Clinical Trials Register

Summary
EudraCT Number:	2021-005327-20
Sponsor's Protocol Code Number:	TEMPLE02
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-12-14
Trial 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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2021-005327-20

A.3

Full title of the trial

TEMPLE - Thiopurine Enhanced Mutations for PD-1/Ligand-1 Efficacy

A.3.1

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

TEMPLE - A phase Ib/II study to determine the safety, tolerability and
efficacy of Atezolizumab given in combination with thiopurine therapy in
patients with advanced and/or metastatic solid tumors

A.3.2

Name or abbreviated title of the trial where available

TEMPLE

A.4.1

Sponsor's protocol code number

TEMPLE02

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	Rigshospitalet
B.1.3.4	Country	Denmark
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	Børnecancerfonden
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Roche A/S
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Rigshospitalet
B.5.2	Functional name of contact point	Kristoffer Staal Rohrberg
B.5.3	Address:
B.5.3.1	Street Address	Blegdamsvej 9
B.5.3.2	Town/ city	Copenhagen
B.5.3.3	Post code	2100
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4535456353
B.5.6	E-mail	kristoffer.staal.rohrberg@regionh.dk

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	Yes
D.2.1.1.1	Trade name	Tecentriq
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
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.3.4	Pharmaceutical form	Concentrate and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Infusion (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Atezolizumab
D.3.9.3	Other descriptive name	Tecentriq
D.3.9.4	EV Substance Code	SUB178312
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	1200
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)	Yes
	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)	Yes
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	Mercaptopurine
D.2.1.1.2	Name of the Marketing Authorisation holder	Aspen Pharma Trading Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Mercaptopurine
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.3.8	INN - Proposed INN	Mercaptopurine
D.3.9.1	CAS number	50-44-2
D.3.9.4	EV Substance Code	SUB12149MIG
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	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: 3
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	Tioguanine
D.2.1.1.2	Name of the Marketing Authorisation holder	Aspen Pharma Trading Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Tioguanine
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.3.8	INN - Proposed INN	TIOGUANINE
D.3.9.1	CAS number	154-42-7
D.3.9.4	EV Substance Code	SUB11084MIG
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	40
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.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Metastatic or advanced solid tumors with an intermediate tumor mutational burden

E.1.1.1

Medical condition in easily understood language

Incurable solid cancers forms where the tumor is not hypermutated

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10065147
E.1.2	Term	Malignant solid tumor
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase Ib: To characterize safety and tolerability of Atezolizumab given in combination with 6-thioguanine and 6-mercaptopurine
Phase II: To evaluate the anti-tumor activity in terms of objective response in patients treated with Atezolizumab, 6-thioguanine and 6- mercaptopurine

E.2.2

Secondary objectives of the trial

To evaluate the efficacy and anti-tumor activity in patients treated with Atezolizumab given in combination with 6-thioguanine and 6-mercaptopurine

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed written informed consent.
2. Age ≥ 18 years.
3. Performance status (WHO) of 0-1.
4. Histologically confirmed advanced and/or metastatic solid tumors for which standard curative measures do not exist.
5. Radiologically measurable disease according to RECIST v1.1.
6. Life expectancy estimated by the Investigator to be ≥12 weeks.
7. Metastatic Lesion(s) or primary tumour accessible for biopsy
8. Intermediate tumor mutational burden of 5-10 mutations/mb
9. Adequate organ function assessed by screening laboratory values:
a. Absolute lymphocyte count ≥ 0.5 x 109/L
b. Neutrophils ≥ 1.5 x 109/L
c. Platelets ≥ 100 x 109/L. For patients with primary hepatocellular carcinoma platelet counts ≥65 x 109/L is allowed.
d. Hemoglobin ≥ 90 g/L (5.6 mmol/L) and at least 4 weeks since blood transfusion
e. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or calculated by Cockroft-Gault formula or directly measured creatinine clearance ≥ 50 mL/min at screening
f. AST ≤ 3 x ULN without, and ≤ 5 x ULN with hepatic metastasis
g. Bilirubin ≤ 1.5 x ULN (except patients with Gilbert’s syndrome, who must have total bilirubin < 3.0 mg/dL)
10. Ability to take oral medications.
11. Woman of childbearing potential must have been tested negative in a serum pregnancy test within 5 days prior to study drug initiation.
12. Male and female patients who have the potential to reproduce must agree to use a highly effective method of birth control (i.e., pregnancy rate of less than 1 % per year) during the study and for 5 months after the discontinuation of study medication. Women must refrain from donating eggs and men must refrain from donating sperm during this same period.

