A study of the drugs AZD2014 and rituximab in relapsed or refractory diffuse large B-cell lymphoma

ISRCTN	ISRCTN10760016
DOI	https://doi.org/10.1186/ISRCTN10760016
EudraCT/CTIS number	2014-003588-39
ClinicalTrials.gov number	NCT02752204
Secondary identifying numbers	19208

Submission date: 01/07/2015
Registration date: 01/07/2015
Last edited: 14/10/2022

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-azd2014-for-diffuse-large-b-cell-lymphoma-torch

Contact information

Ms Kathryn Paterson
Public

Cancer Research UK Clinical Trials Unit
School of Cancer Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom

Study information

Study design	Non-randomised; Interventional; Design type: Treatment
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use contact details to request a participant information sheet
Scientific title	A phase II study to determine the safety and efficacy of the dual mTORC inhibitor AZD2014 and to investigate additional toxicities in combination with rituximab in relapsed refractory DLBCL
Study acronym	Torch
Study objectives	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). We 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.
Ethics approval(s)	NRES Committee West Midlands – Edgbaston, 18/05/2015, ref: 15/WM/0126
Health condition(s) or problem(s) studied	Topic: Cancer; Subtopic: Lymphoma; Disease: Lymphoma (other)
Intervention	AZD2014 is a close analogue of AZD8055 and a selective inhibitor of mTOR kinase. AZD2014 has greater inhibitory activity against mTORC1 compared to rapamycin: AZD2014 decreases p4EBP1 Thr37/46, inhibits the translation initiation complex and decreases overall protein synthesis. AZD2014 also inhibits the mTORC2 biomarkers pAKTSer473 and pNDRG1Thr346. AZD2014 has broad antiproliferative activity across multiple tumour cell lines.azd2014 is provided as an oral tablet free of charge to study pa; Rituximab, Rituximab is licenced within the EU for the treatment of patients with CD20 positive diffuse large B cell non Hodgkin's lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy and is therefore a standard treatment for these patients. 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.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	AZD2014 Rituximab
Primary outcome measure	Best overall response rate (PR plus CR) (using the Revised Response Criteria for Malignant Lymphoma); Timepoint(s): during the first 6 cycles
Secondary outcome measures	1. Tolerability rate (based on toxicity assessments using CTCAE v 4.0 criteria) of single agent AZD2014; Timepoint(s):during stage 1 of the study 2. Tolerability rate of additional toxicities when rituximab is combined with AZD2014 at its standard dose; Timepoint(s): During stage 2 only 3. Best overall response rate post 6 cycles until the end of the trial, assessed using Revised Response Criteria; Timepoint(s): post 6 cycles 4. Overall survival (OS); Timepoint(s): at 1 year 5. Progression free survival (PFS); Timepoint(s): at 1 year 6. Duration of response; Timepoint(s):End of trial 7. Maximum % decrease in the radiological sum of the product of the diameters (SPD) from baseline by CT NCAP; Timepoint(s):From baseline to the end of the study 8. Correlation of response with pharmacodynamic biomarkers, cell of origin studies, lymphoid-related mutational analysis and potential predictive biomarkers of response; Timepoint(s): baseline to Post 2 cycle, post cycle 6 and progression 9. To determine the response to AZD2014 by PET CT criteria and analyse the effect; Timepoint(s): Post 2 cycle and post cycle 6
Overall study start date	15/07/2015
Completion date	05/02/2019

