Clinical Trials /

Acalabrutinib and Durvalumab in Primary and Secondary Central Nervous System Lymphoma

NCT04462328

Description:

BTK inhibition and checkpoint blockade are promising classes of therapy for central nervous system (CNS) lymphoma and have demonstrated efficacy with acceptable toxicity. A multidrug approach may carry a higher chance of durable efficacy in this aggressive disease that carries significant morbidity and mortality. Given the poor outcomes and limited options for patients who are not candidates for high-dose methotrexate, the investigators seek to evaluate the combination in this patient population.

Related Conditions:
  • Primary Central Nervous System Lymphoma
  • Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Acalabrutinib and Durvalumab in Primary and Secondary Central Nervous System Lymphoma
  • Official Title: Phase I Study With Dose Expansion of Acalabrutinib and Durvalumab (MEDI 4736) in Primary and Secondary Central Nervous System Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 20-x250
  • NCT ID: NCT04462328

Conditions

  • Primary Central Nervous System Lymphoma
  • Secondary Central Nervous System Lymphoma

Interventions

DrugSynonymsArms
DurvalumabImfinziExpansion Cohort: Durvalumab + Acalabrutinib
AcalabrutinibCalquenceExpansion Cohort: Durvalumab + Acalabrutinib

Purpose

BTK inhibition and checkpoint blockade are promising classes of therapy for central nervous system (CNS) lymphoma and have demonstrated efficacy with acceptable toxicity. A multidrug approach may carry a higher chance of durable efficacy in this aggressive disease that carries significant morbidity and mortality. Given the poor outcomes and limited options for patients who are not candidates for high-dose methotrexate, the investigators seek to evaluate the combination in this patient population.

Trial Arms

NameTypeDescriptionInterventions
Phase I Dose Level 1: Durvalumab + AcalabruitinibExperimentalAcalabrutinib 100 mg twice per day by mouth on days 1-28 Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle
  • Durvalumab
  • Acalabrutinib
Phase I Dose Level 2: Durvalumab + AcalabruitinibExperimentalAcalabrutinib 200 mg twice per day by mouth on days 1-28 Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle
  • Durvalumab
  • Acalabrutinib
Expansion Cohort: Durvalumab + AcalabrutinibExperimentalAcalabrutinib 100 mg or 200 mg (depends on tolerable dose found in Phase I portion of study) twice per day by mouth on days 1-28 Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle
  • Durvalumab
  • Acalabrutinib

Eligibility Criteria

        Inclusion Criteria:

        -Histologically documented primary CNS lymphoma or secondary diffuse large B-cell lymphoma
        (DLBCL) isolated to the CNS with either:

          -  Relapsed or refractory disease with at least 1 prior therapy OR

          -  Ineligible for high dose methotrexate based therapy as determined by the treating
             physician, including previously untreated patients.

        Note: For patients with history of histologically documented systemic DLBCL with CNS
        relapse, biopsy of the CNS lesion is recommended but not required.

          -  Patients must have evaluable disease. This includes radiographic evidence of
             parenchymal disease or leptomeningeal enhancement or thickening, or disease detected
             in the CSF.

             *Patients with vitreous involvement alone are not eligible.

          -  ECOG performance status of 0, 1, or 2. Patients with ECOG performance status of 3 are
             permitted if their performance status limitations are due to lymphoma in the opinion
             of the treating physician.

          -  Participants must have adequate bone marrow and organ function shown by:

               -  Absolute neutrophil count (ANC) ≥ 1.0 x 109/L

               -  Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 7 days prior
                  to study registration

               -  Prothrombin time (PT), partial thromboplastin time (PTT), and international
                  normalized ratio (INR) < 2 times the upper limit of normal

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times
                  the upper limit of normal

               -  Serum bilirubin ≤ 1.5 times the upper limit of normal

               -  Creatinine clearance > 30 mL/min calculated by the Cockcroft-Gault formula using
                  actual body weight

          -  Age ≥ 18 years of age

          -  Body weight >30 kg

          -  Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             female pre-menopausal patients. Women will be considered post-menopausal if they have
             been amenorrheic for 12 months without an alternative medical cause. The following
             age-specific requirements apply:

               -  Women <50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).

               -  Women ≥50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses >1 year ago, had
                  chemotherapy-induced menopause with last menses >1 year ago, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy).

          -  Female subjects of childbearing potential must have a negative pregnancy test no more
             than 3 days prior to the start of study treatment.

          -  Able to understand and willing to sign an IRB approved written informed consent
             document. A legally authorized representative can consent on behalf of a patient who
             is able to understand the purpose and risk of the study but not able to provide a
             signature on the ICF and authorization to use PHI due to neurologic deficits (e.g.
             motor or language deficits)

        Exclusion Criteria:

          -  Concurrent use of other approved or investigational antineoplastic agents (with the
             exception of corticosteroids)

          -  Participation in another clinical study with an investigational product during the 4
             weeks prior to the first day of study treatment.

          -  Prior chemotherapy or targeted small molecule therapy (or other therapy for CNS
             lymphoma) within 3 weeks prior to the first day of study treatment (or 5 half-lives
             (whichever is shorter)), or 2 weeks prior to the first day of study treatment for
             monoclonal antibodies

             *The patient must have recovered to baseline or ≤ grade 1 from prior toxicities of
             therapy with the exception of alopecia. Recovery to ≤ grade 2 neuropathy is permitted

          -  External beam radiation therapy to the CNS within 14 days of the first day of study
             treatment.

          -  Patient requires more than 8 mg of dexamethasone daily or the equivalent for control
             of CNS symptoms at the time of initiation of study therapy.

          -  History of intracranial hemorrhage or clinically significant stroke within 6 months
             prior to enrollment

          -  Inability to swallow oral medications.

          -  History of significant gastrointestinal disease that would limit absorption of oral
             medications.

          -  Active concurrent malignancy requiring active therapy.

          -  Prior therapy with a checkpoint inhibitor, including durvalumab.

          -  Prior therapy with BTK inhibitor.

          -  Warfarin or any other Coumadin-derivative anticoagulant or vitamin K antagonists.
             Patients must be off warfarin-derivative anticoagulants for at least seven days prior
             to starting the study drug. Use of low molecular weight heparin and novel oral
             anticoagulants (eg. rivaroxaban, apixaban) is permitted if required.

          -  Concurrent use of a moderate or strong inhibitor or inducer of the P450 isoenzyme
             CYP3A. Participants must be off P450/CYP3A inhibitors and inducers prior to starting
             the study drug.

          -  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.

          -  Use of systemic immunosuppressant therapy, including cyclosporine A, tacrolimus,
             sirolimus, and other such medications, or chronic administration of > 10 mg/day of
             prednisone or the equivalent. This does not refer to patients on corticosteroids for
             CNS lymphoma symptoms. Participants must be off of immunosuppressant therapy (with the
             exception of steroids) for at least 14 days prior to the first day of study treatment.
             The items listed below are exceptions to this criterion:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent

               -  Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

          -  Receipt of live attenuated vaccine within 30 days prior to the first day of study
             treatment. Note: Patients, if enrolled, should not receive live vaccine while
             receiving IP and up to 30 days after the last day of study treatment.

          -  Suspicion of or confirmed progressive multifocal leukoencephalopathy

          -  Active autoimmune disease (including autoimmune hemolytic anemia and immune
             thrombocytopenia purpura) requiring systemic treatment within the past two years (i.e.
             with the use of disease modifying agents, corticosteroids, or immunosuppressive
             drugs). The following are exceptions to this criterion:

               -  Patients with vitiligo or alopecia

               -  Patients with hypothyroidism (e.g., due to Hashimoto syndrome) stable on hormone
                  replacement

               -  Any chronic skin condition that does not require systemic therapy

               -  Patients without active disease in the last 5 years may be included but only
                  after consultation with the study physician

               -  Patients with celiac disease controlled by diet alone

               -  Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroids
                  replacement therapy for adrenal or pituitary insufficiency, etc.)

          -  Significant medical diseases or conditions, as assessed by the investigator, that
             would substantially increase the risk to benefit ratio of participating in the study.
             This includes, but is not limited to, acute myocardial infarction in the past 6
             months, unstable angina, uncontrolled diabetes mellitus, significant active
             infections,, severely immunocompromised state, and congestive heart failure, New York
             Heart Association Class III-IV.

          -  Known bleeding diathesis (e.g. von Willebrand's disease), hemophilia, or active
             bleeding.

          -  Known Human immunodeficiency virus (HIV) infection.

          -  Known active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as
             determined by serologic tests and/or PCR.

          -  History of invasive fungal infection, including invasive aspergillosis, or known
             active tuberculosis.

          -  Major surgery ≤ 28 days prior to starting the trial treatment (or has not recovered
             from the side effects of such surgery) or plans to have surgery within 2 weeks of the
             first dose of the study drug.

          -  Prior allogenic stem cell transplant (autologous stem cell transplant is NOT an
             exclusion).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safe and tolerable dose of regimen
Time Frame:Completion of first 12 weeks of treatment within phase I portion of study (estimated to be 14 months)
Safety Issue:
Description:Defined as Dose Level 2 if 0 or 1 dose limiting toxicities (DLTs) are seen in patients at that dose level, or Dose Level 1 if 2+ DLTs are seen in Dose Level 2 but only 0 or 1 DLTs are seen in patients at Dose Level 1. A DLT is defined as the occurrence of an adverse event (AE) that is at least possibly related to the investigational product (IP) or investigational regimen (IR)

Secondary Outcome Measures

Measure:Overall response rate (complete response (CR) + partial response (PR))
Time Frame:Through completion of treatment (estimated to be 6 months)
Safety Issue:
Description:CR is defined as disappearance of all contrast-enhancing CNS (brain and spine if latter abnormal at baseline) disease, absence of any systemic corticosteroids prescribed to treat lymphoma (prophylactic steroid eye drops, topical steroids, corticosteroid antiemetics and steroids prescribed for non-disease reasons [e.g. asthma exacerbation, dermatologic or rheumatologic conditions] are allowed and not considered in the definition of CR), resolution of abnormal ocular findings on ophthalmological examination, negative CSF cytology/flow cytometry. PR is defined as >50% reduction in contrast-enhancing CNS (brain and spine if latter abnormal at baseline) disease either with minor abnormalities on ophthalmological examination or normal ophthalmological examination OR disappearance of all contrast-enhancing CNS (brain and spine if latter abnormal at baseline) but only reduction of vitreous cells or retinal infiltrates or residual suspicious or positive CSF cytology.
Measure:Duration of response
Time Frame:Through 2 years post treatment (estimated to be 2 years and 6 months)
Safety Issue:
Description:-The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Measure:Time to response
Time Frame:Through completion of treatment (estimated to be 6 months)
Safety Issue:
Description:-Time to response is measured from the start of treatment until the time measurement criteria are met for first objective tumor response (CR or PR, whichever is first recorded).
Measure:Progression-free survival (PFS)
Time Frame:Through 2 years post treatment (estimated to be 2 years and 6 months)
Safety Issue:
Description:PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive disease is defined as > 25% increase in contrast-enhancing CNS (brain and spine if latter abnormal at baseline) disease, appearance of any new, measurable (>/= 10mm) contrast-enhancing disease or recurrent or new ocular or CSF disease. Progression free survival will include all patients with at least one response assessment. Patients will be censored for progression free survival and duration of response if alive and without disease progression at completion of follow-up period.
Measure:Overall survival (OS)
Time Frame:Through 2 years post treatment (estimated to be 2 years and 6 months)
Safety Issue:
Description:OS is defined as the duration of time from start of treatment to time of death. All patients who receive treatment on study will be included in overall survival. Patients will be censored for overall survival is alive at last study data collection point (completion of follow-up).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

July 2, 2020