Core: Relapsed or Refractory Diffuse Large B-Cell Lymphoma Clinical Trial
Official title:
A Modular Phase I/IIa, Open-Label, Multicentre Study to Assess AZD2014 in Combination With Novel Anti-Cancer Agents in Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma (INHIBITOR Study)
This is a modular study of AZD2014 in combination with novel anti-cancer agents in patients with different subtypes of relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL). Module 1, a combination with ibrutinib in patients with non-germinal centre B-cell-like (non-GCB) DLBCL, will consist of Part A, a Phase I dose-finding arm in which the safety and tolerability of the combination will be assessed, and Part B, a Phase II dose-expansion phase to assess the efficacy of the combination.
This is a modular, Phase I/IIa, open-label, multicentre study of AZD2014, administered
orally, in combination with up to 2 novel anti-cancer agents, to patients with different
subtypes of relapsed or refractory DLBCL.
Module 1 will assess the combination of AZD2014 and ibrutinib in patients with non-GCB DLBCL
and will consist of 2 parts. Part A will be a Phase I dose-finding study in which the safety
and tolerability of the combination will be assessed. Part B will be a Phase IIa single-arm
dose-expansion phase to assess the efficacy of the combination.
Part A will follow a Continuous Reassessment Method (CRM) based on a Bayesian Adaptive
Design to identify the AZD2014/ibrutinib dose combinations where the incidence of
dose-limiting toxicity (DLT) is less than 33% during the first cycle. It is anticipated that
approximately 30 evaluable patients with non-GCB DLBCL who are not eligible for stem cell
transplant may be enrolled. The total number of patients, however, will depend upon the
number of cohorts necessary to establish a tolerated combination dose. Determination of
tolerated doses will be primarily based on the DLTs seen in Cycle 1. Each cycle will be 28
days. Part A will also include an assessment of single- and multiple-dose pharmacokinetics
of the combination of AZD2014 and ibrutinib.
In Part B approximately 50 evaluable patients with non-GCB DLBCL will be enrolled. Patients
will receive AZD2014 and ibrutinib at the doses established in Part A in 28-day cycles until
there is unacceptable toxicity, disease progression, or the patient withdraws consent.
Assessment for response or progressive disease will occur after Cycle 3 and every 3 cycles
through the first year, and then every 6 cycles (6 months) thereafter.
In Part B, predictive power monitoring will be used, which could result in stopping Part B
for futility. An administrative interim analysis of overall response rate will be conducted
thereafter for internal decision making, and the primary analysis will be conducted
following data analysis at the primary data cut-off date. The criteria for success will be
based on a confidence interval (CI) approach.
Part B will also include an assessment of the impact of repeat intermittent treatment of
AZD2014 at the MTD on the pharmacokinetics (PK) of ibrutinib in a sub-group of 9 patients
(Part B1). The remaining 41 patients (Part B2) will have sparse PK sampling.
In order to be eligible for Module 1 participants must have pathologically confirmed DLBCL
of non-GCB subtype. Participants meeting any of the following criteria may not be enrolled
in Module 1:
1. Previous treatment with a Bruton's tyrosine kinase (BTK) inhibitor and/or mammalian
target of rapamycin (mTOR) pathway inhibitors.
2. History of severe allergic or anaphylactic reactions to kinase inhibitors or history of
hypersensitivity to active or inactive excipients of ibrutinib or drugs with a similar
chemical structure or class to ibrutinib.
3. Recent infection requiring systemic treatment that was completed within 14 days prior
to the first dose of study drug.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment