Acalabrutinib + Durvalumab for Central Nervous System Lymphoma

Recruiting at 1 trial location

Overseen By Neha Mehta-shah, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Washington University School of Medicine

Must not be taking: Warfarin, CYP3A inhibitors

Disqualifiers: Secondary CNS lymphoma, Active malignancy, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 4

Duration: 12 weeks

25 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting the study. You must stop using warfarin or similar anticoagulants at least seven days before, and you cannot use moderate or strong inhibitors or inducers of the enzyme CYP3A. Additionally, you must stop any systemic immunosuppressant therapy (except steroids for CNS symptoms) at least 14 days before starting the study.

What data supports the effectiveness of the drug Durvalumab in treating central nervous system lymphoma?

Durvalumab has shown effectiveness in treating advanced non-small-cell lung cancer, particularly in patients with high PD-L1 expression, and has been used successfully in combination with chemotherapy for small-cell lung cancer, suggesting potential benefits in other cancer types. ^{1 2 3 4 5}

Is the combination of Acalabrutinib and Durvalumab safe for humans?

Durvalumab has been studied in various cancers and generally shows acceptable safety, though it can cause immune-related side effects like autoimmune encephalitis (inflammation of the brain). Safety data for Acalabrutinib in combination with Durvalumab specifically for central nervous system lymphoma is not available, but Durvalumab alone has been used safely in other conditions. ^{2 3 6 7 8}

How is the drug Acalabrutinib + Durvalumab unique for treating central nervous system lymphoma?

Acalabrutinib + Durvalumab is unique because it combines a targeted therapy (Acalabrutinib) with an immune checkpoint inhibitor (Durvalumab), which may offer a novel approach by both directly targeting cancer cells and enhancing the immune system's ability to fight the cancer. This combination is being explored for central nervous system lymphoma, a condition with limited standard treatment options. ^{1 2 4 6 8}

What is the purpose of this trial?

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.

Research Team

Neha Mehta-shah, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for adults over 18 with primary CNS lymphoma that's relapsed or resistant to treatment, or those who can't have high-dose methotrexate therapy. Participants need a certain level of white blood cells and organ function, no HIV, and must not be pregnant. They should be able to perform daily activities with little to no assistance (ECOG status 0-2). People with secondary CNS lymphoma or recent other treatments are excluded.

Inclusion Criteria

I can care for myself, but my daily activities might be limited.

I weigh more than 30 kilograms.

My condition has returned or didn't respond to treatment, or I can't have high dose methotrexate due to other health issues.

Exclusion Criteria

I am currently receiving treatment for another cancer.

I need more than 8 mg of dexamethasone daily for my CNS symptoms.

I am suspected of or confirmed to have PML.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Acalabrutinib and Durvalumab in 28-day cycles to determine tolerability and efficacy

12 weeks

4 visits (in-person) per cycle

Expansion Cohort

Participants receive the determined tolerable dose of Acalabrutinib and Durvalumab

6 months

Monthly visits (in-person)

Follow-up

Participants are monitored for progression-free survival and overall survival

2 years

Treatment Details

Interventions

• Acalabrutinib
• Durvalumab

Trial Overview The study tests Acalabrutinib combined with Durvalumab in patients with primary central nervous system lymphoma. It aims to see if this drug combo is effective when standard therapies fail or aren't suitable. The trial was adjusted after finding the combination less effective in secondary CNS lymphoma cases.

Participant Groups

Group I: Phase I Dose Level 2: Durvalumab + Acalabruitinib Experimental Treatment 2 Interventions

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

Group II: Phase I Dose Level 1: Durvalumab + Acalabruitinib Experimental Treatment 2 Interventions

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

Group III: Expansion Cohort: Durvalumab + Acalabrutinib Experimental Treatment 2 Interventions

* 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

Acalabrutinib is already approved in United States, European Union for the following indications:

Approved in United States as Calquence for:

• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma

Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

Durvalumab, a PD-L1 blocking antibody, has shown clinical efficacy and a manageable safety profile in treating advanced non-small-cell lung cancer, especially in patients with ≥25% PD-L1 expression.

