Acalabrutinib and Durvalumab in Primary and Secondary Central Nervous System Lymphoma

NCT04462328 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 202009139
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 2

Brief Summary

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. 08/30/2022: The study was originally designed for those with primary and secondary central nervous system (CNS) lymphoma. However, the first three patients who were enrolled all had secondary CNS lymphoma and most had germinal center phenotype disease with double hit phenotypes. In these three patients, two dose limiting toxicities were seen including 1 patient with grade 4 neutropenia at the time of disease progression and one with pneumonia in the setting of disease progression and worsening of existing heart disease. The third patient came off for clinical progression within cycle 1. Given the lack of response in patients with secondary CNS lymphomas, who do not exhibit the same biology as primary CNS lymphoma patients, Amendment 3 updates the study to only include patients with primary CNS lymphomas.

Conditions

Primary Central Nervous System Lymphoma

Outcome Measures

Primary Outcomes (2)

• Tolerability as defined as tolerable dose

  * 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)

  Completion of first 12 weeks of treatment within phase I portion of study (estimated to be 14 months)

• Safety as defined by frequency of toxicities assessed by CTCAE v 5.0

  From start of treatment through 90 days after treatment (estimated to be 9 months)

Secondary Outcomes (5)

• Overall response rate (complete response (CR) + partial response (PR))

  Through completion of treatment (estimated to be 6 months)

• Duration of response

  Through 2 years post treatment (estimated to be 2 years and 6 months)

• Time to response

  Through completion of treatment (estimated to be 6 months)

• Progression-free survival (PFS)

  Through 2 years post treatment (estimated to be 2 years and 6 months)

• Overall survival (OS)

  Through 2 years post treatment (estimated to be 2 years and 6 months)

Study Arms (3)

Phase I Dose Level 1: Durvalumab + Acalabruitinib

EXPERIMENTAL

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

Drug: Durvalumab; Drug: Acalabrutinib

Phase I Dose Level 2: Durvalumab + Acalabruitinib

EXPERIMENTAL

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

Drug: Durvalumab; Drug: Acalabrutinib

Expansion Cohort: Durvalumab + Acalabrutinib

EXPERIMENTAL

* 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

Drug: Durvalumab; Drug: Acalabrutinib

Interventions

Durvalumab DRUG

Durvalumab will be administered over 60 minutes

Also known as: Imfinzi

Expansion Cohort: Durvalumab + Acalabrutinib; Phase I Dose Level 1: Durvalumab + Acalabruitinib; Phase I Dose Level 2: Durvalumab + Acalabruitinib

Acalabrutinib DRUG

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

Also known as: Calquence

Expansion Cohort: Durvalumab + Acalabrutinib; Phase I Dose Level 1: Durvalumab + Acalabruitinib; Phase I Dose Level 2: Durvalumab + Acalabruitinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically documented primary CNS lymphoma 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 that for which a patient could be considered ineligible for high dose methotrexate include renal impairment, liver disease, heart failure or having ascites or effusions.
• Note: Patients with leptomeningeal disease only must have been previously treated with intrathecal therapy Note: Patients with secondary CNS lymphoma are excluded even if the disease is isolated to the CNS.
• Presence of evaluable disease. This includes radiographic evidence of parenchymal disease or leptomeningeal enhancement or thickening, or disease detected in the CSF.
• Note: 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.
• 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 initiation of protocol treatment
• Prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) \< 2 times the upper limit of normal (unless attributed to lupus anticoagulant or attributed to anticoagulant such as a direct oral anticoagulant)
• 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

You may not qualify if:

• Diagnosis of secondary CNS lymphoma (even if disease is isolated to CNS).
• Vitreous involvement alone.
• 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
• Recovered to baseline or ≤ grade 1 from prior toxicities of therapy with the exception of alopecia (no recovery required) and neuropathy (recovery to ≤ grade 2 is permitted).
• External beam radiation therapy to the CNS within 14 days of the first day of study treatment.
• 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. This could include refractory nausea, vomiting, chronic gastrointestinal disease, bariatric surgery such as gastric bypass, partial or complete bowel obstruction, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of study treatment.
• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• AstraZeneca: collaborator

Study Sites (2)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

The Ohio State University Hospital

Columbus, Ohio, 43210, United States

Location

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Interventions

durvalumab; acalabrutinib

Study Officials

• Neha Mehta-Shah, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 2, 2020
• First Posted: July 8, 2020
• Study Start: April 29, 2021
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): May 31, 2028
• Last Updated: March 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)