Clinical Trial: Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy vs Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients With Chronic Lymphoc

Brief Summary: This randomized phase III trial studies ibrutinib and rituximab to see how well they work compared to fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as rituximab, interfere with the ability of cancer cells to grow and spread. It is not yet known whether fludarabine phosphate, cyclophosphamide, and rituximab may work better than ibrutinib and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Detailed Summary:

PRIMARY OBJECTIVES:

I. To evaluate the ability of Ibrutinib-based induction therapy to prolong progression free survival (PFS) compared to standard fludarabine phosphate, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy for younger patients with chronic lymphocytic leukemia (CLL).

SECONDARY OBJECTIVES:

I. Evaluate overall survival (OS) of patients based on treatment arm. II. Monitor and assess toxicity of treatment with Ibrutinib-based induction relative to standard FCR chemotherapy.

III. To compare quality of life (QOL) in CLL patients during the first 6 months of treatment among patients receiving Ibrutinib-based induction therapy relative to standard FCR chemoimmunotherapy.

IV. To compare QOL over the long-term in CLL patients receiving continuous therapy using Ibrutinib to that of CLL patients who completed FCR therapy.

V. Determine the effect of pretreatment clinical and biological characteristics (e.g. disease stage, immunoglobulin heavy chain variable region gene [IGHV] mutation status, fluorescent in situ hybridization [FISH]) on clinical outcomes (e.g. complete response, PFS) of the different arms.

VI. Determine if the minimal residual disease (MRD) status as assessed by flow cytometry at different time points during and after treatment is an effective surrogate marker for prolonged PFS and overall survival.

VII. Compare the genetic abnormalities and dynamics of intra-clonal architecture of CLL patients before and after treatment with chemoimmunotherapy (CIT) and non-CIT approaches and explore relationships with
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

• Change in quality of life assessed using Functional Assessment of Cancer Therapy -Leukemia (FACT-Leu) Trial Outcome Index (TOI) [ Time Frame: Baseline to 12 months after beginning therapy ]
• PFS [ Time Frame: The time from randomization to progression or to death without documentation of progression, assessed up to 10 years ]
  A stratified logrank test applied to all patients as randomized will be the primary analysis, with age, ECOG performance status, disease stage, and baseline cytogenetic abnormalities as stratification factors. The same analysis applied to eligible patients only will also be performed as a sensitivity analysis. Cox proportional hazards models will be used to assess possible effects of clinical and biological characteristics on outcome, including age, gender, disease stage, cytogenetic abnormalities, ECOG performance status, and important mutations.

Original Primary Outcome:

• PFS [ Time Frame: The time from randomization to progression or to death without documentation of progression, assessed up to 10 years ]
  A stratified logrank test applied to all patients as randomized will be the primary analysis, with age, ECOG performance status, disease stage, and baseline cytogenetic abnormalities as stratification factors. The same analysis applied to eligible patients only will also be performed as a sensitivity analysis. Cox proportional hazards models will be used to assess possible effects of clinical and biological characteristics on outcome, including age, gender, disease stage, cytogenetic abnormalities, ECOG performance status, and important mutations.
• Change in quality of life assessed using Functional Assessment of Cancer Therapy -Leukemia (FACT-Leu) Trial Outcome Index (TOI) [ Time Frame: Baseline to 12 months after beginning therapy ]

Current Secondary Outcome:

• Adherence to prescription assessed by the Moriskey Adherence Scale (Arm A only) [ Time Frame: Up to 24 months ]
  Descriptive statistics will be used to summarize trend in adherence to prescription.
• Change in FACT-Leu TOI score [ Time Frame: Baseline to 3 months after beginning therapy ]
  The change in FACT-Leu TOI score will be compared between arm A and arm B to assess the short-term effect of the two therapies on QOL.
• Change in FACT-Leu TOI score [ Time Frame: Baseline to 6 months after beginning therapy ]
  The change in FACT-Leu TOI score from the time of randomization to 6 months after beginning therapy will be compared between the two treatment arms in order to provide additional information regarding the toxicity of the different regimens.
• Impact of CLL on QOL [ Time Frame: Baseline ]
  The social well-being and emotional well-being components of the FACT-General (G) will be administered at study entry. The entire FACT-Leukemia instrument (FACT-G and the leukemia subscale) at baseline will be analyzed using descriptive statistics to assess the impact of CLL on QOL independent of treatment.
• Incidence of toxicity, defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment, graded according to NCI Common Terminology for Adverse Events version 4.0 [ Time Frame: Up to 10 years ]
  The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. In addition, all adverse event data that is graded as 3, 4, or 5 will be reviewed and classified as either "unrelated or unlikely to be related" to study treatment in the event of an actual relationship developing.
• OS [ Time Frame: Time from randomization until death due to any cause, assessed up to 10 years ]
  A stratified logrank test applied to all patients as randomized will be the primary analysis for OS, with age, ECOG performance status, disease stage, and baseline cytogenetic abnormalities as stratification factors. The same analysis applied to eligible patients only will also be performed as a sensitivity analysis. Cox proportional hazards models will be used to assess possible effects of clinical and biological characteristics on outcome, including age, gender, disease stage, cytogenetic abnormalities, ECOG performance status, and important mutations.

Original Secondary Outcome:

• OS [ Time Frame: Time from randomization until death due to any cause, assessed up to 10 years ]
  A stratified logrank test applied to all patients as randomized will be the primary analysis for OS, with age, ECOG performance status, disease stage, and baseline cytogenetic abnormalities as stratification factors. The same analysis applied to eligible patients only will also be performed as a sensitivity analysis. Cox proportional hazards models will be used to assess possible effects of clinical and biological characteristics on outcome, including age, gender, disease stage, cytogenetic abnormalities, ECOG performance status, and important mutations.
• Incidence of toxicity, defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment, graded according to NCI Common Terminology for Adverse Events version 4.0 [ Time Frame: Up to 10 years ]
  The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. In addition, all adverse event data that is graded as 3, 4, or 5 will be reviewed and classified as either "unrelated or unlikely to be related" to study treatment in the event of an actual relationship developing.
• Change in FACT-Leu TOI score [ Time Frame: Baseline to 3 months after beginning therapy ]
  The change in FACT-Leu TOI score will be compared between arm A and arm B to assess the short-term effect of the two therapies on QOL.
• Change in FACT-Leu TOI score [ Time Frame: Baseline to 6 months after beginning therapy ]
  The change in FACT-Leu TOI score from the time of randomization to 6 months after beginning therapy will be compared between the two treatment arms in order to provide additional information regarding the toxicity of the different regimens.
• Impact of CLL on QOL [ Time Frame: Baseline ]
  The social well-being and emotional well-being components of the FACT-General (G) will be administered at study entry. The entire FACT-Leukemia instrument (FACT-G and the leukemia subscale) at baseline will be analyzed using descriptive statistics to assess the impact of CLL on QOL independent of treatment.
• Adherence to prescription assessed by the Moriskey Adherence Scale (Arm A only) [ Time Frame: Up to 24 months ]
  Descriptive statistics will be used to summarize trend in adherence to prescription.

Dates:
Date Received: January 27, 2014
Date Started: February 2014
Date Completion:
Last Updated: May 18, 2017
Last Verified: May 2017