The drug is being evaluated in various treatment settings, including as a monotherapy and in combination with other therapies, showing promising results particularly after chemoradiation, although lower response rates were noted in patients with EGFR and ALK mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. Mezquita, L., Planchard, D.[2018]

In the phase II ATLANTIC study, durvalumab demonstrated encouraging overall survival (OS) rates in heavily pretreated patients with advanced non-small cell lung cancer (NSCLC), with median OS ranging from 9.3 to 13.3 months depending on tumor characteristics.

The safety profile of durvalumab remained consistent with previous reports, showing no new safety concerns, indicating it is a tolerable treatment option for patients with advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final overall survival and safety update for durvalumab in third- or later-line advanced NSCLC: The phase II ATLANTIC study. Garassino, MC., Cho, BC., Kim, JH., et al.[2021]

A 72-year-old male with small-cell lung cancer developed autoimmune limbic encephalitis and diabetes while being treated with Durvalumab, highlighting the potential for serious autoimmune reactions associated with immune checkpoint inhibitors.

The case demonstrated a timeline of autoantibody development, with GABABR1 antibodies appearing early and GAD65 antibodies later, emphasizing the need for monitoring patients for neurological symptoms during ICI treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Report: Limbic encephalitis following treatment with durvalumab for small-cell lung cancer. Moss, TT., Stavem, K., Aandahl, A., et al.[2023]

In a study of 121 patients with stage III non-small cell lung cancer treated with durvalumab, those with over 50% PD-L1 expression had significantly better outcomes, with a 1-year survival rate of 97% compared to 73% and 78% for lower expression groups.

Higher PD-L1 expression (>50%) was strongly associated with improved progression-free survival and overall survival, indicating that PD-L1 levels could be a key factor in predicting the effectiveness of durvalumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor PD-L1 expression is associated with outcomes in stage III non-small cell lung cancer (NSCLC) patients treated with consolidation durvalumab. Jazieh, K., Gad, M., Saad, A., et al.[2022]

Durvalumab, an immune checkpoint inhibitor, combined with chemotherapy, was effective in treating a 62-year-old female patient with extensive-stage small-cell lung cancer (ES-SCLC) and preexisting Lambert-Eaton myasthenic syndrome (LEMS), achieving nearly complete response without worsening her LEMS symptoms.

The treatment led to a significant decrease in the titer of anti-P/Q-type voltage-gated calcium channel antibodies, suggesting that ICI therapy may not only be safe but could also improve symptoms of preexisting paraneoplastic syndromes like LEMS in patients with ES-SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab for Extensive-Stage of Small-Cell Lung Cancer With Lambert-Eaton Myasthenic Syndrome. Machiyama, H., Minami, S.[2023]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

Durvalumab has been approved for use in patients with locally advanced PD-L1-positive non-small cell lung cancer (NSCLC) after chemoradiotherapy, based on its efficacy demonstrated in the PACIFIC trial and subsequent analysis of 211 patients in the Expanded Access Program (EAP).

In the EAP, 126 patients who received durvalumab were included, some of whom had oligometastatic disease and a history of autoimmune conditions, indicating that durvalumab may be effective and safe for a broader patient population than previously studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP. Faehling, M., Schumann, C., Christopoulos, P., et al.[2020]

Durvalumab, an immunotherapy drug for non-small cell lung cancer (NSCLC), has shown significant activity and acceptable tolerability, especially in patients with at least 25% PD-L1 tumor expression, and has been established as a standard treatment following chemoradiation based on the PACIFIC study results.

While durvalumab is effective in wild-type EGFR and ALK patients, its efficacy is lower in those with EGFR mutations or ALK-positive status, highlighting the need for ongoing research into combination therapies and the management of treatment-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. Mezquita, L., Planchard, D.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. [2018]

2. Ireland pubmed.ncbi.nlm.nih.gov

Final overall survival and safety update for durvalumab in third- or later-line advanced NSCLC: The phase II ATLANTIC study. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Case Report: Limbic encephalitis following treatment with durvalumab for small-cell lung cancer. [2023]

4. China pubmed.ncbi.nlm.nih.gov

Tumor PD-L1 expression is associated with outcomes in stage III non-small cell lung cancer (NSCLC) patients treated with consolidation durvalumab. [2022]

5. Canada pubmed.ncbi.nlm.nih.gov

Durvalumab for Extensive-Stage of Small-Cell Lung Cancer With Lambert-Eaton Myasthenic Syndrome. [2023]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. [2019]