCL)
  • Official Title: A Phase Ib/II Combination of Acalabrutinib With R-CHOP for Patient Diffuse Large B-cell Lymphoma (DLBCL)

Clinical Trial IDs

  • ORG STUDY ID: RHM CAN 1129
  • NCT ID: NCT03571308

Conditions

  • Non Hodgkin Lymphoma

Interventions

DrugSynonymsArms
R-CHOP + acalabrutinibRituximab, Cyclophosphamide, Vincristine, Doxorubicin, Prednisolone, AcalabrutinibR-CHOP + Acalabrutinib

Purpose

Previously untreated CD20 positive diffuse large B-cell lymphoma (DLBCL) requiring full course chemoimmunotherapy.

Detailed Description

      Open-label non-randomised phase Ib/II study conducted in two stages. Stage 1 will be dose
      escalation in a modified classical 6+6 design. Stage 2 will be an expansion cohort to gain
      additional information on safety and efficacy at the recommended phase II dose of
      acalabrutinib.
    

Trial Arms

NameTypeDescriptionInterventions
R-CHOP + AcalabrutinibExperimentalOpen-label non-randomised phase Ib/II study conducted in two stages. Phase I will see two doses of acalabrutinib tested. R-CHOP + acalabrutinib will be given for 6 cycles on a 21 day cycle and then two cycles of acalabrutinib only for a total of 56 days. Acalabrutinib will be introduced at Cycle 2. Phase II will see the recommended phase 2 dose used on the same treatment regimen.
  • R-CHOP + acalabrutinib

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should
             be available to forward to a central laboratory for gene expression profiling and
             pathology review.

          -  Measurable disease of at least 15mm.

          -  Not previously treated for lymphoma and fit enough to receive combination
             chemoimmunotherapy with curative intent.

          -  Stage IAX (bulk defined as lymph node diameter >10cm) to stage IV disease and deemed
             to require a full course of chemotherapy. Patients with non-bulky IE disease will not
             be eligible.

          -  ECOG performance status 0-2 or 3 if this is directly attributable to lymphoma.

          -  Adequate bone marrow function with platelets > 100x109/L; neutrophils > 1.0x109/L at
             study entry, unless lower figures are attributable to lymphoma.

          -  Measured or calculated creatinine clearance > 30mls/min, (calculated using the formula
             of Cockcroft and Gault [(140-Age) x Mass (kg) x (1.04 (for women) or 1.23 (for
             men))/Serum Creatinine (µmolL)].

          -  Serum bilirubin < 35μmol/L and transaminases < 2.5x upper limit of normal at time of
             study entry

          -  Cardiac function sufficient to tolerate 300mg/m2 of doxorubicin. A pre-treatment
             echocardiogram or MUGA is required to establish baseline LVEF equal to or greater than
             55%.

          -  No concurrent uncontrolled medical condition.

          -  Life expectancy > 3 months.

          -  Aged 16 years or above.

          -  Willing and able to participate in all required evaluations and procedures in this
             study protocol including swallowing capsules without difficulty.

          -  Ability to understand the purpose and risks of the study and provide signed and dated
             informed consent.

        Exclusion Criteria:

        Patients will be excluded from the study entry if any of the following criteria are met:

          -  Previous history of treated or untreated indolent lymphoma. However newly diagnosed
             patients with DLBCL who are found to also have small cell infiltration of the bone
             marrow or other diagnostic material (discordant lymphoma) will be eligible.

          -  Patients who have received immunisation with a live vaccine within four weeks prior to
             enrolment will be ineligible.

          -  Diagnosis of primary mediastinal lymphoma.

          -  Diagnosis of primary Central Nervous System lymphoma.

          -  History of stroke or intracranial haemorrhage in preceding 6 months.

          -  History of bleeding diathesis (eg, haemophilia, von Willebrand disease).

          -  Requires or receiving anticoagulation with warfarin or equivalent antagonists (eg,
             phenprocoumon) within 7 days of first dose of acalabrutinib. However patients using
             therapeutic low molecule weight heparin or low dose aspirin will be eligible.

          -  Prior exposure to a BCR inhibitor (eg, Btk inhibitors, phosphoinositide-3 kinase
             (PI3K), or Syk inhibitors) or BCL-2 inhibitor (eg, ABT-199)

          -  Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer.

          -  Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole,
             lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receiving
             proton pump inhibitors who switch to short-acting H2-receptor antagonists or antacids
             are eligible for enrolment into this study.

          -  Uncontrolled systemic infection.

