Acalabrutinib and Durvalumab in Primary and Secondary Central Nervous System Lymphoma

Study 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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion 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).

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT04462328
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Washington University School of Medicine
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Neha Mehta-Shah, M.D.
Principal Investigator Affiliation Washington University School of Medicine
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

OtherIndustry
Overall Status Not yet recruiting
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Primary Central Nervous System Lymphoma, Secondary Central Nervous System Lymphoma
Study Website: View Trial Website
Arms & Interventions

Arms

Experimental: Phase I Dose Level 1: Durvalumab + Acalabruitinib

Acalabrutinib 100 mg twice per day by mouth on days 1-28 Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle

Experimental: Phase I Dose Level 2: Durvalumab + Acalabruitinib

Acalabrutinib 200 mg twice per day by mouth on days 1-28 Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle

Experimental: Expansion Cohort: Durvalumab + Acalabrutinib

Acalabrutinib 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

Interventions

Drug: - Durvalumab

Durvalumab will be administered over 60 minutes

Drug: - Acalabrutinib

Patients will take acalabrutinib orally every 12 hours (+/- 3 hours) daily.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Washington University School of Medicine, Saint Louis, Missouri

Status

Address

Washington University School of Medicine

Saint Louis, Missouri, 63110

Site Contact

Neha Mehta-shah, M.D.

mehta-n@wustl.edu

314-747-7510

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