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 36; UK Sample Size: 36
Total final enrolment	36
Key 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: 6.1. Post-menopausal defined as amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments 6.2. 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 ≥ 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
Key exclusion criteria	1. Prior chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, immunotherapy, other anti-cancer agents, and any investigational agents within 14 days 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 day 1 1.1. 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: 10.1. Coronary artery bypass graft 10.2. Angioplasty 10.3. Vascular stent 10.4. Myocardial infarction 10.5. Angina pectoris 10.6. Congestive heart failure New York Heart Association Grade ≥2 10.7. Ventricular arrhythmias requiring continuous therapy 10.8. Supraventricular arrhythmias including atrial fibrillation, which are uncontrolled 10.9. 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] <50%) 12. Torsade’s de Pointes within 12 months of study entry 13. Mean (3 consequent ECGs 1 minute apart) resting QTcF or QTcB >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 16.1. Absolute neutrophil count <1.5 x 10 9/L (without GCSF/GMCSF support) 16.2. Platelet count <100 x 10 9/L 16.3. Haemoglobin <90 g/L (transfusions permissable) 16.4. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)>2.5 times the upper limit of normal (ULN) if no demonstrable liver involvement or >5 times ULN in the presence of liver involvement 16.5. Total bilirubin >1.5 times ULN unless in the presence of Gilbert’s syndrome with an elevated indirect fraction 16.6. Serum creatinine >1.5 times ULN concurrent with creatinine clearance ≤50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 times the ULN 17. Current refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD2014 18. History of known hypersensitivity to active or inactive excipients of AZD2014 or drugs with a similar chemical structure/class to AZD2014 19. Judgment by the Investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements 20. Previous history of other active malignant disease other than fully excised basal or squamous call carcinoma of the skin, carcinoma in situ of the uterine cervix or localised disease treated with curative intent using surgery alone, within last 3 yrs
Date of first enrolment	31/07/2015
Date of final enrolment	25/04/2017

Locations

Countries of recruitment

England
Scotland
United Kingdom
Wales

Study participating centres

The Churchill Hospital

Headley Way, Headington
Oxford
OX3 9DU
United Kingdom

Royal Liverpool University Hospital

Prescot Street
Liverpool
L7 8XP
United Kingdom

The Christie Hospital

Wilmslow Road
Manchester
M20 4BX
United Kingdom

Derriford Hospital

Derriford Road
Plymouth, Devon
PL6 8DH
United Kingdom

Guys Hospital

Great Maze Pond
London
SE1 9RT
United Kingdom

Aberdeen Royal Infirmary

Foresterhill
Aberdeen
AB25 2ZB
United Kingdom

Norfolk and Norwich University Hospital

Colney Lane
Norwich
NR4 7UY
United Kingdom

Southampton General Hospital

Tremona Road
Southampton
SO16 6YD
United Kingdom

University Hospital of Wales

Heath Park
Cardiff
CF14 4XN
United Kingdom

University College London Hospital

253 Euston Road
London
NW1 2BU
United Kingdom

Sponsor information

University of Birmingham
University/education

Edgbaston
Birmingham
B15 2TT
England
United Kingdom

"ROR"	https://ror.org/03angcq70

Funders

Funder type

Charity

Leukaemia and Lymphoma Research
Private sector organisation / Other non-profit organizations

Location: United Kingdom

Results and Publications

Intention to publish date	30/06/2019
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Other
Publication and dissemination plan	We intend to publish the results in a disease relevant peer reviewed journal. We will also endeavour to present the results at both national and international meeting. The expected publication date is late summer/Autumn 2018.
IPD sharing plan	The datasets generated during and/or analysed during the current study may be available upon request (contact details to be confirmed)

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/10/2019	13/08/2019	Yes	No
Protocol file	version 4.0	06/07/2016	14/10/2022	No	No
HRA research summary			28/06/2023	No	No

Additional files

ISRCTN10760016_PROTOCOL_V4.0_06Jul16.pdf

Editorial Notes

14/10/2022: Protocol uploaded (not peer reviewed).
16/01/2020: ClinicalTrials.gov number added.
13/08/2019: Publication reference added.
26/03/2019: The following changes were made:
1. The overall trial end date was changed from 31/07/2018 to 05/02/2019.
2. The intention to publish date was changed from 01/09/2018 to 30/06/2019.
3. The total final enrolment was added.
27/04/2017: The recruitment end date was changed from 31/01/2017 to 25/04/2017.
07/02/2017: The James Cook Hospital, Bradford Royal Infirmary, The Royal Hallamshire Hospital and Queen Elizabeth Hospital have been removed as trial participating centres and University Hospital of Wales has been added.
09/03/2016: The following trial participating centres have been added to the study record: Guy's Hospital, The James Cook Hospital, Aberdeen Royal Infirmary, Bradford Royal Infirmary, Norfolk and Norwich University Hospital, Southampton General Hospital, The Royal Hallamshire Hospital, Queen Elizabeth Hospital, University College London Hospital
09/03/2016: Cancer Help UK lay summary link added.
03/03/2016: The following trial participating centres have been removed from the study record: St Bartholomew's Hospital, Royal Free Hospital, Nottingham City Hospital, Freeman Hospital, Gartnavel Royal Hospital, University Hospital Southampton, University College London Hospital.