          -  Major surgery in the preceding 4 weeks of first dose of study drug. If a subject had
             major surgery, they must have recovered adequately from any toxicity and/or
             complications from the intervention before the first dose of study drug.

          -  Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
             congestive heart failure, or myocardial infarction within 6 months of screening, or
             any Class 3 or 4 cardiac disease as defined by the New York Heart Association
             Functional Classification, or corrected QT interval (QTc) > 480 msec at screening.

          -  Serological positivity for Hepatitis B, C, or known HIV infection. As per standard of
             care, prior to initiation of immunochemotherapy, the results of hepatitis serology
             should be known prior to commencement of therapy.

               -  Positive test results for chronic HBV infection (defined as positive HBsAg
                  serology) will not be eligible. Patients with occult or prior HBV infection
                  (defined as negative HBsAg and positive total HBcAb) will not be eligible.
                  Patients who have protective titres of hepatitis B surface antibody (HBsAb) after
                  vaccination will be eligible.

               -  Positive test results for hepatitis C (HCV antibody serology testing) will not be
                  eligible.

          -  Women who are sexually active and can bear children must agree to use highly effective
             forms of contraception or abstinence during the study and for 12 months after the last
             treatment dose. Highly effective forms of contraception are defined in Section 4.7.

          -  Breastfeeding or pregnant women.

          -  Men who are sexually active and can father children must agree to use highly effective
             forms of contraception or abstinence during the study and for 12 months after the last
             treatment dose. Highly effective forms of contraception are defined in Section 4.7.

          -  Men must agree to refrain from sperm donation during the study and for 12 months after
             the last treatment dose.

          -  Serious medical or psychiatric illness likely to affect participation or that may
             compromise the ability to give informed consent.

          -  Prior malignancy (other than DLBCL), except for adequately treated basal cell or
             squamous cell skin cancer, in situ cervical cancer, or other cancer from which the
             subject has been disease free for ≥ 2 years or which will not limit survival to < 2
             years. Note: these cases must be discussed with SCTU.

          -  Malabsorption syndrome, disease significantly affecting gastrointestinal function,
             resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory
             bowel disease, or partial or complete bowel obstruction or gastric restrictions and
             bariatric surgery, such as gastric bypass.

          -  Any immunotherapy within 4 weeks of 1st dose of the study.

          -  Concurrent participation in another therapeutic clinical trial.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Dose limiting toxicity of acalabrutinib combined to R-CHOP
Time Frame:18 months
Safety Issue:
Description:Define recommended dose for Phase II evaluation of acalabrutinib with R-CHOP examining safety and toxicity of combination

Secondary Outcome Measures

Measure:Pharmacokinetics of acalabrutinib using area under the plasma concentration versus time curve (AUC)
Time Frame:24 months
Safety Issue:
Description:To determine the pharmacokinetic (PK) profile of acalabrutinib when given in combination with R-CHOP in patients with DLBCL
Measure:Maximum Plasma Concentration (Cmax) of acalabrutinib
Time Frame:24 months
Safety Issue:
Description:To determine the pharmacokinetic (PK) profile of acalabrutinib when given in combination with R-CHOP in patients with DLBCLPK parameter.
Measure:Time after administration when maximum concentration of acalabrutinib in the plasma is reached (Tmax)
Time Frame:24 months
Safety Issue:
Description:To determine the pharmacokinetic (PK) profile of acalabrutinib when given in combination with R-CHOP in patients with DLBCL
Measure:Time required for concentration of acalabrutinib to reach half original value (T1/2)
Time Frame:24 months
Safety Issue:
Description:To determine the pharmacokinetic (PK) profile of acalabrutinib when given in combination with R-CHOP in patients with DLBCL
Measure:Overall response rate of the combination acalabrutinib and R-CHOP according to cell of origin.
Time Frame:24 months
Safety Issue:
Description:To evaluate the effect of acalabrutinib in combination with R-CHOP on outcomes according to cell of origin
Measure:Two years progression-free survival
Time Frame:24 months
Safety Issue:
Description:To measure the duration of response to acalabrutinib in combination with R-CHOP over a follow-up period of 2 years
Measure:Two years overall survival
Time Frame:24 months
Safety Issue:
Description:To measure the duration of response to acalabrutinib in combination with R-CHOP over a follow-up period of 2 years

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University Hospital Southampton NHS Foundation Trust

Trial Keywords

  • Diffused Large B-Cell Lymphoma
  • Acalabrunitib
  • Bruton Tyrosine Kinase
  • R-CHOP
  • Molecular Profiling
  • Chemoimmunotherapy

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