A Phase 3 Study of Duvelisib Versus Ofatumumab in Patients With Relapsed or Refractory CLL/SLL (DUO)

Study Overview
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Brief Summary
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A Phase 3 clinical trial to examine the efficacy of duvelisib monotherapy versus ofatumumab monotherapy in subjects with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Detailed Description
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This is an open-label, two- arm, randomized phase 3, superiority trial designed to evaluate the efficacy and safety of duvelisib compared to ofatumumab administered to patients who have been diagnosed with CLL/SLL whose disease is relapsed or refractory. Approximately 150 subjects will receive a starting dose of 25 mg duvelisib BID initially over the course of 21-day treatment cycle followed by 28-day treatment cycles for up to 18 cycles or until disease progression or unacceptable toxicity (whichever comes first). After 18 complete cycles of treatment, subjects may receive additional cycles of duvelisib until disease progression or unacceptable toxicity if they, in the judgment of the Investigator, may derive benefit from continued treatment, and if the subject meets the criteria for additional treatment at Cycle 19 Day 1. Approximately 150 subjects will receive a starting dose of 300 mg ofatumumab on Day 1 followed by seven weekly doses of 2000 mg. Thereafter, subjects will receive 2000 mg ofatumumab once every month for four months. Administration of ofatumumab will not exceed the 12 doses (within 7 cycles).

Official Title
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A Phase 3 Study of Duvelisib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma (DUO)

