Combining Atezolizumab with Thiopurine Therapy for Advanced Solid Tumors

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

This study is testing if combining a cancer drug called Atezolizumab with thiopurine therapy can help people with advanced solid tumors feel better and improve their treatment outcomes.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 39 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Rigshospitalet, Denmark (other)
• Drugs / interventions: denosumab, Atezolizumab
• Locations: 1 site (Copenhagen)
• Trial ID: NCT05276284 on ClinicalTrials.gov

What this trial studies

The TEMPLE project is a single-center, prospective phase Ib and II trial aimed at evaluating the safety, tolerability, and efficacy of Atezolizumab in combination with thiopurine therapy (6-mercaptopurine and 6-thioguanine) in patients with advanced or metastatic solid tumors that have an intermediate tumor mutational burden. The study will first determine the maximum tolerated dose of the combination therapy in a phase Ib trial, followed by a phase II trial that will assess treatment efficacy based on data from the initial phase. The goal is to enhance the mutational burden and neoepitope presence, potentially improving patient responses to immune checkpoint inhibitors.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with advanced or metastatic solid tumors and an intermediate tumor mutational burden.

Not a fit: Patients with solid tumors that do not have an intermediate tumor mutational burden or those with curable disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly improve treatment responses in patients with advanced solid tumors who currently have limited options.

How similar studies have performed: While the combination of thiopurines with immune checkpoint inhibitors is innovative, preliminary studies have shown promise in enhancing treatment efficacy, suggesting potential for success.

Eligibility criteria

Inclusion Criteria:

The patient MUST MEET ALL the following criteria to be enrolled in the study:

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:

   1. Absolute lymphocyte count ≥ 0.5 x 109/L
   2. Neutrophils ≥ 1.5 x 109/L
   3. Platelets ≥ 100 x 109/L. For patients with primary hepatocellular carcinoma platelet counts ≥65 x 109/L is allowed.
   4. Hemoglobin ≥ 90 g/L (5.6 mmol/L) and at least 4 weeks since blood transfusion
   5. 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
   6. AST ≤ 3 x ULN without, and ≤ 5 x ULN with hepatic metastasis
   7. 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:

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. 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:

   1. Grade ≤ 2 alopecia, asthenia, dermatologic events.
   2. Grade ≤ 2 anemia if hemoglobin ≥ 90 g/L (5.6 mmol/L)
   3. 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.

Where this trial is running

Copenhagen

• University Hospital of Copenhagen, Rigshospitalet — Copenhagen, Denmark (RECRUITING)

Study contacts

• Principal investigator: Kristoffer S Rohrberg, MD PhD — MD, Phd, Consultant, Head of Phase 1 Unit, Department of Oncology, Rigshospitalet
• Study coordinator: Kristoffer S Rohrberg, MD, PhD

Conditions: Solid Tumor, Adult, Metastatic Cancer