E.4

Principal exclusion criteria

Any of the following :
1. Pregnancy, lactation, or breastfeeding.
2. History or clinical evidence of central nervous system (CNS) primary tumors or metastases including leptomeningeal metastases, unless they have been previously treated, are asymptomatic, and have had no requirement for steroids or anticonvulsants in the last 14 days prior to Screening.
3. Known deficiency in thiopurine methyltransferase (TPMT) or NUDT15
4. Use, or have used, any concomitant anti-cancer medications within the previous 30 days or 5 half-lives of the medication (whichever is shortest) prior to first dose (bisphosphonates, denosumab and androgen deprivation therapies such as LHRH (GnRH) agonists are allowed if patient is on stable treatment for at least 4 weeks prior to first dose). Limited field radiotherapy for palliative purpose is allowed at any time.
5. Participants with immune-related adverse events attributed to prior immunomodulatory therapy must have resolved to Grade ≤ 1 (according to NCI CTCAE v 5.0) or baseline other than adverse events that are clinically non-significant and/or stable on supportive therapy, and are not expected to interfere with treatment in the study such as:
a. Grade ≤ 2 alopecia, asthenia, dermatologic events.
b. Grade ≤ 2 anemia if hemoglobin  90 g/L (5.6 mmol/L)
c. Grade 2 (> 1.5-2.0 x ULN) asymptomatic amylase and/or lipase elevation with no abdominal pain and no characteristic CT findings. However, weekly monitoring of amylase and lipase is required in this case.
6. Be an organ transplant recipient.
7. Have a history of prior other malignancy (with the exception of localized prostate cancer, adequately treated basal skin cancer or carcinoma in-situ of the cervix) within 2 years prior to first dose.
8. Have a severe autoimmune disorder requiring treatment during the last 12 months prior to first dose. Diabetes on stable anti-diabetic medication, hypothyroidism and adrenocortical deficiency on stable substitution therapy are allowed.
9. Be on chronic therapy with systemic immunosuppressant medication (inhaled, intra articular and low dose systemic corticosteroids, e.g. 7.5 mg or less prednisolone per day is allowed, provided that treatment has been unchanged for at least 4 weeks prior to first dose of IMP).
10. Known HIV, active hepatitis B or hepatitis C infection.
11. Participants with a history of severe allergic anaphylactic reactions to chimeric or humanized antibodies or known hypersensitivity to Chinese hamster ovary cell products or to any component of the Atezolizumab formulation
12. Any condition that, in the opinion of the Investigator, would place the patient at increased risk or preclude the patient’s compliance with the study.

E.5 End points

E.5.1

Primary end point(s)

Phase 1:
- Dose-limiting Toxicity according to CTCAE v5.0
- Maximum tolerated dose and/or recommended phase 2 dose
Phase 2
- Objective response rate according to RECIST criteria version 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase 1: Dose-limiting-toxicity evaluation period of 4 weeks
Phase 2: Patients will be evaluated with relevant imaging every 9th
week. (cycle 3,6,9 an subsequent every third cycle)

E.5.2

Secondary end point(s)

- Progression Free Survival
- Overall Survival
- Duration of Response

E.5.2.1

Timepoint(s) of evaluation of this end point

Patients will be followed up for overall survival by yearly check of medical records until death or loss to follow up, up to two years after the end of this study.

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

Yes

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

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

First test of combinational treatment with Atezolizumab, 6- mercaptopurine and 6-thioguanine

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

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

LVLS.
Patients will be followed up for overall survival by yearly check of medical records until death or loss to follow up, up to two years after the end of this study.

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-01-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-02-08

P. End of Trial
P.	End of Trial Status	Trial now transitioned

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials