Core: Relapsed or Refractory Diffuse Large B-Cell Lymphoma Clinical Trial
— INHIBITOROfficial 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)
| Verified date | September 2016 |
| Source | AstraZeneca |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | United States: Food and Drug Administration |
| Study type | Interventional |
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.
| Status | Withdrawn |
| Enrollment | 0 |
| Est. completion date | April 2019 |
| Est. primary completion date | April 2019 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years to 130 Years |
| Eligibility |
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. |
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| n/a | |||
| Lead Sponsor | Collaborator |
|---|---|
| AstraZeneca |
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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. | Yes |
| Primary | 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. | No |
| Primary | 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) | Yes |
| Secondary | 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. | Throughout the study, approximately 9 months. | Yes |
| Secondary | 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. | Single dose and Cycle 1 Day 22 | No |
| Secondary | 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. | Single dose and Cycle 1 Day 22 over 12 hours (AZD2014) and 24 hours (ibrutinib) post dose | No |
| Secondary | 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). | 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. | No |
| Secondary | 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). | 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. | No |
| Secondary | 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). | 24 weeks of treatment | No |
| Secondary | 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. | 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. | No |