Clinical Trials /

Acalabrutinib With DA-EPOCH-R or R-CHOP for People With Untreated Diffuse Large B-cell Lymphoma

NCT04002947

Description:

Background: Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. Most people with this cancer can be cured. But those who are not cured have a poor prognosis. Researchers want to add another drug to standard treatment see if it can improve the cure rate. Objective: To see if the drug acalabrutinib given with rituximab and standard combination chemotherapy can improve the cure rate of aggressive B-cell lymphomas such as diffuse large B-cell lymphoma. Eligibility: People ages 18 and older with an aggressive B-cell lymphomas that have not been treated Design: Participants will be screened with: Blood and urine tests Physical exam Medical history Tumor biopsy Bone marrow biopsy: A needle will remove marrow from the participant s hipbone. Lumbar puncture: If necessary, a needle will remove fluid from the participant s spinal canal. Imaging scans Participants will take the study drug for up to 14 days. It is a pill taken 2 times a day. Then they will have more scans. They will get rituximab and chemotherapy. They may get these drugs through a needle in an arm vein. Or they may them through a tube placed in a vein in their chest or in their neck. They might also keep taking the study drug. Each treatment cycle lasts 21 days. They will have up to 6 cycles. Participants may have 4 doses of another drug injected into their spinal fluid. Participants will have repeats of the screening tests throughout the study. Participants will have a follow-up visit 30 days after their last treatment, then every 3 months for 2 years, then every 6 months for 3 years, and then yearly. ...

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Acalabrutinib With DA-EPOCH-R or R-CHOP for People With Untreated Diffuse Large B-cell Lymphoma
  • Official Title: A Phase 2 Study of Acalabrutinib With DA-EPOCH-R or R-CHOP for Patients With Untreated Diffuse Large B-cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 190116
  • SECONDARY ID: 19-C-0116
  • NCT ID: NCT04002947

Conditions

  • Diffuse Large B-Cell Lymphoma
  • Non Hodgkin's Lymphoma
  • DLBCL
  • NHL

Interventions

DrugSynonymsArms
DA-EPOCH1
Rituximab1
CHOP1
Acalabrutinib1

Purpose

Background: Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. Most people with this cancer can be cured. But those who are not cured have a poor prognosis. Researchers want to add another drug to standard treatment see if it can improve the cure rate. Objective: To see if the drug acalabrutinib given with rituximab and standard combination chemotherapy can improve the cure rate of aggressive B-cell lymphomas such as diffuse large B-cell lymphoma. Eligibility: People ages 18 and older with an aggressive B-cell lymphomas that have not been treated Design: Participants will be screened with: Blood and urine tests Physical exam Medical history Tumor biopsy Bone marrow biopsy: A needle will remove marrow from the participant s hipbone. Lumbar puncture: If necessary, a needle will remove fluid from the participant s spinal canal. Imaging scans Participants will take the study drug for up to 14 days. It is a pill taken 2 times a day. Then they will have more scans. They will get rituximab and chemotherapy. They may get these drugs through a needle in an arm vein. Or they may them through a tube placed in a vein in their chest or in their neck. They might also keep taking the study drug. Each treatment cycle lasts 21 days. They will have up to 6 cycles. Participants may have 4 doses of another drug injected into their spinal fluid. Participants will have repeats of the screening tests throughout the study. Participants will have a follow-up visit 30 days after their last treatment, then every 3 months for 2 years, then every 6 months for 3 years, and then yearly. ...

Detailed Description

      Background:

        -  Gene-expression profiling (GEP) has identified two dominant molecular subtypes,activated
           B cell like (ABC) and germinal center B cell like (GCB), that arise by distinct
           mechanisms, have distinct prognoses, and respond differently to targeted therapy

        -  Recently, genetic subtypes of DLBCL have been described within molecular subtypes that
           have distinct genotypic, epigenetic, and clinical characteristics providing biologic
           rationale for precision medicine strategies in DLBCL

        -  Frontline treatment of DLBCL is either rituximab, cyclophosphamide, doxorubicin,
           vincristine, and prednisone (R-CHOP), or infusional rituximab, cyclophosphamide,
           doxorubicin, etoposide, vincristine, and prednisone (DA-EPOCH-R) but up to 40% of
           patients are not cured with frontline treatment

        -  Bruton s tyrosine kinase (BTK) is a key component of the B-cell receptor (BCR)-signaling
           cascade and selective BTK inhibitors have clinical activity preferentially in ABC-DLBCL

        -  Acalabrutinib is a selective, small molecule, second-generation BTK inhibitor approved
           for relapsed mantle cell lymphoma and demonstrated activity in DLBCL

        -  The molecular characterization of tumors that respond to DLBCL BTK inhibitors is
           incomplete; although responses occur more commonly in ABC-DLBCL, cases of GCBDLBCL show
           minor responses, and no information is available within genetic subtypes of DLBCL

        -  Patients with minor responses during 2-week window of treatment with acalabrutinib
           (100mg BID) as a single agent may benefit from acalabrutinib added to standard
           combination therapy as part of frontline therapy

      Objectives:

      -To determine the response rate, including minor response (MR), to acalabrutinib administered
      for 14 days in molecular and genetic subtypes of untreated DLBLC (ABC, GCB, unclassified,
      genetic subtypes)

      Eligibility:

        -  Histologically confirmed DLBCL or high-grade B-cell lymphoma

        -  Primary mediastinal B-cell lymphoma (PMBL) and CNS involvement excluded

        -  Stages II-IV

        -  HIV negative or positive

        -  Available FFPE or fresh frozen biopsy

        -  Adequate organ function

        -  Age >=18 years

      Design:

        -  Open-label, single center, non-randomized phase 2 study, with enrollment of 100
           untreated DLBCL patients. It is estimated that there may be 50% who are ABC (~50
           patients), and 50% who are GCB or unclassified (~50 patients). The accrual ceiling will
           be set at 112 to allow for inevaluable patients.

        -  The study will start with an initial 2-week window of treatment with acalabrutinib
           (100mg BID) as a single agent, with collection and assessment of molecular correlates as
           well as response rates (by imaging) by molecular subtype

        -  Treatment with chemoimmunotherapy (R-CHOP or DA-EPOCH-R) either alone or in combination
           with acalabrutinib will depend on response during window; those with less than 25%
           reduction during window will receive chemoimmunotherapy alone, while those with at least
           a 25% reduction in tumor lesions (sum of the products of the longest diameter) will
           receive combination therapy of chemoimmunotherapy with acalabrutinib (100mg BID on days
           1-10 of each cycle); those with clinical progression during window will move immediately
           to chemoimmunotherapy

        -  Secondary objectives include integrative genomic analysis of all untreated DLBCL that
           respond or are resistant to acalabrutinib for 14 days, event-free survival (EFS),
           progression free survival (PFS) and overall survival (OS) of combination therapy of
           acalabrutinib and chemoimmunotherapy will be assessed
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalAcalabrutinib 100 mg orally twice a day for 14 days; Following window: patients with > or = to 25% tumor reduction, treat with DA-EPOCH-R or RCHOP + acalabrutinib 100mg orally twice a day for the first 10 days, for 6 cycles; whereas, patients with <25% tumor reduction, treat with DA-EPOCH-R or RCHOP alone for 6 cycles
  • DA-EPOCH
  • Rituximab
  • CHOP
  • Acalabrutinib

Eligibility Criteria

        -INCLUSION CRITERIA:

          1. Patients must have a confirmed histologic diagnosis of an aggressive B-cell lymphoma
             with morphologic appearance of DLBCL or high-grade B-cell lymphoma (HGBL) confirmed by
             the Laboratory of Pathology, NCI, with no prior treatment for DLBCL or HGBL. The
             following subtypes are included:

               -  DLBCL, NOS, Activated B-cell type (ABC)

               -  DLBCL, NOS, Germinal center B-cell type (GCB)

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

               -  Primary cutaneous DLBCL, leg-type

               -  EBV+ DLBCL, NOS

               -  DLBCL associated with chronic inflammation

               -  ALK+ large B-cell lymphoma

               -  High-grade B-cell lymphoma, NOS

               -  High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements

          2. A formalin-fixed tissue block or 15 slide of tumor sample (archival or fresh) must be
             available for performance of correlative studies.

             NOTE: Tumor tissue may be from any previously collected tissue and adequacy is at the
             discretion of the Principal Investigator. Patients must be willing to have a tumor
             biopsy if adequate archival tissue is not available (i.e., post-enrollment and prior
             to treatment).

          3. Measurable lymph nodes or masses of at least 1.5 centimeters (cm) on baseline CT or
             MRI

          4. Stage II, III, or IV disease as classified by the Ann Arbor Classification

          5. Age greater than or equal to 18 years

             NOTE: Because no dosing or adverse event data are currently available on the use of
             acalabrutinib in patients <18 years of age, children are excluded.

          6. ECOG performance status less than or equal to 2.

          7. Adequate organ and marrow function as defined below unless dysfunction is felt to be
             secondary to lymphoma involvement as determined by the treating investigator:

               -  absolute neutrophil count* >=1,000/mcL

               -  hemoglobin* >= 8 g/dL (transfusions permitted to meet criteria)

               -  Platelets >= 75,000/mcL (transfusions not permitted)

               -  total bilirubin <= 1.5 X institutional ULN (or <= 3 X institutional ULN for
                  patients with documented Gilberts syndrome or cholestatic obstruction or
                  involvement by lymphoma)

               -  AST(SGOT)/ALT(SGPT) <= 3 X institutional ULN (>= 5 x ULN for patients with
                  cholestatic obstruction or involvement by lymphoma

               -  Serum creatinine <= 2.0 mg/dL

             OR

             -Creatinine clearance >=40 mL/min/1.73 m2 for patients with creatinine levels above 2
             mg/dL

             *RBC transfusions and use of G-CSF will be allowed in order to meet eligibility
             parameters.

             NOTE: In patients without bone marrow involvement, transfusions of RBCs are permitted
             to achieve the criterion hemoglobin of 8g/dl, but transfusions of platelets are not
             permitted to achieve the criterion platelet count of >75,000/mcL. In patients with
             bone marrow involvement, all transfusions are permissible at the discretion of the
             investigator.

          8. Effects of acalabrutinib on the developing human fetus are unknown. For these reasons
             the following measures apply:

               -  Women of childbearing potential must have a negative serum or urine pregnancy
                  test within 7 days prior to enrollment.

               -  Women of childbearing potential (WOCBP) who are sexually active must agree to
                  highly-effective contraception (e.g., hormonal or barrier method of birth
                  control; abstinence) prior to study entry, for the duration of study
                  participation, and for at least 2 days after the last dose of acalabrutinib or 12
                  months after the last dose of combined chemotherapy, whichever is later. Male
                  subjects must use highly effective contraception prior to study entry, for the
                  duration of study participation, and for 12 months after the last dose of
                  combined chemotherapy; there is no contraception timing requirement post-last
                  dose of acalabrutinib alone if male subject does not initiate chemotherapy on
                  study after the acalabrutinib window.

               -  Participants must not be planning to conceive or father children within the
                  projected duration of the trial, starting with the pre-screening/screening visit
                  through 2 days after the last dose of acalabrutinib or 12 months after the last
                  dose of combined chemotherapy, whichever is later.

               -  Should a woman become pregnant or suspect she is pregnant while she or her
                  partner is participating in this study, she should inform her treating physician
                  immediately.

               -  WOCBP is defined as any female who has experienced menarche and who has not
                  undergone successful surgical sterilization or who is not postmenopausal (i.e.,
                  amenorrheic for >12 months without alternative medical cause; post-menopausal
                  status in females under 55 years of age should be confirmed with a serum
                  folliclestimulating hormone [FSH] level within applicable local laboratory
                  reference range for postmenopausal women).

          9. Ability of patient or Legally Authorized Representative (LAR) to understand and the
             willingness to sign a written informed consent document.

         10. Any HIV status will be included in this study; status must be confirmed prior to
             enrollment.

        EXCLUSION CRITERIA:

          1. Patients who meet histologic criteria for the following subtypes are excluded:

               -  Primary DLBCL of the central nervous system (PCNSL)

               -  Primary mediastinal B-cell lymphoma (PMBL)

               -  Plasmablastic lymphoma

               -  Intravascular large B-cell lymphoma

               -  B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and
                  classical Hodgkin lymphoma

          2. Patients who, at the discretion of the investigator, need immediate cytoreductive
             chemotherapy such as patients with evidence of spontaneous tumor lysis or impending
             organ compromise are not eligible.

          3. Current or prior anti-cancer treatment for DLBCL prior to enrollment. Short course of
             corticosteroids (<7 days) for acute issues prior to study enrollment are permitted.

          4. Major surgical procedure within 28 days 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

          5. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole,
             lansoprazole, dexlansoprazole, rabeprazole or pantoprazole). Subjects receiving
             proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible
             for enrollment to this study

          6. Requires treatment with moderate or strong CYP3A inhibitors or inducers

          7. Presence of concomitant indolent lymphomas such as follicular lymphoma, marginal zone
             lymphomas, or chronic lymphocytic leukemia/small lymphocytic lymphoma that are best
             categorized as composite or transformed lymphomas are excluded

             NOTE: Patients with evidence of small monoclonal B-cell clones isolated to the bone
             marrow or peripheral blood that meet criteria for monoclonal B-cell lymphocytosis are
             not excluded

          8. Known lymphomatous involvement of the CNS

          9. Pregnant women, or women who intend to become pregnant during the study are excluded
             from this study because of potential teratogenic effects associated with
             acalabrutinib, R-CHOP, and/or DA-EPOCH-R

         10. The potential for all study treatments to be excreted in breast milk of nursing
             mothers is unknown. Because there is an unknown but potential risk for adverse events
             in nursing infants secondary to treatment of the mother with acalabrutinib,
             breastfeeding must be discontinued.

         11. Uncontrolled intercurrent illness including, but not limited to the following that may
             limit interpretation of results or that could increase risk to the patient at the
             discretion of the investigator:

               -  Uncontrolled active systemic infection

               -  Any condition that requires anticoagulation with warfarin or equivalent vitamin K
                  antagonist

               -  Active bleeding, history of bleeding diathesis (e.g., hemophilia or von
                  Willebrand disease)

               -  Suspected or confirmed Progressive Multifocal Leukoencephalopathy (PML)

               -  Active hepatitis C infection. NOTE: Subjects who are hepatitis C antibody
                  positive will need to have a negative HCV PCR result before enrollment. Those
                  with a positive PCR for hepatitis C are excluded.

               -  Active hepatitis B infection. NOTE: Patients who are hepatitis B surface antigen
                  (HbcsAg) or hepatitis B core antibody (HbcAb) positive (unless immunized) will
                  need to have a negative HBV PCR result before enrollment. Those with a positive
                  PCR for hepatitis B are excluded. Those with a negative PCR for hepatitis B will
                  be treated with antivirals designed to prevent hepatitis B reactivation (e.g.,
                  entecavir) and have monitoring for hepatitis B reactivation with PCR

               -  Diagnosed or treated for malignancy other than DLBCL, except:

                    1. Malignancy treated with curative surgical resection and no evidence of
                       active disease for 2 years prior to enrollment

                    2. Adequately treated non-melanoma skin cancer without evidence of disease

                    3. Adequately treated carcinoma in situ without evidence of disease

               -  History of hemorrhagic stroke or intracranial hemorrhage in preceding 6 months

               -  Clinically significant cardiovascular disease such as uncontrolled or symptomatic
                  arrhythmias, congestive heart failure, or myocardial infarction within 6 months
                  of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as
                  defined by the New York Heart Association Functional Classification. Subjects
                  with controlled atrial fibrillation/flutter during screening are eligible.

               -  Uncontrolled autoimmune hemolytic anemia

               -  Inability to swallow oral medications, or disease involve that significantly
                  limits absorption of oral medication

               -  Known mental or physical illness that would interfere with cooperation with the
                  requirements of the trial or confound the results or interpretation of the
                  results of the trial and, in the opinion of the treating investigator, would make
                  the patient inappropriate for entry into the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate
Time Frame:every 2 cycles
Safety Issue:
Description:The response rate will be determined and reported along with a 95% confidence interval.

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:every 3-6 months for 5 years then yearly
Safety Issue:
Description:The response rate will be determined and reported along with a 95% confidence interval.
Measure:Complete response rate
Time Frame:6 cycles
Safety Issue:
Description:The response rate will be determined and reported along with a 95% confidence interval.
Measure:Event-free survival
Time Frame:every 3-6 months for 5 years then yearly
Safety Issue:
Description:The response rate will be determined and reported along with a 95% confidence interval.
Measure:Safety and tolerability
Time Frame:initiation of study drug until 30 days after last dose
Safety Issue:
Description:Incidence of adverse events (i. e., grade and frequency)
Measure:Overall survival
Time Frame:every 3-6 months for 5 years then yearly
Safety Issue:
Description:The response rate will be determined and reported along with a 95% confidence interval.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • BTK Inhibitor
  • Calquence
  • ACP-196
  • Monoclonal Antibody

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