relasped or refractory Non-hodgkin lymphoma. MedDRA version: 18.0 Level: PT Classification code 10012821 Term: Diffuse large B-cell lymphoma recurrent System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 18.0 Level: PT Classification code 10012822 Term: Diffuse large B-cell lymphoma refractory System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: AZD2014
Product Code: AZD2014
Pharmaceutical Form: Tablet
CAS Number: 1009298-59
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-50
Trade Name: Ma
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) relapsing after at least 1 course of potentially curative, anti-CD20 antibody containing regimen (e.g. RCHOP, GCHOP, RGCVP). High grade transformation from low grade lymphoma (e.g. follicular lymphoma, lymphoplasmacytic lymphoma, chronic lymphocytic leukaemia) is permitted. Patients must have relapsed post-ASCT or be considered not suitable for ASCT. 2. Tissue biopsy (or bone marrow trephine if no other tissue available) confirming histology within 3 months of enrolment. 3. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses 4. Aged at least 18 years. 5. Eastern Cooperative Oncology Group (ECOG) performance status of = 2 6. Females should be using adequate contraceptive measures (as described in the protocol, different for patient receving rituximab*), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: - Post-menopausal defined as amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments - Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 7. Male patients should be willing to use barrier contraception (i.e. condoms)as described in the protocol, (different for patient receving rituximab*) 8. Ability to swallow and retain oral medication 9. CT measurable disease with at least 1 lesion having short axis = 1.5cm or splenomegaly = 13cm in cranio-caudal length attributable to relapsed lymphoma 10. Patients must have negative virology for HIV and hepatitis C prior to trial entry. Patients with an isolated anti-hepatitis B sAg antibody may be entered as this indicates previous vaccination. These patients MUST have HBV DNA tested. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 3 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 33
Exclusion criteria
Exclusion criteria: 1. Prior chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, immunotherapy, other anticancer agents, and any investigational agents within 14days of registration (not including palliative radiotherapy at focal sites). Corticosteroids are permitted during screening but should be weaned down to a max dose of prednisolone 10mg daily (or equivalent) by cycle 1 day1. - With the exception of alopecia, any unresolved toxicities from prior chemotherapy should be no greater than CTCAE(Version 4.0) Grade 2 at the time of registration. 2. Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study 3. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 if taken within the stated washout periods before the first dose of study treatment 4. Exposure to potent or moderate inhibitors or inducers of CYP2C8 if taken within the stated washout periods before the first dose of study treatment 5. 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 within the appropriate wash-out period (minimum of 5x the reported terminal elimination half-life of each drug) before the 1st dose of study treatment 6. Previous treatment with any first generation mTORC1 inhibitors (rapamycin, sirolimus, temsirolimus, everolimus) or any dual mTORC1/2 inhibitors 7. Patients who have experienced intolerable AEs prejudged by the treating Investigator due to other mTORC1 or mTORC1/2 inhibitors, PI3 kinase inhibitors, or AKT inhibitors 8. Patients with proven central nervous system (CNS) involvement 9. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases (e.g., severe hepatic impairment, interstitial lung disease (e.g.bilateral, diffuse, parenchymal lung disease), uncontrolled chronic renal diseases (e.g. glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular acidosis) or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, active bleeding diatheses or active infection 10. Patients who have experienced any of the following procedures/conditions currently or in the preceding 12 months: - coronary artery bypass graft - angioplasty - vascular stent - myocardial infarction - angina pectoris - congestive heart failure New York Heart Association Grade =2 - ventricular arrhythmias requiring continuous therapy - supraventricular arrhythmias including atrial fibrillation, which are uncontrolled - haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other central nervous system bleeding 11. Abnormal echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) at baseline (left ventricular ejection fraction [LVEF] 470 msec as per local reading 14. Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events 15. Patients with Diabetes Type I or uncontrolled Type II (HbA1c >7 mmol/L assessed locally) as judged by the local investigator 16. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values unless due to underlying NHL infiltration -
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the safety and activity of AZD2014 as a single agent in the treatment of Diffuse large B-Cell Lymphoma (DLBCL) by measuring the best overall response to the treatment within 6 cycles. ;Secondary Objective: Assing the long term activity of the treatment by looking at the best overall response rate post 6 cycles until the end of the trial. Assing the safety and tolerability of the trial treatment Assing the overall survival at 1 year Assing the Progression free survival at 1 year Assing the Duration of response Measuring the maximum % change in the radiological sum of the product of the diameters (SPD) of the patients disease from baseline to the end of the trial by CT of the Neck Cheast Abdomen Pelvis ;Primary end point(s): • Best overall response rate during the first 6 cycles of AZD2014 will be assessed using contrast-enhanced CT scans of the neck, chest, abdomen and pelvis, using the Revised Response Criteria for Malignant Lymphoma. ;Timepoint(s) of evaluation of this end point: within the first 24 weeks (6 cycles of treatment) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Best overall response rate post 6 cycles until the end of the trial, assessed using Revised Response Criteria • Tolerability rate (based on toxicity assessments using CTCAE v 4.0 criteria) • Overall survival at 1 year • Progression free survival at 1 year • Duration of response • Maximum % decrease in the radiological sum of the product of the diameters (SPD) from baseline by CT NCAP ;Timepoint(s) of evaluation of this end point: Tolerablity rate is assess during the first 6 cycles of treatment. Best overall response, and maximum % change in SPD will be assesed over the duration of treatment. Duration of response will be assesed over the course of the trial with at least 1 years follow-up. Progression free and overall survival will be assesd at 1 year from the start of treatment. | — |
Countries
United Kingdom
Outcome results
None listed