Diffuse Large B-Cell Lymphoma
Conditions
Keywords
Relapsed, Refractory, Lymphoma
Brief summary
The aim of this clinical trial is to see if the drug called AZD2014 is effective and safe to use to treat patients with relapsed or refractory Diffuse Large BCell Lymphoma (DLBCL). The trial will also be looking at combining the antibody (Rituximab) with the drug AZD2014 in a small number of patients to see if this can be done without increasing the toxicity. 36 patients will be recruited to the trial. 30 will receive AZD2014 alone and the remaining 6 will receive AZD2014 plus rituximab. AZD2014 will be given as a 125mg tablet that is to be taken twice a day for 2 days out of every 7 (i.e. on days 1 and 2 of every week). Rituximab will be given via IV infusion on day 1 of every 28 days (once every 4 weeks) for a maximum of 6 cycles.
Detailed description
This is a prospective, single arm, multicentre, phase II clinical trial utilising a two stage design. Stage one will assess the safety and activity of AZD2014 as a single agent in the treatment of DLBCL in 30 patients. Stage two will assess the additional toxicity of combining AZD2014 with Rituximab in an additional 6 patients. Stage two will be recruited following the full recruitment of stage 1. Stage 2 recruitment will be staggered with 3 patients recruited and their safety data evaluated prior to the recruitment of the remaining 3 patients. Post treatment biopsies will be requested at relapse in patients receiving rituximab to assess for evidence of synergy. Once registered to the study, patients will receive AZD2014 125mg bd on an intermittent schedule of 2 days of treatment followed by 5 days with no treatment. Treatment would be on days 1, 2, 8, 9, 15, 16, 22 and 23 of each course 28 days in duration. Treatment is on-going until progression or withdrawal due to toxicity or patient's choice. For the second stage of the trial, rituximab 375mg/m2 will also be administered intravenously on day 1 of the 28 day cycle for a total of 6 cycles in combination with AZD2014. All patients will be followed for a minimum of 1 year up until disease progression or death. For patients still on AZD2014 treatment after 1 year (no progression) treatment should still be reviewed at least 3 monthly. Safety, progression and survival data will be collected every 3 months. Assessments should be as per local practice with a CT scan conducted every 3/4 months. At progression, patients will then be followed up annually for survival data. Tissue, saliva and blood samples will be collected during treatment to determine the activity of AZD2014 on downstream targets, and correlating with response. This will include biopsy tissue from the pre-treatment sample, any biopsy performed on treatment and at relapse post-AZD2014 should this occur
Interventions
DRUGAZD 2014
AZD2014 125mg BD - 2 days on 5 days off in a 28 day cycle
DRUGRituximab
Rituximab 375mg/m2 will be administered intravenously on day 1 of a 28 day cycle for a total of 6 cycles.
Sponsors
Bloodwise
AstraZeneca
Cancer Research UK
University of Birmingham
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 receiving 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 receiving 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 ≥ 14cm in cranio-caudal length attributable to relapsed lymphoma 10. Patients must have negative virology for HIV, hepatitis B 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.
Exclusion criteria
Patients must not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Best overall response rate (PR plus CR) (using the Revised Response Criteria for Malignant Lymphoma ) during the first 6 cycles | Data in relation to this outcome will be collected over the first 6 cycles of therapy - each cycle is 28 days in duration |
Secondary
| Measure | Time frame |
|---|---|
| Tolerability rate of additional toxicities when rituximab is combined with AZD2014 at its standard dose (stage 2 only) | Adverse events information will be collected from the start of stage 2 during the 18 month recruitment period of the trial and during the one year follow up period |
| Best overall response rate post 6 cycles until the end of the trial, assessed using Revised Response Criteria | Information will be collected from cycle 6 ( each cycle is 28 days) during the 18 month recruitment period of the trial until the end of the trial |
| Overall survival (OS) at 1 year | Information relating to this outcome will be collected up to and including the one year time point |
| Tolerability rate (based on toxicity assessments using CTCAE v 4.0 criteria) of single agent AZD2014 | Adverse events information will be collected throughout the 18 month recruitment period of the trial and during the one year follow up period |
| Duration of response | Information relating to this outcome will be collected throughout the trial during the 18 month recruitment period and during the one year follow up period |
| Maximum % decrease in the radiological sum of the product of the diameters (SPD) from baseline by CT NCAP | Information relating to this outcome will be collected throughout the 18 month recruitment period of the trial |
| Progression free survival (PFS) at 1 year | Information relating to this outcome will be collected up to and including the one year time point |
Countries
United Kingdom
Outcome results
None listed