Phase II Basket Trial of Atezolizumab and Tiragolumab in Patients with Solid Tumors, Including HNSCC, dMMR/MSI-H Tumors, and Metastatic Melanoma
- Trial ID
- 2024-512616-21-00
Trial statistics
Objectives
The primary objective of this study is to determine the **pathological response rate (pTR)** in patients with localized head and neck squamous cell carcinoma (HNSCC) in cohort 1. Additionally, the study aims to evaluate the response rates in patients with advanced or metastatic deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) cancer, PD-1 resistant metastatic melanoma, and locally advanced or metastatic solid tumors in cohorts 2, 3, and 4. These objectives are clinically relevant as they assess the efficacy of atezolizumab and tiragolumab in diverse cancer types, potentially guiding therapeutic decisions and improving patient outcomes.
Secondary objectives include:
- Determining the safety of atezolizumab and tiragolumab in patients with localized HNSCC, advanced or metastatic dMMR/MSI cancer, anti-PD-1 resistant metastatic melanoma, and other solid tumors.
- Assessing disease-free survival (DFS) in patients with localized HNSCC, with events defined as local recurrence, regional recurrence, distant metastases, and death from any cause.
- Evaluating objective response rate (ORR), progression-free survival (PFS), and duration of objective response (DOR) according to (i)RECIST in cohorts 2, 3, and 4.
- Correlating circulating tumor DNA (ctDNA), TIGIT, PD-1, PD-L1, and CD8 IHC expression in tumor tissue with pathological response in cohort 1, and RECIST1.1 and iRECIST in cohorts 2, 3, and 4.
- Correlating the presence and kinetics of ctDNA in blood with pathological response in cohort 1, and RECIST1.1 and iRECIST in cohorts 2, 3, and 4.
Participants
The clinical trial involves a study population comprising both **male** and **female** participants, with an age range starting from 18 years and above. The trial does not include a vulnerable population. Participants are required to have a life expectancy of at least 12 weeks and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are in relatively good health. The study targets individuals with specific medical conditions, including head and neck squamous cell carcinoma (HNSCC), metastatic deficient mismatch repair (dMMR)/MSI-high (MSI-H) tumors, irresectable or metastatic melanoma, and locally advanced or metastatic solid tumors. The selection criteria emphasize the ability to safely obtain a histological biopsy and the presence of measurable disease as defined by RECIST v1.1. Participants must have adequate organ and bone marrow function, and those of childbearing potential must agree to use highly effective contraception. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as an open-label, phase II basket trial to evaluate the efficacy and safety of **atezolizumab** and **tiragolumab** in patients with various advanced or metastatic solid tumors, including head and neck squamous cell carcinoma (HNSCC), metastatic deficient mismatch repair (dMMR)/MSI-high (MSI-H) tumors, irresectable or metastatic melanoma, and other locally advanced or metastatic solid tumors. The trial employs a non-randomized, controlled methodology, with the primary objective of determining the pathological response rate (pTR) in patients with localized HNSCC and the overall response rate (ORR) in patients with advanced or metastatic dMMR/MSI cancer, PD-1 resistant metastatic melanoma, and other solid tumors. The trial is expected to last until October 2026, with recruitment starting in October 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as measurable disease, adequate organ function, and ECOG performance status of 0-1. Following successful screening, participants will receive treatment with the investigational drugs via **intravenous use**. Follow-up visits will be scheduled to monitor safety, assess adverse events, and evaluate treatment efficacy through imaging and laboratory tests. The end-of-study visit will conclude the participant's involvement, with assessments to determine the final treatment outcomes.
The expected duration of participant involvement is up to 24 months, corresponding to the maximum treatment period for the investigational drugs. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous safety assessments, including the incidence and severity of adverse events, changes in laboratory results, and vital signs, ensuring participant safety throughout the study duration.
Treatment
The clinical trial involves the administration of **Tiragolumab**, a **concentrate for solution for infusion**. Tiragolumab is a human monoclonal antibody (mAb) that targets TIGIT, a protein involved in immune regulation. The pharmaceutical form is a concentrate that is prepared for intravenous use. The maximum daily dose is 600 mg, with a total dose not exceeding 600 mg over a treatment period of up to 24 weeks. The administration is conducted intravenously, and the dosing schedule is determined by the study protocol. Participant compliance is monitored through regular assessments and documentation of infusion sessions.
In addition to Tiragolumab, the trial includes the administration of **Tecentriq** (Atezolizumab), which is also a **concentrate for solution for infusion**. Atezolizumab is a monoclonal antibody that inhibits PD-L1, a protein that plays a role in suppressing the immune system. The maximum daily dose for Tecentriq is 1200 mg, with a total dose not exceeding 1200 mg over a 24-week treatment period. The route of administration is intravenous, and the solution is prepared according to the manufacturer's instructions. Compliance with the dosing regimen is ensured through scheduled visits and infusion records.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial. The focus is on evaluating the efficacy and safety of the combination of Tiragolumab and Tecentriq in patients with specific types of solid tumors. The trial is designed to assess the pathological response rate and other clinical outcomes in the targeted patient cohorts.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **pathologic response rate (pTR)** of the primary tumor in patients with head and neck squamous cell carcinoma (HNSCC) and the overall response rate (ORR) according to (i)RECIST 1.1 in patients with advanced or metastatic dMMR/MSI cancer, metastatic melanoma, and other locally advanced or metastatic solid tumors. These assessments will help determine the effectiveness of the treatment regimen involving Atezolizumab and Tiragolumab.
