Evaluation of Atezolizumab, Tiragolumab, and Ipilimumab in Advanced Triple Negative Breast Cancer: TONIC-3 Trial
- Trial ID
- 2023-507875-23-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the TONIC-3 trial is to determine the **efficacy** and safety of novel immunomodulatory strategies in patients with advanced **Triple Negative Breast Cancer (TNBC)**. This is clinically relevant as TNBC is an aggressive subtype of breast cancer with limited treatment options, and novel strategies could potentially improve patient outcomes.
Secondary objectives include:
- Evaluating the efficacy of novel immunotherapy combinations.
- Exploring the utility of the patient-derived tumor-fragment (PDTF) platform as an ex vivo platform for response prediction.
- Assessing the feasibility of generating TNBC molecular subtype data before the start of treatment.
- Testing novel treatment strategies in well-defined subgroups of TNBC patients based on clinical features or biomarkers.
- Gaining insight into the composition and cell state of the tumor microenvironment (TME) of advanced TNBC and assessing treatment-induced changes.
- Exploring biomarkers to predict response to specific treatment approaches.
Participants
The clinical trial involves participants diagnosed with **advanced triple-negative breast cancer** (TNBC), specifically those with unresectable recurrent or metastatic disease. The study population includes both male and female subjects aged 18 years and older, with a **World Health Organization (WHO) performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants were selected based on specific inclusion criteria, such as having metastatic or incurable locally advanced TNBC with confirmed estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) negativity, and a maximum of three lines of chemotherapy for metastatic disease. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. Key laboratory values, such as bilirubin, alkaline phosphatase, and transaminases, are considered for eligibility, ensuring participants have adequate organ function. The trial aims to evaluate the efficacy and safety of novel immunomodulatory strategies in this patient population.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of novel immunomodulatory strategies in patients with advanced **triple-negative breast cancer** (TNBC). This is a phase II, randomized, double-blind, controlled trial. The trial will involve the administration of three investigational products: **atezolizumab**, **tiragolumab**, and **ipilimumab**, all delivered via intravenous infusion. The trial is expected to commence recruitment on February 1, 2024, and conclude by February 1, 2026, with a maximum treatment period of 24 months for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as histological confirmation of ER and HER2 negativity and a WHO performance status of 0 or 1. Following the screening, participants will be randomized to receive the investigational products. Regular follow-up visits will be scheduled to monitor progression-free survival, adverse events, and other secondary endpoints, such as objective response rate and overall survival. Mandatory biopsies will be conducted at baseline and after one cycle of treatment, with optional biopsies at 12 weeks and at progression.
The expected length of participant involvement is up to 24 months, contingent upon disease progression and tolerability of the treatment. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any clinical judgment indicating that continued participation is not in the best interest of the participant. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, during which final assessments will be conducted to evaluate the primary and secondary endpoints.
Treatment
The clinical trial involves the administration of **Tecentriq**, a concentrate for solution for infusion, containing the active substance **atezolizumab**. This medication is provided in a pharmaceutical form suitable for intravenous infusion. The maximum daily dose is 1200 mg, with a total dose not exceeding 1200 mg over a treatment period of up to 24 weeks. The administration is conducted via intravenous infusion, and the product is manufactured by Roche Registration GmbH. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
Another experimental medication used in the trial is **Tiragolumab**, also a concentrate for solution for infusion. The active substance, **tiragolumab**, is administered intravenously. The maximum daily and total dose is 600 mg, with a treatment duration of up to 24 weeks. This product is developed by F. Hoffmann-La Roche Ltd. The administration schedule is strictly followed, and participant compliance is closely monitored to maintain the integrity of the trial data.
The trial also includes the administration of **YERVOY**, a concentrate for solution for infusion, containing the active substance **ipilimumab**. This medication is administered intravenously, with a dosing regimen of 1 mg/kg. The treatment period extends up to 24 weeks. YERVOY is produced by Bristol-Myers Squibb Pharma EEIG. The trial protocol includes measures to ensure accurate dosing and participant adherence to the treatment schedule.
Efficacy
The efficacy of the clinical trial titled "NOvel Immunotherapy strategies for advanced Triple negative breast Cancer (TNBC) patients: TONIC-3 trial" will be assessed using several primary and secondary endpoints. The primary endpoints include the **progression-free survival** (PFS) rate, which is measured by the proportion of patients free of progression after 12 weeks of treatment. This is determined from the time of administration of the first treatment to tumor progression or death from any cause, according to RECIST 1.1 criteria. Additionally, adverse events will be measured according to CTCAE v5.0 and immune-related toxicity.
