Clinical Trials /

Acalabrutinib in Combination With R-CHOP for Previously Untreated Diffuse Large B-cell Lymphoma (DLBCL)

NCT04546620

Description:

This study evaluates the addition of Acalabrutinib to current standard therapy of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) for patients with previously untreated CD20 positive Diffuse Large B-cell Lymphoma (DLBCL) requiring full course chemoimmunotherapy. All patients will receive one cycle of R-CHOP. Two thirds of patients (Arm B) will go on to receive a further 5 cycles (every 21 days) of R-CHOP with Acalabrutinib. Acalabrutinib will be taken orally twice daily continuously in 21 day cycles. One third of patients (Arm A) will continue with 5 cycles of R-CHOP. Patients will be followed up for 24 months initially and for disease status and survival until the last patient recruited has completed 24 months of follow-up.

Related Conditions:
  • ALK-Positive Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Double-Hit Lymphoma
  • EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • HHV8-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • High Grade B-Cell Lymphoma, Not Otherwise Specified
  • T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
  • Triple-Hit Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Acalabrutinib in Combination With R-CHOP for Previously Untreated Diffuse Large B-cell Lymphoma (DLBCL)
  • Official Title: A Randomised Phase II Evaluation of Molecular Guided Therapy for Diffuse Large B-Cell Lymphoma With Acalabrutinib

Clinical Trial IDs

  • ORG STUDY ID: RHM CAN1500
  • NCT ID: NCT04546620

Conditions

  • Diffuse Large B Cell Lymphoma

Interventions

DrugSynonymsArms
R-CHOPRituximab, Cyclophosphamide, Doxorubicin, Vincristine, PrednisoloneArm A Control
R-CHOP + acalabrutinibRituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone, AcalabrutinibArm B Experimental

Purpose

This study evaluates the addition of Acalabrutinib to current standard therapy of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) for patients with previously untreated CD20 positive Diffuse Large B-cell Lymphoma (DLBCL) requiring full course chemoimmunotherapy. All patients will receive one cycle of R-CHOP. Two thirds of patients (Arm B) will go on to receive a further 5 cycles (every 21 days) of R-CHOP with Acalabrutinib. Acalabrutinib will be taken orally twice daily continuously in 21 day cycles. One third of patients (Arm A) will continue with 5 cycles of R-CHOP. Patients will be followed up for 24 months initially and for disease status and survival until the last patient recruited has completed 24 months of follow-up.

Detailed Description

      Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin's lymphomas.
      Whilst the majority of patients will respond well to conventional treatment (R-CHOP -
      rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone), a significant number
      of patients lymphoma will not respond to initial therapy or their disease will return after
      completion of therapy. In a number of B-cell diseases an enzyme called, Bruton tyrosine
      kinase (BTK) prevents death of tumour cells, including in DLBCL. Acalabrutinib is an orally
      active BTK-inhibitor and it is thought that stopping BTK being activated may help in treating
      B-cell diseases. It is hypothesised that the addition of Acalabrutinib to standard R-CHOP
      immunochemotherapy may improve outcomes of patients with DLBCL.

      REMoDL-A is a randomised, phase II, open label, multicentre study that will be open in up to
      50 centres. Up to 553 patients (453 randomised) will be recruited,

      Following informed consent all patients will receive 1 cycle of conventional R-CHOP
      chemotherapy. At the same time the diagnostic pathology block will be sent for molecular
      profiling by the Haematological Malignancy Diagnostic Service (HMDS). The delivery of the
      first cycle of R-CHOP will allow a sufficient interval for real time determination of
      molecular phenotype. Patients whose biopsies yield sufficient tumour material for profiling
      will be randomised 2:1 in favour of the experimental arm (R-CHOP + acalabrutinib).

      The primary objective will be to establish if combining acalabrutinib with R-CHOP improves
      efficacy, compared to R-CHOP alone, for the treatment of previously untreated patients with
      DLBCL to a degree that justifies further development of this approach.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A ControlActive Comparator6 cycles of standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) immunochemotherapy every 21 days.
  • R-CHOP
Arm B ExperimentalExperimental1 cycle of standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) immunochemotherapy followed by 5 cycles of R-CHOP + acalabrutinib taken twice daily for 21 day cycles.
  • R-CHOP + acalabrutinib

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material must
             be available to forward to HMDS for gene expression profiling and central pathology
             review. The following diagnoses by 2016 WHO classification of lymphoid neoplasms may
             be included:

               -  DLBCL, not otherwise specified (NOS)

               -  T-cell/histiocyte-rich large B-cell lymphoma

               -  Epstein-Barr virus positive DLBCL, NOS

               -  ALK-positive large B-cell lymphoma

               -  HHV8-positive DLBCL, NOS

               -  High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
                  (double-hit or triple-hit lymphoma)

               -  High-grade B-cell lymphoma, NOS

          -  At least one bi-dimensionally measurable lesion, defined as >1.5 cm in its longest
             dimension as measured by CT or MRI.

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

          -  Stage IAX (bulk defined as lymph node mass [either single or conglomerate] diameter
             >7.5cm) 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 < 1.5x 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
             institutional normal range.

          -  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:

          -  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 or secondary CNS involvement.
             Those patients presenting with neurological symptoms should be investigated for CNS
             involvement. Routine CNS imaging or diagnostic lumbar puncture will not be required in
             the absence of symptoms.

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

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

          -  History of drug-specific hypersensitivity or anaphylaxis to any study drug (including
             active product or excipient components).

          -  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 as will
             those receiving direct oral anticoagulants.

