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

NCT05276284 | Completed Phase 1 DMC

• 1 other identifier: TEMPLE01
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

The TEMPLE study is a single-center prospective phase Ib and II trial to determine the safety, tolerability and efficacy of Atezolizumab given in combination with thiopurine therapy (6-mercaptopurine and 6-thioguanine) in patients with advanced and/or metastatic solid tumors with an intermediate tumor mutational burden. Maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) will be determined in a single armed, open label phase Ib trial with a fixed dose of Atezolizumab in combination with thiopurine therapy with a dose-limiting toxicity (DLT) period of 4 weeks. A total of 27-39 patients will be enrolled in the TEMPLE study. Phase Ib will enroll 3-18 patients depending on the number of DLTs and need for dose de-escalation. Data from patients treated in the phase Ib study at RP2D will be included when assessing endpoints in the phase II part of the study. Phase II will enroll a total of 27 patients (including 3-6 patients treated at RP2D in the phase I part of the trial) in a Simon's 2 stage design (13 in stage 1 and 14 in stage 2).

Conditions

Solid Tumor, Adult; Metastatic Cancer

Outcome Measures

Primary Outcomes (3)

• Adverse events

  Type and number of adverse events

  3-6 months

• Dose limiting toxicities

  Dose limiting toxicities (DLTs) and the MTD for determination of RP2D of Atezolizumab, 6TG and 6MP

  28 days

• Best overall response

  Complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), unconfirmed (iUPD) and confirmed PD (iCPD), assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1

  One year

Secondary Outcomes (3)

• Progression Free Survival

  Two years

• Overall Survival

  Two years

• Duration of response

  Two years

Study Arms (1)

TEMPLE

EXPERIMENTAL

Study drugs: Atezolizumab, 6-mercaptopurine and 6-thioguanine

Combination Product: Atezolizumab, 6-mercaptopurine, 6-thioguanine

Interventions

Atezolizumab, 6-mercaptopurine, 6-thioguanine COMBINATION_PRODUCT

Combination therapy with Atezolizumab, 6-mercaptopurine and 6-thioguanine

TEMPLE

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The patient MUST MEET ALL the following criteria to be enrolled in the study:
• Signed written informed consent.
• Age ≥ 18 years.
• Performance status (WHO) of 0-1.
• Histologically confirmed advanced and/or metastatic solid tumors for which standard curative measures do not exist.
• Radiologically measurable disease according to RECIST v1.1.
• Life expectancy estimated by the Investigator to be ≥12 weeks.
• Metastatic Lesion(s) or primary tumour accessible for biopsy
• Intermediate tumor mutational burden of 5-10 mutations/mb
• Adequate organ function assessed by screening laboratory values:
• Absolute lymphocyte count ≥ 0.5 x 109/L
• Neutrophils ≥ 1.5 x 109/L
• Platelets ≥ 100 x 109/L. For patients with primary hepatocellular carcinoma platelet counts ≥65 x 109/L is allowed.
• Hemoglobin ≥ 90 g/L (5.6 mmol/L) and at least 4 weeks since blood transfusion
• 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

You may not qualify if:

• Any of the following :
• Pregnancy, lactation, or breastfeeding.
• 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.
• Deficiency in thiopurine methyltransferase (TPMT) or NUDT15.
• 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.
• 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:
• Grade ≤ 2 alopecia, asthenia, dermatologic events.
• Grade ≤ 2 anemia if hemoglobin ≥ 90 g/L (5.6 mmol/L)
• 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.
• Be an organ transplant recipient.
• 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.
• 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.
• 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).
• Known HIV, active hepatitis B or hepatitis C infection.
• 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

Sponsors & Collaborators

• Kristoffer Rohrberg: lead

Study Sites (1)

University Hospital of Copenhagen, Rigshospitalet

Copenhagen, 2100, Denmark

Location

Related Publications (1)

• Nazerai L, Willis SC, Yankilevich P, Di Leo L, Bosisio FM, Frias A, Bertolotto C, Nersting J, Thastrup M, Buus S, Thomsen AR, Nielsen M, Rohrberg KS, Schmiegelow K, De Zio D. Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade. Oncoimmunology. 2022 Dec 17;12(1):2158610. doi: 10.1080/2162402X.2022.2158610. eCollection 2023.

  PMID: 36545256 DERIVED

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

atezolizumab; Mercaptopurine; Thioguanine

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfhydryl Compounds; Sulfur Compounds; Organic Chemicals; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Kristoffer S Rohrberg, MD PhD

  MD, Phd, Consultant, Head of Phase 1 Unit, Department of Oncology, Rigshospitalet

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor- investigator

Model Details: The TEMPLE study is a single-center prospective phase Ib and II trial to determine the safety, tolerability and efficacy of Atezolizumab given in combination with thiopurine therapy in patients with advanced and/or metastatic solid tumors with an intermediate tumor mutational burden.

Study Record Dates

• First Submitted: February 4, 2022
• First Posted: March 11, 2022
• Study Start: September 1, 2022
• Primary Completion: December 31, 2024
• Study Completion: September 1, 2025
• Last Updated: January 14, 2026

Record last verified: 2026-01

Locations

DK (1)