Clinical Trials Register

Summary
EudraCT Number:	2014-003588-39
Sponsor's Protocol Code Number:	RG_14-212
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-04-21
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2014-003588-39

A.3

Full title of the trial

Torch: 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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Torch: A study to determine the safety and efficacy of the drug AZD2014 and to investigate additional toxicities in combination with rituximab in relapsed or refractory Diffuse Large B-Cell Lymphoma

A.3.2

Name or abbreviated title of the trial where available

Torch

A.4.1

Sponsor's protocol code number

RG_14-212

A.5.4

Other Identifiers

Name:

CAS number

Number:

NH2003

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University of Birmingham
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	AZD2014
D.3.2	Product code	AZD2014
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	1009298-59
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10 to 50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Mabthera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Rituximab
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Rituximab
D.3.9.1	CAS number	174722-31-7
D.3.9.4	EV Substance Code	AS2
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	100 to 500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	genetically engineered chimeric murine/human monoclonal antibody

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

relasped or refractory Non-hodgkin lymphoma.

E.1.1.1

Medical condition in easily understood language

a cancerous condition that caused lymphocyte cells to form tumours. A type of non-hodgkin lymphoma.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10012821
E.1.2	Term	Diffuse large B-cell lymphoma recurrent
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10012822
E.1.2	Term	Diffuse large B-cell lymphoma refractory
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Collection of blood samples for molecular and free DNA analysis- intergrated into the trial protocol and consent form.
Objective - Correlation of response with pharmacodynamic biomarkers and potential predictive biomarkers of response

E.3

Principal 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.

E.4

Principal 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] <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
− Absolute neutrophil count <1.5 x 10 9/L (without GCSF/GMCSF support)
− Platelet count <75 x 10 9/L
− Haemoglobin <90 g/L (transfusions permissable)
− 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
− Total bilirubin >1.5 times ULN unless in the presence of Gilbert’s syndrome with an elevated indirect fraction
− 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 tahn 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 3y

E.5 End points

E.5.1

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.

E.5.1.1

Timepoint(s) of evaluation of this end point

within the first 24 weeks (6 cycles of treatment)

E.5.2

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

E.5.2.1

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.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of trial will be 6 months after the last data capture. This will allow sufficient time for the completion of protocol procedures, data collection and data input. The Trials Office will notify the MHRA and main REC that the trial has ended and will provide them with a summary of the clinical trial report within 12 months of the end of trial.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1