Acalabrutinib in CNSL

• ClinicalTrials.gov Identifier: NCT04906902
• Recruitment Status: Recruiting
• First Posted: May 28, 2021
• Last Update Posted: November 29, 2022
• Sponsor: Dana-Farber Cancer Institute
• Information provided by (Responsible Party): Lakshmi Nayak, MD, Dana-Farber Cancer Institute

Study Description

Brief Summary:

This research study is a Phase 1/2 clinical trial testing the safety, tolerance and efficacy of the drug Acalabrutinib for people with recurrent or refractory central nervous system lymphoma (CNSL).

Condition or disease	Intervention/treatment	Phase
Central Nervous System Lymphoma; Refractory Central Nervous System Lymphoma; Recurrent Central Nervous System Lymphoma	Drug: Acalabrutinib	Phase 1; Phase 2

Detailed Description:

This is an open-label, dose-escalation phase 1/2 study to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of Acalabrutinib in patients with recurrent or refractory CNS lymphoma (R/R CNSL).

Acalabrutinib has been studied in lab experiments and in other types of cancer, and information from these studies suggests that acalabrutinib may be beneficial for people with recurrent or refractory central nervous system lymphoma (CNSL). Acalabrutinib targets a vulnerable part of cancer cells which leads to an inhibition of the growth of cancer cells.

The U.S. Food and Drug Administration (FDA) has not approved acalabrutinib for recurrent or refractory central nervous system lymphoma (CNSL) but it has been approved for other uses.

The research study procedures include: screening for eligibility and study treatment including evaluations and follow up visits.

Participants will receive study treatment for up to 2 years as long as they do not have serious side effects and their disease does not get worse.

Approximately 15 to 21 participants will be enrolled in phase1 and approximately 28 patients will be enrolled Phase 2.

AstraZeneca, a pharmaceutical company, is supporting this research study by providing funding for the research study and the study drug, acalabrutinib.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 49 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Study of Acalabrutinib in Recurrent or Refractory Central Nervous System Lymphoma (CNSL)
• Actual Study Start Date: August 23, 2021
• Estimated Primary Completion Date: January 31, 2024
• Estimated Study Completion Date: January 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Acalabrutinib Dose Escalation; Phase 1 Dose escalation will occur using a 3+3 dose escalation approach, evaluating three separate dose levels.; Acalabrutinib 200mg 2x daily; Acalabrutinib 300mg 2x daily; Acalabrutinib 400mg 2x daily	Drug: Acalabrutinib; Capsule taken by mouth twice daily; Other Name: Calquence
Experimental: Acalabrutinib Dose Expansion; Phase 2 Participants will receive Acalabrutinib at the pre-determined dosage established in Phase 1.	Drug: Acalabrutinib; Capsule taken by mouth twice daily; Other Name: Calquence

Outcome Measures

Primary Outcome Measures :

1. Maximum-tolerated dose (MTD) [ Time Frame: Enrollment to end of treatment up to 2 years ]
   Highest dose of acalabrutinib that did not cause a dose limiting toxicity. Dose Limiting Toxicity (DLT) rates will be summarized and 95% exact binomial confidence interval (CI) will be reported.

Secondary Outcome Measures :

1. Objective response rate (ORR). [ Time Frame: Enrollment to end of treatment up to 2 years ]
   Clinical assessment and International Primary cns lymphoma Collaborative Group (IPCG) criteria (Abrey, 2005)
2. Duration of response (DOR) [ Time Frame: Every 8 weeks up to 2 years ]
   Clinical assessment and International Primary cns lymphoma Collaborative Group (IPCG) criteria (Abrey, 2005)
3. Progression-free survival (PFS) [ Time Frame: Enrollment to end of treatment up to 2 years ]
   Evaluated by the Kaplan-Meier method and medians will be provided with 95% CI
4. Overall survival (OS) [ Time Frame: Time from randomization (or registration) to death due to any cause, or censored at date last known alive. ]
   Evaluated by the Kaplan-Meier method and medians will be provided with 95% CI
5. Treatment-related toxicity [ Time Frame: Enrollment to end of treatment up to 2 years ]
   Assessed by CTCAE version 5.0.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Participants must be able to understand and willing to sign a written informed consent document.
• Participant must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care.
• Participant must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study.
• Participants must be at least 18 years old on day of signing informed consent.
• Participants must have a ECOG Performance Status 0-1 (see Appendix A).
• Life expectancy of > 3 months (in the opinion of the investigator).
• Participants with recurrent or refractory (R/R)R/R must have histologically confirmed DLBCL CNS lymphoma (from brain biopsy, CSF or vitreous biopsy, and includes PCNSL and SCNSL) for Phase I; R/R histologically confirmed DLBCL PCNSL (from brain biopsy only) for Phase II. Participants should have evidence of R/R disease on MRI or on CSF cytology. Participants must have received at least 1 line of CNS-directed prior therapy. There is no maximum limit on the number of prior therapies.
• Confirmation of availability of sufficient tissue from brain biopsy for correlative studies is required prior to enrollment (for phase II only); these samples must be sent to the DFCI Coordinating Center within 60 days of registration.

The following amount of archived tissue is required: At least 10 but up to 20 unstained formalin-fixed, paraffin-embedded (FFPE) slides. Histologically confirmed tissue will be required from the time of relapse or at the time of initial surgery.

• Participants must have recovered to ≤ grade 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy.
• Participants must be able to undergo MRI.

• Participants must demonstrate adequate as defined below (all screening labs should be performed within 14 days of registration but before 1st dose of study drug):

  • Hematology

    • White Blood Count (WBC) ≥ 2 K/µL
    • Platelet count ≥ 100 K/µL
    • Absolute Neutrophil Count ≥ 1.5 K/µL
    • Hemoglobin > 9.0 g/dL or ≥ 5.6 mmol/L (Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks)
    • Serum creatinine ≤1.5 x institutional ULN OR Measured or calculated creatinine clearance ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN (Creatinine clearance should be calculated per institutional standard)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤5 × ULN for participants with liver metastases)
    • Total bilirubin (TBILI) ≤ 1.5 x institutional ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x institutional ULN) OR Direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN)

• Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib. For male subjects with a pregnant or non-pregnant WOCBP partner, no contraception measures are required. Highly effective methods of contraception include:

  • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, which may be oral, intravaginal, or transdermal
  • Progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injectable, or implantable
  • Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
  • Bilateral tubal occlusion
  • Vasectomy of a female subject's male partner (with medical assessment and confirmation of vasectomy surgical success)
  • Sexual abstinence (only if refraining from heterosexual intercourse during the entire period of risk associated with the study treatments)

Exclusion Criteria:

• Participants unable to undergo MRI brain.
• Participants with > Grade 2 intracranial hemorrhage.
• Participants with active systemic disease.
• Participants with uncontrolled intercurrent illness.
• Participants with prior exposure to BTK inhibitors
• Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for ≥ 3 years.
• Participants who have received prior systemic anti-cancer therapy including investigational agents or radiotherapy within 4 weeks prior to dosing. OR 5 half-lives, whichever is shorter Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
• Clinically significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification or corrected QT interval (QTc) > 480 msec at screening. Note: Subjects with controlled, asymptomatic atrial fibrillation can enroll on study.
• Has difficulty with or is unable to swallow oral medication or has significant gastrointestinal disease that would limit absorption of oral medication.
• Known history of infection with HIV, prior history of PML or any active significant infection (eg, bacterial, viral, or fungal).
• Known history of hypersensitivity or anaphylaxis to acalabrutinib including active product or excipient components.
• Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand disease).
• Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura).
• Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer.
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
• Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) >2x ULN.
• Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
• History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug.
• Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
• Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative polymerase chain reaction (PCR) and must be willing to undergo DNA PCR testing during the study to be eligible. Those who are HBsAg positive or hepatitis B PCR positive will be excluded.
• Subjects who are hepatitis C antibody positive will need to have a negative PCR result to be eligible. Those who are hepatitis C PCR positive will be excluded.
• Breast feeding or pregnant
• Concurrent participation in another therapeutic trial.
• Liver cirrhosis categorized at Child Pugh Score C.
• Uncontrolled hypertension despite optimal medical management.

Contacts and Locations

Contacts

Contact: Lakshmi Nayak, MD; 617-632-2166; Lakshmi_Nayak@dfci.harvard.edu

Contact: Amanda Spearman; 617-632-9314; Amanda_Spearman@dfci.harvard.edu

Locations

United States, Massachusetts

Brigham and Women's Hospital; Recruiting

Boston, Massachusetts, United States, 02115

Contact: Lakshmi Nayak, MD 617-632-2166 Lakshmi_Nayak@dfci.harvard.edu

Principal Investigator: Lakshmi Nayak, MD

Dana Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02115

Contact: Lakshmi Nayak, MD 617-632-2166 Lakshmi_Nayak@dfci.harvard.edu

Principal Investigator: Lakshmi Nayak, MD

Sponsors and Collaborators

Dana-Farber Cancer Institute

Investigators

• Principal Investigator: Lakshmi Nayak, MD; Dana-Farber Cancer Institute

More Information

• Responsible Party: Lakshmi Nayak, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT04906902
• Other Study ID Numbers: 21-059
• First Posted: May 28, 2021
• Last Update Posted: November 29, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Lakshmi Nayak, MD, Dana-Farber Cancer Institute:

Central Nervous System Lymphoma; Refractory Central Nervous System Lymphoma; Recurrent Central Nervous System Lymphoma

Additional relevant MeSH terms:

Lymphoma; Recurrence; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Acalabrutinib; Antineoplastic Agents