Study of Ibrutinib in Combination With Rituximab in Previously Untreated Subjects With Follicular Lymphoma

Study Overview
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Brief Summary
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This is an open-label, Phase 2 study designed to assess the efficacy and safety of ibrutinib combined with rituximab in previously untreated subjects with Follicular Lymphoma (FL).

Detailed Description
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This is an open-label, Phase 2 study designed to assess the efficacy and safety of ibrutinib combined with rituximab in previously untreated subjects with FL. There are two study treatment arms. Subjects enrolled into main study treatment arm will receive ibrutinib continuously until disease progression or unacceptable toxicity. In addition, subjects will receive rituximab once weekly for four doses for the first four weeks of study treatment. Subjects enrolled into the exploratory study treatment arm will receive ibrutinib continuously as a single agent for the first eight weeks, then ibrutinib concurrently with rituximab once weekly for four doses. After the rituximab treatment, subjects will receive ibrutinib continuously until disease progression or unacceptable toxicity.

Official Title
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A Multicenter, Open-Label, Phase 2 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination With Rituximab in Previously Untreated Subjects With Follicular Lymphoma

Conditions
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Follicular Lymphoma, B-cell Lymphoma, Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: rituximab


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria: Histologically documented FL (Grade 1, 2 and 3A) Not previously treated with prior anti-cancer therapy for FL Stage II, III or IV disease At least one measurable lesion ≥ 2 cm in longest diameter by CT and/or MRI scan Men and women ≥ 18 years of age Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 Key Exclusion criteria: Medically apparent central nervous system lymphoma or leptomeningeal disease FL with evidence of large cell transformation Any prior history of other hematologic malignancy besides FL or myelodysplasia History of other malignancies, except Malignancy treated with curative intent and with no known active disease present for ≥5 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician. Adequately treated non-melanoma skin cancer or lentigomaligna without evidence of disease. Adequately treated carcinoma in situ without evidence of disease. Currently active, clinically significant cardiovascular disease or myocardial infarction within 6 months of screening Known anaphylaxis or Immunoglobulin E (IgE)-mediated hypersensitivity to murine proteins or to any component of rituximab (Rituxan®) Requires anti-coagulation with warfarin or a vitamin K antagonist. Requires treatment with strong cytochrome P450 (CYP) 3A inhibitors. Known bleeding diathesis or hemophilia

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: Main Study Arm 1<br>Subjects enrolled into this arm will receive ibrutinib continuously until disease progression or unacceptable toxicity. In addition, subjects will receive rituximab once weekly for four doses for the first four weeks of study treatment. | Drug: Ibrutinib<br>* All subjects will receive 560 mg of Ibrutinib orally.<br>* Other names: PCI-32765;Drug: rituximab<br>* All subjects will receive rituximab 375 mg/m2 intravenously<br>* Other names: Rituxan;|
| Experimental: Exploratory Study Arm 2<br>Subjects enrolled into this arm will receive ibrutinib continuously as a single agent for the first eight weeks, then ibrutinib concurrently with rituximab once weekly for four doses. After the rituximab treatment, subjects will receive ibrutinib continuously until disease progression or unacceptable toxicity. | Drug: Ibrutinib<br>* All subjects will receive 560 mg of Ibrutinib orally.<br>* Other names: PCI-32765;Drug: rituximab<br>* All subjects will receive rituximab 375 mg/m2 intravenously<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR): Proportion of Subjects Achieving the Best Overall Responses of Complete Response (CR) or Partial Response (PR) | Number of subjects achieving the best overall responses of CR or PR prior to the initiation of the next line of antineoplastic therapy as assessed by investigator per the Cheson et al, 2007 criteria. Target lesions are measured by CT, unless MRI is used as the assessment modality for lesions in anatomical locations not amenable to CT. CR is defined as the disappearance of all evidence of disease. PR is defined as >=50% decrease in the sum of the product of the diameters of up to 6 largest dominant masses. | Subjects in Arm 1 will have imaging assessments every 12 weeks for the first 8 assessments, then every 24 weeks. Subjects in Arm 2 will have imaging assessments starting at week 9, then every 12 weeks for 8 assessments, then every 24 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR is defined as the interval between the date of the first documented response (CR, PR) and the date of the first documented evidence of progressive disease (PD) or death. DOR will be analyzed for the subjects who achieve an overall response during the duration of study. | Up to 45 months | 
| Progression Free Survival (PFS) | PFS is defined as the time interval between the date of the first dose and the date of the earliest occurrence of PD or death due to any cause, whichever occurs first. PD is characterized by any new lesion or increase by >=50% of previously involved sites from nadir. | Up to 45 months | 
| Overall Survival (OS) | Subjects will be followed for survival information up to three years after the last dose of study treatment, until new treatment or death, whichever occurs first. OS is defined as the duration of time from the date of the first dose to the date of death from any cause. | Up to 45 months | 
| Number of Participants With Treatment-emergent Adverse Events | Frequency, severity, and relatedness of treatment-emergent adverse events (AEs) Frequency of treatment-emergent AEs requiring discontinuation of study drug or dose reductions | Up to 45 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacyclics (PCYC), PCYC, Lymphoma, Follicular Lymphoma, FL, Rituximab, Ibrutinib, Rituxan, Non-Hodgkin's Lymphoma (NHL), NHL, B-cell Lymphoma