Clinical Trial: Ibrutinib in Treating Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma in Patients With HIV Infection

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: Phase I and Pharmacokinetic Study of Ibrutinib in HIV-Infected Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Multiple Myeloma

Brief Summary: This phase I trial studies the side effects and best dose of ibrutinib in treating B-cell non-Hodgkin lymphoma that has returned or does not respond to treatment in patients with human immunodeficiency virus (HIV) infection. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether it is safe for patients with HIV infection to receive ibrutinib while also taking anti-HIV drugs.

Detailed Summary:

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of single-agent ibrutinib in combination with antiretroviral therapy (ART) specifically with respect to ibrutinib metabolism in HIV-infected patients with relapsed or refractory B-cell neoplasms.

II. To determine the maximum tolerated dose (MTD) of ibrutinib in this setting.

SECONDARY OBJECTIVES:

I. To characterize ibrutinib pharmacokinetics in relation to ART-cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) interactions.

II. To describe toxicity in relation to plasma concentrations of ibrutinib and its main metabolite.

III. To estimate objective response rate, clinical benefit, times to tumor response and progression, and 6-month and 1-year progression-free and overall survival.

IV. To describe changes in HIV viral load, immunologic parameters, and Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8) deoxyribonucleic acid (DNA) copy numbers in plasma and in peripheral blood mononuclear cells (PBMC) in relation to ibrutinib therapy.

OUTLINE: This is a dose-escalation study.

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.


Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • Incidence of toxicities assessed using National Cancer Institute (NCI) CTCAE version 4.0 [ Time Frame: Up to 30 days ]
  • MTD of ibrutinib defined as the dose level in which no more than 1 out of 6 patients experiences a dose limiting toxicity assessed using NCI CTCAE version 4.0 [ Time Frame: 28 days ]


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 1-year OS [ Time Frame: From start of study treatment to death, assessed at 6 months ]
    Probabilities of 1-year OS will be estimated with the Kaplan-Meier method and reported with 95% CI.
  • 1-year PFS [ Time Frame: From start of study treatment to relapse, progression, or death from any cause, whichever occurs first, assessed at 6 months ]
    Probabilities of 1-year PFS will be estimated with the Kaplan-Meier method and reported with 95% CI.
  • 6-month overall survival (OS) [ Time Frame: From start of study treatment to death, assessed at 6 months ]
    Probabilities of 6-month OS will be estimated with the Kaplan-Meier method and reported with 95% CI.
  • 6-month progression free survival (PFS) [ Time Frame: From start of study treatment to relapse, progression, or death from any cause, whichever occurs first, assessed at 6 months ]
    Probabilities of 6-month PFS will be estimated with the Kaplan-Meier method and reported with 95% CI.
  • Changes in EBV DNA copy numbers in plasma and in PBMCs in relation to ibrutinib therapy [ Time Frame: Baseline to up to 30 days ]
    Changes will be analyzed with descriptive statistics. Where there are sufficient data, repeated measures analysis of variance will be used to assess the effect of ibrutinib on these parameters across time. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. non-parametric analogue to a repeated measures analysis of variance) will be used.
  • Changes in HHV-8 DNA copy numbers in plasma and in PBMCs in relation to ibrutinib therapy [ Time Frame: Baseline to up to 30 days ]
    Changes will be analyzed with descriptive statistics. Where there are sufficient data, repeated measures analysis of variance will be used to assess the effect of ibrutinib on these parameters across time. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. non-parametric analogue to a repeated measures analysis of variance) will be used.
  • Changes in HIV viral load [ Time Frame: Baseline to up to 30 days ]
    Changes will be analyzed with descriptive statistics. Where there are sufficient data, repeated measures analysis of variance will be used to assess the effect of ibrutinib on these parameters across time. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. non-parametric analogue to a repeated measures analysis of variance) will be used.
  • Changes in immunologic parameters [ Time Frame: Baseline to up to 30 days ]
    Changes will be analyzed with descriptive statistics. Where there are sufficient data, repeated measures analysis of variance will be used to assess the effect of ibrutinib on these parameters across time. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. non-parametric analogue to a repeated measures analysis of variance) will be used.
  • Clinical benefit [ Time Frame: Up to 30 days ]
    The proportion of patients achieving clinical benefit and their corresponding 95% CIs will be reported.
  • Objective response rate [ Time Frame: Up to 30 days ]
    The proportion of patients achieving objective responses and their corresponding 95% confidence intervals (CIs) will be reported.
  • Pharmacokinetic (PK) parameters of ibrutinib in relation to ART-CYP3A4 interactions, including half-life (T1/2), oral clearance (CL/F), and area under the curve (AUC) [ Time Frame: Course 1, day 8: pre-dose, 0.5, 1, 2, 4, 6, 8, and 24 hours ]
    Relevant individual PK parameters will be estimated using non-compartmental or compartmental PK methods. For each stratum, the PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. Pharmacokinetic parameters (i.e., T1/2, CL/F, and AUC) will be compared across relevant antiretroviral therapies using non-parametric statistical testing techniques.
  • Plasma concentrations of ibrutinib and its main metabolite [ Time Frame: Up to 30 days ]
    Correlations with toxicity will be explored using non-parametric statistical testing techniques.
  • Time to tumor progression [ Time Frame: Up to 30 days ]
    Time to tumor progression will be reported descriptively with medians and ranges.
  • Time to tumor response [ Time Frame: From the first study treatment until documentation of first objective response, assessed up to 30 days ]
    Time to tumor response will be reported descriptively wi

