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Core: Relapsed or Refractory Diffuse Large B-Cell LymphomaPhase 1INHIBITORNCT02780830

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

A Phase 1 study testing AZD2014 and Ibrutinib in people with Core: Relapsed or Refractory Diffuse Large B-Cell Lymphoma and Module 1: Non-GCB Diffuse Large B-Cell Lymphoma, run by AstraZeneca.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 to 130 years
What is being tested?
AZD2014 and Ibrutinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
Jun 2016to Apr 2019
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 130 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Core Inclusion Criteria

  1. Males and Females (M/F) ≥18
  2. Histopathologically confirmed DLBCL
  3. Progressive Disease (PD) after autologous stem cell transplantation (ASCT) or ineligible for ASCT
  4. 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
  5. ≥1 lesion on computerized tomography (CT) or magnetic resonance imaging (MRI) >1.5 cm
  6. Adequate hematologic function
  7. Adequate hepatic and renal function
  8. Prothrombin time (PT)/international normalised ratio (INR) <1.5 x upper limit of normal (ULN) and activated partial thromboplastin time <1.5 x ULN
  9. Serum potassium within normal limits (WNL)
  10. ECOG perf. status of 0 or 1
  11. Female patients willing to use 2 forms of contraception, not breast feeding
  12. Male patients surgically sterile or willing to use effective barrier method of contraception

Core Exclusion Criteria

  1. Previous allogenic stem cell transplant. Patients may have previous ASCT > 3 months prior
  2. Prior standard anti-lymphoma therapy or radiation therapy ≤ 14 days
  3. Concurrent systemic immunosuppressive therapy ≤ 28 days
  4. Major surgery < 4 weeks or minor surgery < 14 days
  5. Haemopoeitic growth factors < 7 days or pegylated G-CSF and darbepoetin < 14 days
  6. History of severe allergic or anaphylactic reactions to kinase inhibitors or hypersensitivity to active or inactive excipients of vistusertib
  7. Live, attenuated vaccine < 4 weeks
  8. Unresolved toxicities from prior anti-cancer therapy with the exception of alopecia.
  9. Bleeding disorders or haemophilia
  10. History of stroke or intracranial haemorrhage < 6 months
  11. Central nervous system (CNS) involvement by lymphoma or spinal cord compression
  12. 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
  13. History of other malignancies
  14. History of HIV, active or chronic hepatitis C, or hepatitis B
  15. 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.
  16. Abnormal echo/MUGA at baseline
  17. Mean resting QTc >450 msec obtained from 3 ECGs
  18. Factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, or family history of sudden unexplained death <40 years-of-age
  19. Type I or uncontrolled Type 2 diabetes mellitus.
  20. Clinically significant pre-existing renal disease or high risk of developing renal impairment.
  21. Refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting GI function, resection of stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
  22. Concomitant use of therapeutic anticoagulants with the exception of short-acting heparins
  23. Exposure to potent or moderate inhibitors or inducers of CYP 3A4/5, multi drug resistance 1 (MDR1) permeability glycoprotein (Pgp), or breast cancer resistance protein (BCRP)
  24. Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2.

About this study

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.

Read the detailed description

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.
Being tested
AZD2014, Ibrutinib
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
Medical subject headings
Lymphoma, Large B-Cell, Diffuse, Lymphoma, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AZD2014Drug

    Also called Vistusertib

    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.

  • IbrutinibDrug

    Also called IMBRUVICA®

    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.

Study groups in NCT02780830
Study groupRoleWhat they receive
AZD2014 plus Ibrutinib CombinationExperimentalAZD2014 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.
Receives: Drug: AZD2014; Drug: Ibrutinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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).

    Measured: Throughout the study, approximately 9 months.

  2. 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)

    Measured: 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.

  3. 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.

    Measured: 28 days (1 cycle)

Secondary outcomes (7)

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

    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 ECGs.

    Measured: Throughout the study, approximately 9 months.

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

    Plasma pharmacokinetics (PK) - AZD2014 (Part A only) and ibrutinib (Part A and B1) maximum concentration.

    Measured: Single dose and Cycle 1 Day 22

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

    Plasma PK - AZD2014 (Part A only) and ibrutinib (Part A and B1) area under concentration time curve.

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

  4. 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 assessed through the number of patients who achieve a disease response (i.e. complete response or partial response) as assessed by the Cheson revised response criteria for malignant lymphoma (2014).

    Measured: 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.

  5. 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.

    DoR will be assessed as the time between disease response being achieved and progressive disease as assessed by the Cheson revised response criteria for malignant lymphoma (2014) or death (in the absence of progression).

    Measured: 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.

  6. The anti-tumour activity of the combination of AZD2014 and ibrutinib will be determined in patients in both Parts A and B by evaluating disease control rate (DCR) at 24 weeks as the percentage of patients who achieve stable disease or a tumour response.

    DCR will be assessed through the percentage of patients who achieve stable disease or a disease response (i.e. complete response or partial response) at 24 weeks of treatment without an intervening progression as assessed by the Cheson revised response criteria for malignant lymphoma (2014).

    Measured: 24 weeks of treatment

  7. The anti-tumour activity of the combination of AZD2014 and ibrutinib will be determined in Part A and Part B patients by evaluating progression-free survival (PFS).

    PFS will be assessed as the time from start of dosing until the date of progression as assessed by the Cheson revised response criteria for malignant lymphoma (2014) or death in the absence of progression.

    Measured: PFS will be assessed from the date of first dose until 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.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 May 2016 (estimated)
  2. Study startJun 2016
  3. Primary completionApr 2019 (estimated)
  4. Study completionApr 2019 (estimated)

Why it stopped: Study D2276C00001 was not started. No patients were enrolled. The sponsor decided to pursue an alternate design.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02780830
Sponsor's protocol ID
D2276C00001
Other IDs
LYM 103
Acronym
INHIBITOR
Status last verified
Sep 2016
First submitted
27 Apr 2016
Last updated
15 Sep 2016
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing AZD2014 and Ibrutinib in people with Core: Relapsed or Refractory Diffuse Large B-Cell Lymphoma and Module 1: Non-GCB Diffuse Large B-Cell Lymphoma, run by AstraZeneca.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 15 Sep 2016. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The incidence of adverse events (including adverse events detected via laboratory assessment, vital signs and ECG) (Part A). (time frame: Throughout the study, approximately 9 months.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02780830.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Sep 2016.

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