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: Duvelisib
* Drug: Ofatumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of active CLL or SLL that meets at least one of the IWCLL 2008 criteria for requiring treatment (Binet Stage ≥ B and/or Rai Stage ≥ I) Disease that has progressed during or relapsed after at least one previous CLL/SLL therapy Not appropriate for treatment with a purine-based analogue regimen (per National Comprehensive Cancer Network [NCCN] or European Society for Medical Oncology [ESMO] guidelines), including relapse ≤ 36 months from a purine-based chemoimmunotherapy regimen or relapse ≤ 24 months from a purine-based monotherapy regimen A cytogenetics or fluorescence in situ hybridization (FISH) analysis of the leukemic cells within 24 months of randomization is required to document the presence or absence of del(17p). Note: if a sample from within 24 months is not available, it should be evaluated as part of the screening laboratory evaluation to inform stratification Measurable disease with a lymph node or tumor mass > 1.5 cm in at least one dimension as assessed by computed tomography (CT) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (corresponds to Karnofsky Performance Status [KPS] ≥ 60%) Willingness by subject to be randomized to receive either ofatumumab or duvelisib at the dose and schedule defined in the protocol Must meet the following laboratory parameters: Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≤ 3 x upper limit of normal (ULN) Total bilirubin ≤ 1.5 x ULN Serum creatinine ≤ 2.0 x ULN Hemoglobin ≥ 8.0 g/dL with or without transfusion support Platelet count ≥ 10,000 μL with or without transfusion support For women of childbearing potential (WCBP): negative serum β-human chorionic gonadotropin (βhCG) pregnancy test within 1 week before randomization (WCBP defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally post-menopausal for at least 24 consecutive months [women ≤ 55 years] or 12 consecutive months [women > 55 years]) Willingness of male and female subjects who are not surgically sterile or postmenopausal to use medically acceptable methods of birth control from the first dose of study drug to 30 days after the last dose of duvelisib and for 12 months after last dose of ofatumumab. Sexually active men, and women using oral contraceptive pills, should also use barrier contraception Ability to voluntarily sign consent for and adhere to the entire study visit schedule and all protocol requirements Signed and dated institutional review board (IRB)/independent ethics committee (IEC)-approved informed consent form (ICF) before any study specific screening procedures are performed Exclusion Criteria: History of Richter's transformation or prolymphocytic leukemia Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenia purpura (ITP) that is uncontrolled or requiring > 20 mg once daily (QD) of prednisone (or equivalent) to maintain hemoglobin > 8.0 g/dL or platelets > 10,000 μL without transfusion support Refractory to ofatumumab (progression or relapse <12 months of receiving ofatumumab therapy or <24 months of receiving an ofatumumab- containing regimen) Prior allogeneic transplant (prior autologous stem cell transplant >6 months prior to study entry is permitted) Known central nervous system lymphoma or leukemia; subjects with symptoms of CNS disease must have a negative CT scan or negative diagnostic lumbar puncture prior to randomization Use of any of the following medications or procedures within the specified timeframe: Use of live or live attenuated vaccines within 30 days prior to randomization Chemotherapy, radiation therapy, or ablative therapy within 3 weeks of randomization Tyrosine kinase inhibitor within 7 days of randomization Other investigational therapy (not included above) within 3 weeks of randomization Previous treatment with a PI3K inhibitor or BTK inhibitor Ongoing treatment with chronic immunosuppressants (eg, cyclosporine) or systemic steroids > 20 mg prednisone (or equivalent) QD History of tuberculosis treatment within the preceding two years Ongoing systemic bacterial, fungal, or viral infections at the time of initiation of study treatment (defined as requiring IV antimicrobial, antifungal or antiviral agents) Subjects on antimicrobial, antifungal or antiviral prophylaxis are not specifically excluded if all other inclusion/exclusion criteria are met and there is no evidence of active infection at randomization Human immunodeficiency virus (HIV) infection Prior, current, or chronic hepatitis B or hepatitis C infection History of alcohol abuse or chronic liver disease (other than metastatic disease to the liver) Unable to receive prophylactic treatment for pneumocystis or herpes simplex virus (HSV) Baseline QT interval corrected with Fridericia's method (QTcF) > 480 ms (average of triplicate readings) Note: This criterion does not apply to subjects with a right or left bundle branch block (BBB) Unstable or severe uncontrolled medical condition (eg, unstable cardiac function, unstable pulmonary condition), or any important medical illness or abnormal laboratory finding that would, in the investigator's judgment, increase the subject's risk while participating in this study Concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in situ of the cervix, bladder, or prostate not requiring treatment. Subjects with previous malignancies are eligible provided that they have been disease free for ≥2 years History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months Administration of medications or foods that are strong inhibitors or inducers of CYP3A within 2 weeks of randomization Prior surgery or gastrointestinal dysfunction that may affect drug absorption (eg, gastric bypass surgery, gastrectomy) Major surgery or invasive intervention within 4 weeks prior to randomization Pregnant or breastfeeding women Hypersensitivity to ofatumumab or its excipients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Duvelisib<br>Duvelisib is administered orally and supplied as 5 mg and 25 mg formulated capsules. | Drug: Duvelisib<br>* PI3K Inhibitor<br>* Other names: Copiktra, IPI-145, PI3K Inhibitor;|
| Active Comparator: Ofatumumab<br>Ofatumumab is administered as an intravenous (IV) infusion and is supplied in single-use vials at two strengths, 100 mg/5 mL and 1000 mg/50 mL. | Drug: Ofatumumab<br>* monoclonal antibody<br>* Other names: Arzerra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | The primary efficacy endpoint for the study was PFS, defined as time from randomization to the first documentation of PD as determined by blinded independent review or death due to any cause. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is a key secondary efficacy endpoint with overall response defined as best response of CR, CRi, PR, or PRwL, according to the modified IWCLL/IWG Response Criteria, with modification for treatment-related lymphocytosis as defined in the protocol. | Until disease progression or unacceptable toxicity assessed up to 6 years | 
| Number of Subjects With Hematologic Improvements | Subjects with hematologic improvement included those subjects with abnormally high values for neutrophil count, hemoglobin, or platelet count at Baseline determined to have consistently met the criteria of an improvement for those parameters for a period of at least 60 days during which the subject did not have a transfusion or exogenous cytokines. | 3 years | 
| Overall Survival | A stratified Cox regression analysis was used to test for any treatment effect. | Every 6 months for up to 3 years after first dose | 
| Lymph Node Response Rate | Lymph node response defined as greater than or equal to 50% decrease in the SPD of target lymph nodes | 3 years | 
| Duration of Response (DOR) | Duration of response is defined only for subjects demonstrating a response (eg, CR, CRi, PR, PRwL), with the response and progression statuses both determined by the blinded, central independent review. The analysis will be descriptive for each treatment group only. | Time from the first documentation of response to first documentation of progressive disease or death due to any cause | 
| Treatment-Emergent Adverse Events (TEAEs) and Changes in Safety Laboratory Values | An analysis of TEAEs with an onset within the first 24 weeks of treatment was performed to examine and compare the incidence of events across an equal period for each treatment arm.Twenty-four weeks was anticipated to be the median exposure to ofatumumab. | From 04 Feb 2014 till 19 June 2018 | 
| Number of Subjects With Samples Available for Duvelisib Pharmacokinetics (PK) | Number of subjects with samples available for duvelisib Pharmacokinetics (PK) | Cycle 2, Cycle 3, and Cycle 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 3, CLL/SLL, Pi3K