    Original Secondary Outcome:

    • Pharmacokinetic (PK) parameters of ibrutinib in relation to ART-CYP3A4 interactions, including half-life (T1/2), clearance (Cl), and area under the curve (AUC) [ Time Frame: Course 1, day 8: pre-dose, 0.5, 1, 2, 4, 6, 8, and 24 hours ]
      Relevant individual PK parameters will be estimated using non-compartmental or compartmental PK methods. For each stratum, the PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. Pharmacokinetic parameters (i.e., T1/2, Cl, and AUC) will be compared across relevant antiretroviral therapies using non-parametric statistical testing techniques.
    • Plasma concentrations of ibrutinib and its main metabolite [ Time Frame: Up to 30 days ]
      Correlations with toxicity will be explored using non-parametric statistical testing techniques.
    • Objective response rate [ Time Frame: Up to 30 days ]
      The proportion of patients achieving objective responses and their corresponding 95% confidence intervals (CIs) will be reported.
    • Clinical benefit [ Time Frame: Up to 30 days ]
      The proportion of patients achieving clinical benefit and their corresponding 95% CIs will be reported.
    • Time to tumor response [ Time Frame: From the first study treatment until documentation of first objective response, assessed up to 30 days ]
      Time to tumor response will be reported descriptively with medians and ranges.
    • Time to tumor progression [ Time Frame: Up to 30 days ]
      Time to tumor progression will be reported descriptively with medians and ranges.
    • 6-month progression free survival (PFS) [ Time Frame: From start of study treatment to relapse, progression, or death from any cause, whichever occurs first, assessed at 6 months ]
      Probabilities of 6-month PFS will be estimated with the Kaplan-Meier method and reported with 95% CI.
    • 1-year PFS [ Time Frame: From start of study treatment to relapse, progression, or death from any cause, whichever occurs first, assessed at 6 months ]
      Probabilities of 1-year PFS will be estimated with the Kaplan-Meier method and reported with 95% CI.
    • 6-month overall survival (OS) [ Time Frame: From start of study treatment to death, assessed at 6 months ]
      Probabilities of 6-month OS will be estimated with the Kaplan-Meier method and reported with 95% CI.
    • 1-year OS [ Time Frame: From start of study treatment to death, assessed at 6 months ]
      Probabilities of 1-year OS will be estimated with the Kaplan-Meier method and reported with 95% CI.
    • Changes in HIV viral load [ Time Frame: Baseline to up to 30 days ]
      Changes will be analyzed with descriptive statistics. Where there are sufficient data, repeated measures analysis of variance will be used to assess the effect of ibrutinib on these parameters across time. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. non-parametric analogue to a repeated measures analysis of variance) will be used.
    • Changes in immunologic parameters [ Time Frame: Baseline to up to 30 days ]
      Changes will be analyzed with descriptive statistics. Where there are sufficient data, repeated measures analysis of variance will be used to assess the effect of ibrutinib on these parameters across time. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. non-parametric analogue to a repeated measures analysis of variance) will be used.
    • Changes in EBV DNA copy numbers in plasma and in PBMCs in relation to ibrutinib therapy [ Time Frame: Baseline to up to 30 days ]
      Changes will be analyzed with descriptive statistics. Where there are sufficient data, repeated measures analysis of variance will be used to assess the effect of ibrutinib on these parameters across time. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. non-parametric analogue to a repeated measures analysis of variance) will be used.
    • Changes in HHV-8 DNA copy numbers in plasma and in PBMCs in relation to ibrutinib therapy [ Time Frame: Baseline to up to 30 days ]
      Changes will be analyzed with descriptive statistics. Where there are sufficient data, repeated measures analysis of variance will be used to assess the effect of ibrutinib on these parameters across time. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. non-parametric analogue to a repeated measures analysis of variance)

      Information By: National Cancer Institute (NCI)

      Dates:
      Date Received: April 7, 2014
      Date Started: September 2014
      Date Completion:
      Last Updated: August 18, 2015
      Last Verified: April 2015