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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rigshospitalet

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Sep 2022 → 20 Dec 2024

Decision date (initial)

2024-11-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Børnecancer fonden · Neye Fonden · Roche

External identifiers

EU CT number

2024-517307-37-00

EudraCT number

2021-005327-20

ClinicalTrials.gov

NCT05276284

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

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

Secondary objectives 2

1. To evaluate the efficacy and anti-tumor activity in patients treated with Atezolizumab given in combination with 6TG and 6MP
2. To explore potential predictive and pharmacodynamic biomarkers that may be relevant to the mechanism of action, response to or resistance to Atezolizumab in combination with 6TG and 6MP

Conditions and MedDRA coding

Oncology

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

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

Exclusion criteria 12

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. 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 × 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase Ib: To characterize safety, tolerability, maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of Atezolizumab given in combination with 6TG and 6MP
2. Phase II: To evaluate the anti-tumor activity in terms of objective response rate in patients treated with Atezolizumab, 6TG and 6MP

Secondary endpoints 9

1. To evaluate the efficacy with respect to Progression Free Survival, Overall Survival, and Duration of Response
2. Characterization of immune cells in tumor and peripheral blood prior to, during treatment and upon progression
3. Characterization of the tumor mutational and neoantigen landscape prior to, during treatment, and upon progression using WGS and RNAseq on serial biopsies
4. Characterization of the tumor mutation and neoantigen landscape in circulating tumor cells (ctDNA) prior to, during treatment, and upon progression
5. HLA typing determined by germline WGS as predictor of efficacy
6. Tumor gene expression determined by RNAseq signatures as predictor of efficacy
7. Sequential shallow whole exome ctDNA sequencing to monitor effect
8. Gene variants in PD-1 and CTLA-4 as predictors of response to treatment
9. Correlations between plasma DNA-TG levels and anti-tumor-activity

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rigshospitalet

Sponsor organisation

Rigshospitalet

Address

Blegdamsvej 9

City

Copenhagen Oe

Postcode

2100

Country

Denmark

Scientific contact point

Organisation

Rigshospitalet

Contact name

Kristoffer Staal Rohrberg

Public contact point

Organisation

Rigshospitalet

Contact name

Kristoffer Staal Rohrberg

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications