Acalabrutinib and Durvalumab for the Treatment of Primary or Secondary Central Nervous System Lymphoma
- 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. Examples of medical conditions for which a patient could be considered ineligible for high dose methotrexate include renal impairment, liver disease, heart failure or having ascites or effusions * Patients with leptomeningeal disease only must have been previously treated with intrathecal therapy ** 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
- Eastern Cooperative Oncology Group (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
- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
- Platelets >= 75 x 10^9/L and no platelet transfusion within the past 7 days prior to initiation of protocol treatment
- 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
- Body weight > 30 kg
- Participants must have a documented negative antibody to human immunodeficiency virus (HIV)
- 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 Institutional Review Board (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 informed consent form (ICF) and authorization to use protected health information (PHI) due to neurologic deficits (e.g. motor or language deficits)
- 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. Patients must taper off high dose corticosteroids for the control of CNS symptoms within 14 days after starting on study therapy
- History of intracranial hemorrhage or clinically significant stroke within 6 months prior to first day of study treatment
- 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 Bruton's tyrosine kinase (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) are 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 * Study therapy may be started after 5-half-lives or 7 days (whichever is shorter) have surpassed since last administration of a strong or moderate CYP3A4 inducer/inhibitors
- 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 any time prior to initiating study therapy 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., computed tomography [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 investigational product (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 polymerase chain reaction (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)
I. To determine safety and tolerability of the combination of durvalumab with acalabrutinib in patients with central nervous system (CNS) lymphoma.
I. To evaluate the preliminary efficacy of the combination.
I. To evaluate the pharmacokinetics of acalabrutinib in the cerebrospinal fluid (CSF).
II. To evaluate the characteristics of positron emission tomography (PET) magnetic resonance imaging (MRI) in patients with CNS lymphoma being treated with checkpoint inhibitors.
OUTLINE: This is a dose-escalation study of acalabrutinib.
Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28 and durvalumab intravenously (IV) over 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for up to 2 years and then every 6 months thereafter.
Trial Phase Phase I
Trial Type Treatment
Siteman Cancer Center at Washington University
- Primary ID 202009139
- Secondary IDs NCI-2020-08166
- Clinicaltrials.gov ID NCT04462328