Secondary endpoints will focus on safety assessments, including the incidence, nature, and severity of adverse events graded according to NCI CTCAE 5.0, as well as changes in laboratory test results, vital signs, and physical findings. Additionally, disease-free survival (DFS) in patients with HNSCC will be evaluated, defined as the time from surgery to local, regional, or distant disease recurrence or death. The trial will also assess ORR, progression-free survival (PFS), and duration of response (DOR) according to (i)RECIST, as evaluated by the investigator for specific cohorts. Furthermore, the correlation between TIGIT, PD-1, PD-L1, and CD8 IHC expression on tumor tissue and inflammatory infiltrate with radiographic imaging will be analyzed in certain cohorts.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Tumor lesion(s) of which a histological biopsy can be safely obtained according to standard clinical care procedures.
- Measurable disease, as defined by RECIST v1.1. Previously irradiated lesions should be discarded as target lesions.
- Participate in the GE-269-001 CD8 investigational imaging trial provided that there are slots is that trial.
- Signed informed consent.
- Age ≥18 at the time of signing informed consent.
- Life expectancy ≥12 weeks.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Adequate organ and bone marrow function as defined below: o Hemoglobin ≥9.0 g/dL. o Platelet count ≥100 x 109 /L. o Serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated glomerular filtration rate > 30 mL/min/1.73 m2 . A 24-hour urine creatinine collection may substitute for the calculated creatinine clearance to meet eligibility criteria. o Adequate hepatic function: ▪ Total bilirubin ≤1.5 x ULN (≤3 x ULN if liver tumor involvement); Patients with Gilbert’s syndrome do not need to meet total bilirubin requirements, provided their total bilirubin is unchanged from their baseline. Gilbert’s syndrome must be documented appropriately as past medical history. ▪ Aspartate aminotransferase (AST) ≤2.5 x ULN (≤5 x ULN if liver tumor involvement) ▪ Alanine aminotransferase (ALT) ≤2.5 x ULN (≤5 x ULN if liver tumor involvement) ▪ Alkaline phosphatase (ALP) ≤2.5 x ULN (≤5 x ULN if liver or bone tumor involvement)
- Ability to comply with the protocol.
- For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by the patient and/or partner) to use a highly effective form(s) of contraception (i.e., one that results in a low failure rate (1% per year) when used consistently and correctly.
- For the head and neck squamous cell carcinoma cohort specific eligibility criteria apply • clinical T2-4a, or node positive resectable HPV-unrelated HNSCC (oral cavity, larynx, hypopharynx, p16-negative oropharynx or p16 negative unknown primary) • no evidence of distant metastases. • no previous radiotherapy to the head and neck region.
Exclusion Criteria
- Signs or symptoms of infection within 2 weeks prior to atezolizumab and tiragolumab administration.
- Prior immune checkpoint inhibitor treatment, including but not limited to anti-PD1 and anti- PD-L1 antibodies (only for cohort 1, 2 and 4).
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use atezolizumab and tiragolumab, or that may affect the interpretation of the results or render the patient at high risk from complications.
- Pregnant or lactating women.
- Positive test for HIV, active hepatitis B (chronic or acute defined by positive hepatitis B surface antigen (HBsAg) during screening) or hepatitis C. Patients with a medical history of hepatitis B infection (defined as a positive hepatitis B core antibody (HBcAb) and absence of an HBsAg) are eligible for this study. Patients who test positive for hepatitis C antibodies are only eligible with a negative hepatitis C RNA PCR.
- Acute or chronic active EBV infection at screening EBV status should be assessed by EBV serology (e.g., anti-VCA IgM and IgG, anti-EA IgG, anti-EBNA IgG) and EBV PCR (plasma or serum). If EBV serology results indicate prior EBV infection, patients must have a negative EBV PCR (plasma or serum) to be eligible for the study.
- Active tuberculosis.
- Treatment with systemic immunostimulatory agents (including but not limited to IFNs, IL- 2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to the first full dose of atezolizumab and tiragolumab.
- Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to cycle 1, day 1, with the exception of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for subjects with orthostatic hypotension, low-dose supplemental corticosteroids for adrenocortical insufficiency and topical steroids are allowed.
- medications (e.g., a one-time dose of dexamethasone for nausea) may be allowed in the study after discussion with and approval by the principal investigator (PI).
- Brain metastases, leptomeningeal metastases.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Not Recruiting | 31 Oct 2023 | — |
| Netherlands | — | — | 97 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Tiragolumab | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 600 | 24 | PRD3933958 |
Tecentriq 1 200 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INJECTION | 1200 | 24 | PRD5434939 |