          -  Prior exposure to an inhibitor in the BCR pathway (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 should switch to short-acting H2-receptor antagonists or
             antacids prior to study entry to be eligible for enrolment into this study.

          -  Active significant infection (e.g. progressive multifocal leukoencephalopathy (PML)).

          -  Uncontrolled autoimmune haemolytic anaemia (AIHA) or idiopathic thrombocytopenic
             purpura (ITP).

          -  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.

          -  Corticosteroid use >30 mg/day of prednisone or equivalent, for purposes other than for
             lymphoma symptom control. Patients receiving corticosteroid treatment with <30 mg/day
             of prednisone or equivalent must be documented to be on a stable dose of at least 4
             weeks' duration prior to the start of Cycle 1. If glucocorticoid treatment is urgently
             required for lymphoma symptom control prior to the start of study treatment,
             prednisone 100 mg or equivalent could be given for a maximum of 14 days as a prephase.
             A dose of up to 30mg or prednisolone or equivalent may be used during the screening
             phase to control symptoms.

          -  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.

          -  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.

               1. 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.

               2. Patients positive for HCV antibody are eligible only if polymerase chain reaction
                  (PCR) is negative for HCV RNA.

          -  Women who can bear children must agree to use two highly effective forms of
             contraception or abstinence during the study and for 12 months after the last
             treatment dose.

          -  Breastfeeding or pregnant women.

          -  Men who can father children must agree to use two highly effective forms of
             contraception with additional barrier or abstinence during the study and for 12 months
             after the last treatment dose.

          -  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.

          -  Has difficulty with or is unable to swallow oral medication, or has significant
             gastrointestinal disease, resection of the stomach or small bowel, partial or complete
             bowel obstruction or gastric restrictions and bariatric surgery, such as gastric
             bypass that would limit absorption of oral medication.

          -  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:To establish if combining acalabrutinib with R-CHOP improves efficacy, compared to RCHOP alone, for the treatment of previously untreated patients with DLBCL to a degree that justifies further development of this approach.
Time Frame:Last patient's last follow up, approximately 4.5 years. Patients who do not experience a PFS event will be censored at the date of last follow up.
Safety Issue:
Description:Progression-free survival (PFS) is defined as time from registration to progression/death from any cause.

Secondary Outcome Measures

Measure:To compare PFS between molecular groups.
Time Frame:Last patient's last follow-up, approximately 4.5 years.
Safety Issue:
Description:PFS interaction with cell of origin phenotype (ABC, GCB and unclassifiable).
Measure:To compare PFS between treatment groups.
Time Frame:Last patient's last follow-up, approximately 4.5 years.
Safety Issue:
Description:PFS interaction with clinical variables, including for example IPI, bulk, components of IPI, age and others to be determined in the SAP.
Measure:To compare overall survival (OS) between both treatment and molecular groups.
Time Frame:Last patient's last follow-up, approximately 4.5 years. Patients who do not experience an OS event will be censored at the date of last follow-up.
Safety Issue:
Description:Overall survival (OS), defined as time from registration to death from any cause.
Measure:To compare event free survival (EFS) between both treatment and molecular groups.
Time Frame:Last patient's last follow-up, approximately 4.5 years. Patients who do not experience an EFS event will be censored at the date of last follow-up.
Safety Issue:
Description:Event-free survival (EFS), or time to treatment failure, defined as time from registration to any treatment failure including disease progression, or discontinuation of treatment for any reason.
Measure:To compare disease free survival (DFS) between both treatment and molecular groups.
Time Frame:Last patient's last follow-up, approximately 4.5 years. Patients who do not experience a DFS event will be censored at the date of last follow-up.
Safety Issue:
Description:Disease-free survival (DFS), defined as time of documentation of disease-free state to disease recurrence or death as a result of lymphoma or acute toxicity of treatment.
Measure:To compare time to progression (TTP) between both treatment and molecular groups.
Time Frame:Last patient's last follow-up, approximately 4.5 years. Patients who do not experience a TTP event will be censored at the date of last follow-up.
Safety Issue:
Description:Time to progression (TTP), defined as time from registration until documented lymphoma progression or death as a result of lymphoma. Deaths from other causes are censored at the time of death.
Measure:To compare response duration (RD) between both treatment and molecular groups.
Time Frame:Last patient's last follow-up, approximately 4.5 years. Patients who do not experience a RD event will be censored at the date of last follow-up.
Safety Issue:
Description:Response duration (RD), defined as the time from documentation of response until the documentation of relapse or progression.
Measure:To compare overall response rate (ORR) and complete response rate (CR) between both treatment groups.
Time Frame:Complete and overall response rates, as recorded at the end of treatment (up to 21 weeks) .
Safety Issue:
Description:Assessment using the Lugano Response Criteria for Malignant Lymphoma.
Measure:To assess differences in toxicity between assigned treatments.
Time Frame:At all visits up to 24 months follow-up.
Safety Issue:
Description:Evaluation of toxicity according to CTCAE version 5.
Measure:To assess differences in quality of life between treatment arms.
Time Frame:At baseline, cycle 2 day 1, cycle 3 day 1, cycle 5 day 1, end of treatment and at 3, 6, 12, 20 and 24 month follow-ups. Each cycle is 21 days.
Safety Issue:
Description:Application of the EORTC QLQ-C30 and FACT-Lym questionnaires.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University Hospital Southampton NHS Foundation Trust

Trial Keywords

  • Lymphoma
  • Acalabrutinib
  • R-CHOP
  • DLBCL
  • Non Hodgkin Lymphoma
  • Haematological cancer
  • Bruton Tyrosine Kinase
  • Molecular Profiling
  • Chemoimmunotherapy

Last Updated

September 3, 2020