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.
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. Prior autologous stem cell transplant is
permitted
- 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)
- Unless related to bone marrow involvement with the disease, in which case
platelets must be > 50,000/mm^3
- 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
- NOTE: Subjects on antimicrobial, antifungal, or antiviral prophylaxis are not
specifically excluded if all other inclusion/exclusion criteria are met
- 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
- Subjects with a positive hepatitis B surface antigen (HBsAg)
- Subjects with a positive hepatitis B core antibody (HBcAb) must have negative
hepatitis B virus (HBV) deoxyribonucleic acid (DNA) to be eligible and must be
periodically monitored for HBV reactivation by institutional guidelines
- Subject who are hepatitis C antibody (HepcAb) positive 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
- Investigators who strongly believe that a positive HBcAb is false (negative
hepatitis C [hep C] PCR) due to passive immunization from previous immunoglobulin
infusion therapy should consider the risk-benefit for the patient given the
potential for reactivation
