AZD2014 Plus Novel Anti-Cancer Agents in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

NCT02780830 | Withdrawn Phase 1

• 2 other identifiers: D2276C00001LYM 103
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Core: Relapsed or Refractory Diffuse Large B-Cell Lymphoma; Module 1: Non-GCB Diffuse Large B-Cell Lymphoma

Keywords

Lymphoma; Diffuse Large B-Cell Lymphoma; non-GCB Diffuse Large B-Cell Lymphoma; Relapsed or Refractory non-GCB Diffuse Large B-Cell Lymphoma; Vistusertib; AZD2014; Ibrutinib; Imbruvica

Outcome Measures

Primary Outcomes (3)

• The incidence of adverse events (including adverse events detected via laboratory assessment, vital signs and ECG) (Part A).

  Safety and tolerability will be assessed through the incidence of adverse events. Adverse events will include significant findings on vital signs, clinical chemistry/haematology, coagulation parameters, and electrocardiograms (ECGs).

  Throughout the study, approximately 9 months.

• Overall Response Rate (ORR) in patients with relapsed or refractory DLBCL receiving the combination of AZD2014 and ibrutinib (Part B only) by assessment of the proportion of patients with tumour response.

  ORR will be assessed through the proportion of patients who achieve a disease response (i.e. complete response or partial response) according to the Cheson revised response criteria for malignant lymphoma (2014)

  ORR will be determined at prespecified intervals as the percentage of patients with a documented response before progression or other anti-cancer therapy, assessed up to 5 years.

• Maximum Tolerated Dose (MTD)

  The safety dose-finding portion of each module (Part A) will follow a Bayesian adaptive design, whereby patients will be enrolled to ensure 3-6 evaluable patients per dose to determine the Recommended Phase 2 Dose (RP2D) and/or MTDs of the combination being studied. The Bayesian Adaptive Design Scheme will utilize a practical Continuous Reassessment Method (CRM) as described in each individual module. Determination of tolerated doses will be primarily based on the DLTs seen in Cycle 1.

  28 days (1 cycle)

Secondary Outcomes (7)

• The incidence of adverse events (including adverse events detected via laboratory assessment, vital signs and ECG) (Part B).

  Throughout the study, approximately 9 months.

• Cmax of AZD2014 and ibrutinib following single (Cycle 1 Day 1 Part A, Cycle 0 Day 3 Part B1) and multiple dose.

  Single dose and Cycle 1 Day 22

• AUC for AZD2014 and ibrutinib following single (Cycle 1 Day 1 Part A, Cycle 0 Day 3 Part B1) and multiple dose.

  Single dose and Cycle 1 Day 22 over 12 hours (AZD2014) and 24 hours (ibrutinib) post dose

• Overall Response Rate (ORR) in patients with relapsed or refractory DLBCL receiving the combination of AZD2014 and ibrutinib (Part A only) by assessment of the proportion of patients with tumour response.

  ORR will be determined at prespecified intervals as the percentage of patients with a documented response before progression or other anti-cancer therapy, assessed up to 5 years.

• The anti-tumour activity of the combination of AZD2014 and ibrutinib will be determined in Part A and Part B patients by evaluating duration of response (DoR) by assessment of the amount of time tumour response is maintained.

  The DoR will be determined at prespecified intervals from the time of first response to the date of first documented progression, date of death from any cause, or start of other anti-cancer therapy, whichever comes first, assessed up to 5 years.

Study Arms (1)

AZD2014 plus Ibrutinib Combination

EXPERIMENTAL

AZD2014 and ibrutinib will be dosed together in the morning under fasting conditions. When possible, the morning doses of AZD2014 and ibrutinib should be taken at approximately the same time each day. The morning doses must be taken in a fasted state (water to drink only) from at least 2 hours prior to the dose to at least 1 hour post dose. AZD2014 will be taken orally twice per day on an intermittent dosing schedule, 2 days on and 5 days off of each week. On days of AZD2014 dosing, ibrutinib will be taken with the morning dose of AZD2014.

Drug: AZD2014; Drug: Ibrutinib

Interventions

AZD2014 DRUG

AZD2014 will be supplied as oral tablets. AZD2014 will be taken orally twice per day on an intermittent dosing schedule, 2 days on and 5 days off of each week.

Also known as: Vistusertib

AZD2014 plus Ibrutinib Combination

Ibrutinib DRUG

Ibrutinib will be provided in hard gelatin capsules in opaque high-density polyethylene bottles. On days of AZD2014 dosing, ibrutinib will be taken with the morning dose of AZD2014.

Also known as: IMBRUVICA®

AZD2014 plus Ibrutinib Combination

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and Females (M/F) ≥18
• Histopathologically confirmed DLBCL
• Progressive Disease (PD) after autologous stem cell transplantation (ASCT) or ineligible for ASCT
• Relapsed/refractory de novo disease, defined as: i) recurrence of disease after complete response (CR), partial response (PR), or stable disease (SD); or ii) PD after completion of previous treatment regimen
• ≥1 lesion on computerized tomography (CT) or magnetic resonance imaging (MRI) \>1.5 cm
• Adequate hematologic function
• Adequate hepatic and renal function
• Prothrombin time (PT)/international normalised ratio (INR) \<1.5 x upper limit of normal (ULN) and activated partial thromboplastin time \<1.5 x ULN
• Serum potassium within normal limits (WNL)
• ECOG perf. status of 0 or 1
• Female patients willing to use 2 forms of contraception, not breast feeding
• Male patients surgically sterile or willing to use effective barrier method of contraception

You may not qualify if:

• Previous allogenic stem cell transplant. Patients may have previous ASCT \> 3 months prior
• Prior standard anti-lymphoma therapy or radiation therapy ≤ 14 days
• Concurrent systemic immunosuppressive therapy ≤ 28 days
• Major surgery \< 4 weeks or minor surgery \< 14 days
• Haemopoeitic growth factors \< 7 days or pegylated G-CSF and darbepoetin \< 14 days
• History of severe allergic or anaphylactic reactions to kinase inhibitors or hypersensitivity to active or inactive excipients of vistusertib
• Live, attenuated vaccine \< 4 weeks
• Unresolved toxicities from prior anti-cancer therapy with the exception of alopecia.
• Bleeding disorders or haemophilia
• History of stroke or intracranial haemorrhage \< 6 months
• Central nervous system (CNS) involvement by lymphoma or spinal cord compression
• Corticosteroid use with the exception of control of symptoms relating to underlying disease and/or corticosteroid for other indications up to 20 mg/day prednisone
• History of other malignancies
• History of HIV, active or chronic hepatitis C, or hepatitis B
• Have undergone any of the following procedures or experienced conditions currently or \< 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure \[New York Heart Association (NYHA) grade ≥ 2\], ventricular arrhythmias requiring continuous therapy, supraventricular arrhythmias, atrial fibrillation, haemorrhagic or thrombotic stroke, TIA or CNS bleeding.

Sponsors & Collaborators

• AstraZeneca: lead

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Lymphoma; Recurrence

Interventions

vistusertib; ibrutinib

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Ian W Flinn, MD, PhD

  SCRI Development Innovations, LLC

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2016
• First Posted: May 24, 2016
• Study Start: June 1, 2016
• Primary Completion: April 1, 2019
• Study Completion: April 1, 2019
• Last Updated: September 15, 2016

Record last verified: 2016-09