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About
This phase Ib/II trial studies the side effects of acalabrutinib and duvelisib and how well they work in treating patients with indolent non-Hodgkin lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Acalabrutinib inhibits a signaling molecule called Bruton tyrosine kinase and blocks cancer cell proliferation, growth, and survival. Duvelisib is designed to block a protein called PI3 kinase in order to stop cancer growth and cause changes in the immune system that may allow the immune system to better act against cancer cells. Giving acalabrutinib and duvelisib together may work better to block cancer growth than therapy of either drug alone.
Full description
PRIMARY OBJECTIVES:
I. To assess the safety and tolerability of the combination of acalabrutinib and duvelisib in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL).
II. Determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). III. To estimate the overall response rate (ORR, Lugano 2014, computed tomography [CT] based) of acalabrutinib in combination with duvelisib at 6 months in follicular lymphoma (FL) and marginal zone lymphoma (MZL) cohorts.
SECONDARY OBJECTIVES:
I. To evaluate the activity of acalabrutinib and duvelisib as measured by ORR based on positron emission tomography (PET) scan at 6 months, duration of response (DOR) and 2-year progression-free survival (PFS).
II. To capture patient-reported outcomes (PROs).
EXPLORATORY OBJECTIVE:
I. To determine the correlation of the clinical activity of acalabrutinib in combination with duvelisib with established biomarkers and identify putative novel markers.
OUTLINE: This is a phase Ib, dose-escalation study of duvelisib, followed by a phase II study.
Patients receive acalabrutinib orally (PO) twice daily (BID), and duvelisib PO BID on days 1-28. Treatment repeats every 28 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 19, patients receive acalabrutinib PO BID for up to 60 months in absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, and then every 3 months thereafter.
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Inclusion criteria
>= 18 years of age
Histologically confirmed iNHL of any of the following subtypes recognized by the World Health Organization (WHO) classification: follicular lymphoma and marginal zone lymphoma (splenic, nodal and extranodal)
Patients must meet clinical criteria for requiring treatment
At least two prior systemic therapies for FL (phase 2 portion) and one prior systemic therapy for MZL. Prior autologous stem cell transplant is permitted. Prior CAR-T cell therapy is permitted. For the phase 1 portion, patients receiving one prior systemic therapy are allowed.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Creatinine clearance >= 50 ml/min using a 24-hour creatinine clearance or estimated creatinine clearance using the Cockcroft-Gault equation
Bilirubin < 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 1.5 x ULN
Absolute neutrophil count (ANC) > 1000/mm^3 (without growth factor support)
Platelet > 75,000/mm^3 (without transfusion support)
Hemoglobin >= 8 gm/dL
Willing and able to participate in all required evaluations and procedures in this study protocol
Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information
Radiographically measurable disease by computed tomography (CT) scan, defined as at least one node > 1.5 cm in size or assessable disease
Woman of childbearing potential (WOCBP) who are sexually active must agree to use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib, and 30 days after the last dose of duvelisib. WOCBP should have negative pregnancy test at screening and follow up throughout the study. Male subjects must agree to use highly effective methods of contraception during the study and up to 1 month after last dose of duvelisib. Male fertility may be impaired based on animal data (per duvelisib label)
Exclusion criteria
Prior exposure to a BCR inhibitor (e.g., BTK inhibitors, phosphoinositide-3 kinase [PI3K], or Syk inhibitors) or BCL-2 inhibitor
Patients with grade 3B FL or clinical evidence of transformation to aggressive lymphoma
Central nervous system (CNS) involvement
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 which will not limit survival to < 1 year
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. Note: Subjects with controlled, asymptomatic atrial fibrillation can enroll in study
Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease)
Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura)
Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists
Prothrombin time (PT)/international normalized ratio (INR) or activated partial thromboplastin time (aPTT) (in the absence of lupus anticoagulant) > 2 x ULN
Requires treatment with proton pump inhibitors (e.g., 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 the 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
Pregnancy or lactation, or intending to become pregnant during the study
Concurrent participation in another therapeutic clinical trial
Known history of infection with human immunodeficiency virus (HIV)
History of progressive multifocal leukoencephalopathy
Grade >= 2 toxicity (other than alopecia) continuing from prior anticancer therapy
Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components
History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function
Prior history of drug-induced colitis or drug-induced pneumonitis
History of chronic liver disease or veno-occlusive disease
Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or systemic steroids > 20 mg of prednisone (or equivalent) once daily (QD)
Uncontrolled viral, bacterial, fungal or parasitic infection that is untreated or unresponsive to antimicrobial therapy
Concurrent administration of medications or foods that are strong or moderate inhibitors or strong inducers of cytochrome P450 3A (CYP3A). No prior use within 2 weeks before the start of study intervention
Patients with prior allogeneic transplantation
Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), or herpes zoster (VZV) at screening
History of tuberculosis treatment within the 2 years prior to study entry
Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy). Subjects with clinically significant medical condition of malabsorption, inflammatory bowel disease, chronic conditions which manifest with diarrhea, refractory nausea, vomiting or any other condition that will interfere significantly with drug absorption
Active cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection (i.e., subjects with detectable viral load)
Administration of a live or live attenuated vaccine within 6 weeks of study entry
Infection with hepatitis B, hepatitis C
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Data sourced from clinicaltrials.gov
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