Secondary endpoints will include the objective response rate (ORR), which encompasses complete and partial responses as measured by iRECIST and RECIST 1.1. The clinical benefit rate (CBR) will also be evaluated according to iRECIST and RECIST 1.1. Further, PFS will be measured by time to event, and overall survival (OS) will be assessed as the time from therapy initiation to death from any cause. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration, which is estimated to conclude by February 2026.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Metastatic or incurable locally advanced triple negative breast cancer with confirmation of ER and HER2 negativity (ER <10% and HER2 IHC 0, 1+ or 2+ in the absence of amplification as determined by in situ hybridization, independent of progesterone receptor expression) on a histological biopsy of a metastatic lesion
- Patients with PD-L1 negative disease determined using the Combined Positivity Score (CPS<10) (Dako 22C3 immunohistochemistry) OR previously treated with anti-PD(L)1 in the (neo)adjuvant or metastatic setting (irrespective of PD-L1 status)
- Metastatic lesion accessible for histological biopsy (Mandatory biopsies: baseline, after 1 cycle of treatment. Optional biopsies: 12-weeks, at progression).
- 18 years or older
- WHO performance status of 0 or 1
- Maximum of three lines of chemotherapy (including antibody-drug conjugates and PARP-inhibitors) for metastatic disease and with evidence of progression of disease.
- Measurable or evaluable disease according to RECIST 1.1
- Disease Free Interval (defined as time between first diagnosis or locoregional recurrence and first metastasis) longer than 1 year. This does not apply to patients with de novo metastatic disease or patients who did not receive (neo)adjuvant chemotherapy.
- WBC ≥ 2.0x109/L, ANC ≥ 1.5 x 109/L(without G-CSF use in last 4 weeks), platelets ≥100 x 109/L, Hemoglobin ≥ 5.0 mmol/L
- Bilirubin < 1.5 x upper limit of the normal range (ULN)(except for participants with Gilbert Syndrome <3x ULN); alkaline phosphatase < 2.5 x ULN (< 5 x ULN in case of liver metastases, and < 7 x ULN N22TON, version 1.0 dd 21 July 2023 10 in case of bone metastases); transaminases (ASAT/ALAT) < 3 x ULN (and < 5 x ULN in case of liver metastases), LDH < 2xULN
- Calculated (Cockcroft-Gault) or measured creatinine clearance > 40 mL/min
- Signed informed consent
Exclusion Criteria
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris
- Symptomatic brain metastases, subjects with asymptomatic brain metastases are eligible. Subjects who received prior treatment for brain metastases should be free of progression on magnetic resonance imaging (MRI) for at least 4 weeks after treatment is completed and prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
- History of leptomeningeal disease localization
- History of having received other anticancer therapies within 2 weeks of start of the study drug
- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
- Known hypersensititivy to Chinese hamster ovary cell products or to any component of the atezolizumab or tiragolumab formulation
- History of immunodeficiency, autoimmune disease, conditions requiring immunosuppression (>10 mg daily prednisone equivalents) or chronic infections. Subjects with vitiligo, diabetes mellitus type I, psoriasis not requiring systemic treatment or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement, Sjøgren’s syndrome or conditions not expected to recur in the absence of an external trigger will not be excluded from the study. Adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
- Prior treatment with an anti-CTLA4 or anti-TIGIT antibody
- Administration of live vaccine within 30 days of planned start of study therapy.
- Active other cancer
- Positive test for hepatitis B surface virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Specified by: positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening accompanied by either of the following: negative total hepatitis B core antibody (HBcAb), positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA < 500 IU/mL. The HBV DNA test will be performed only for patients who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb test. Specific for hepatitis C screening: positive HCV antibody test followed by a negative HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test
- Sign of active TB
- Positive HIV test at screening
- Positive EBV viral capsid antigen immunoglobulin M (IgM) test at screening
- History of uncontrolled serious medical or psychiatric illness
- Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
- Current pregnancy pregnancy or breastfeeding. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception: Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 90 days after the final dose of tiragolumab, 5 months after the final dose of atezolizumab. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a woman with a tubal ligation is considered to be of childbearing potential. (The definition of childbearing potential may be adapted for alignment with local guidelines or regulations). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With a female partner of childbearing potential, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period, for 90 days after the final dose of tiragolumab. Men must refrain from donating sperm during this same period. With a pregnant female partner, men must remain abstinent or use a condom during the treatment period for 90 days after the final dose of tiragolumab to avoid exposing the embryo. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Recruiting | 01 Feb 2024 | — |
| Netherlands | — | — | 60 |
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 |
|---|---|---|---|---|---|---|
Tecentriq 1 200 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1200 | 24 | PRD5434939 |
Tiragolumab | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 600 | 24 | PRD7846761 |
YERVOY 5 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1 | 24 | PRD2341715 |