A Phase 3 Extension Study of Duvelisib and Ofatumumab in Participants With CLL/SLL Previously Enrolled in Study IPI-145-07

Study Overview
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Brief Summary
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A Phase 3 (extension) clinical trial to examine the efficacy of IPI-145 (duvelisib) monotherapy or ofatumumab monotherapy in participants with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who experienced disease progression after treatment with IPI-145 or ofatumumab in study IPI-145-07 (NCT02004522).

Detailed Description
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The study was designed as an open-label, two-arm extension evaluation to enable participants who experienced radiologically confirmed disease progression in study IPI-145-07 to receive the alternative treatment (either IPI-145 or ofatumumab) other than what was received during study IPI-145-07. Participants who previously had received ofatumumab in study IPI-145-07 received a starting dose of 25 milligrams (mg) IPI-145 twice daily continuously in a 21-day cycle for Cycle 1, followed by 28-day treatment cycles thereafter for up to 11 cycles or until disease progression, discontinuation from study participation, or start of subsequent therapy, whichever occurred first. After completing approximately 11 cycles of treatment with duvelisib, participants who, in the judgment of the investigator, may have derived benefit from continued treatment may have continued to receive additional cycles of duvelisib until disease progression or unacceptable toxicity. However, to receive additional cycles of duvelisib beyond 11 cycles, participants must have had evidence of response and CLL/SLL requiring treatment according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL)/International Working Group by Cycle 12 Day 1. Participants who previously received IPI-145 in study IPI-145-07 received treatment consistent approved product labeling which consisted of a starting dose of 300 mg ofatumumab on Day 1, followed by seven weekly doses of 2000 mg. Thereafter, participants received 2000 mg ofatumumab once every month for four months unless disease progression or unacceptable toxicity occurred. Administration of ofatumumab was not to exceed the 12 doses (within 7 cycles).

Official Title
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A Study of IPI-145 and Ofatumumab in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Previously Enrolled in Study IPI-145-07 Duvelisib (IPI-145)

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: IPI-145
* Drug: Ofatumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Received either IPI-145 or ofatumumab while participating in study IPI-145-07 and experienced radiologically confirmed disease progression Diagnosis of active CLL or SLL that met at least one of the IWCLL 2008 criteria for requiring treatment Measurable disease with a lymph node or tumor mass >1.5 centimeters in at least one dimension as assessed by computed tomography (CT) Eastern Cooperative Oncology Group performance status of 0-2 Must have met 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 grams/deciliter (g/dL) with or without transfusion support Platelet count ≥10,000 microliters (μL) with or without transfusion support For women of childbearing potential (WCBP): negative serum β-human chorionic gonadotropin pregnancy test within one week before first dose (WCBP defined as a sexually mature woman who had not undergone surgical sterilization or who had 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 participants who were 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 have used 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/independent ethics committee-approved informed consent form before any study-specific screening procedures are performed Exclusion Criteria: Discontinued study participation in Verastem-sponsored IPI-145-07 study Greater than 3 months from confirmed progressive disease on Study IPI-145-07 History of Richter's transformation or prolymphocytic leukemia Autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura that was uncontrolled or requires >20 mg daily of prednisone (or equivalent) to maintain hemoglobin >8.0 g/dL or platelets >10,000 μL without transfusion support Known central nervous system (CNS) lymphoma or leukemia; participants with symptoms of CNS disease must have had a negative CT scan or negative diagnostic lumbar puncture prior to first dose Use of any anticancer medication from documented progressive disease on Study IPI-145-07 to enrollment (Note: corticosteroids to manage CLL/SLL-related symptoms were allowed) Ongoing systemic bacterial, fungal, or viral infections at the time of initiation of study treatment (defined as requiring IV antimicrobial, antifungal or antiviral agents) (Participants 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 Screening and/or Cycle 1 Day 1 [predose]) Human immunodeficiency virus 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 and herpes simplex virus Baseline QT interval corrected with Fridericia's method >480 milliseconds Note: this criterion did not apply to participants with a right or left bundle branch block Concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in situ of the cervix, bladder, or prostate not requiring treatment. Participants with previous malignancies were eligible provided that they had 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 Unstable or severe uncontrolled medical condition (for example, unstable cardiac function, unstable pulmonary condition), or any important medical illness or abnormal laboratory finding that would, in the investigator's judgment, have increased the participant's risk while participating in this study Prior surgery or gastrointestinal dysfunction that may have affected drug absorption (for example, gastric bypass surgery, gastrectomy) Participants to receive duvelisib: Administration of medications or foods that were strong inhibitors or inducers of cytochrome P450 3A within 2 weeks of starting duvelisib Major surgery or invasive intervention within 4 weeks prior to first dose Pregnant or breastfeeding women Participants to receive ofatumumab: 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IPI-145<br>IPI-145 was administered orally and supplied as 5 mg and 25 mg formulated capsules. | Drug: IPI-145<br>* PI3K Inhibitor<br>* Other names: PI3K Inhibitor;|
| Active Comparator: Ofatumumab<br>Ofatumumab was administered as an intravenous (IV) infusion and was supplied in single-use vials at two strengths, 100 mg/5 milliliters (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 |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR was defined as the percentage of participants with a best response (per investigator assessment) of complete response (CR), CR with incomplete marrow recovery (CRi), partial response (PR), or PR with lymphocytosis (PRwL), according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) or revised International Working Group Response (IWG) Criteria, with modification for treatment-related lymphocytosis. The 95% confidence interval was calculated using exact binomial method. Select IWCLL criteria for tumor load assessed by computed tomography (CT): CR/CRi (CLL only), lymphadenopathy (none >1.5 centimeters [cm]), hepatomegaly/splenomegaly (none); PR, lymphadenopathy/hepatomegaly/splenomegaly (decrease ≥50%); PRwL, lymphadenopathy only (decrease ≥50%). Select IWG criteria for tumor load assessed by CT: CR, lymphadenopathy/hepatomegaly/splenomegaly (normal size); PR, lymphadenopathy/hepatomegaly/splenomegaly (decrease ≥50%); PRwL, lymphadenopathy only (decrease ≥50%). | Until progressive disease (PD), death, or other anticancer therapy is initiated (up to 4.5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR was defined as the time from the first documentation of response per investigator assessment to either PD or death due to any cause. DOR was evaluated using the Kaplan-Meier method based on all treated participants with a documentation of response (that is, CR, CRi, PR, or PRwL) as determined by investigator assessment. Select IWCLL criteria for tumor load assessed by CT: CR/CRi (CLL only), lymphadenopathy (none >1.5 cm), hepatomegaly/splenomegaly (none); PR, lymphadenopathy/hepatomegaly/splenomegaly (decrease ≥50%); PRwL, lymphadenopathy only (decrease ≥50%). Select IWG criteria for tumor load assessed by CT: CR, lymphadenopathy/hepatomegaly/splenomegaly (normal size); PR, lymphadenopathy/hepatomegaly/splenomegaly (decrease ≥50%); PRwL, lymphadenopathy only (decrease ≥50%). | From the first documentation of response to the first documentation of PD or death due to any cause (up to 4.5 years) | 
| Progression-free Survival (PFS) | PFS was defined as the time from the first dose of study treatment to the first documentation of either investigator-assessed PD or death resulting from any cause. PFS was determined using the Kaplan-Meier method based on all treated participants with a documentation of response (that is, CR, CRi, PR, or PRwL) as determined by investigator assessment. | From the first dose of study treatment to the first documentation of PD or death from any cause (up to 4.5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 3, CLL/SLL, PI3K