NOvel Immunotherapy Strategies for Advanced Triple Negative Breast Cancer (TNBC) Patients: TONIC-3 Trial (TONIC-3)

This is a single center, non-blinded, multi-cohort, non-comparative phase II trial to study the safety and efficacy of tiragolumab with atezolizumab and/or ipilimumab in advanced triple-negative breast cancer.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Tiragolumab; Drug: Atezolizumab; Drug: Ipilimumab

Detailed Description

Programmed cell death protein 1 (PD1) -blockade is currently being approved for the neoadjuvant treatment of early TNBC as well as for first-line treatment in combination with chemotherapy for patients with Programmed cell death-ligand 1 (PD-L1) -positive TNBC with metastatic disease. However, response rates are modest, responses are not always durable and PD-L1 is a suboptimal biomarker to select patients for this regimen. Therefore, the overarching goal of this TONIC-3 study is to develop novel immunomodulatory strategies for patients with advanced TNBC making use state-of-the-art research tools to better understand the underlying cancer-immune interactions of this disease

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Marleen Kok, MD; Phone Number: 9111 +3120512; Email: m.kok@nki.nl
• Study Contact Backup: Name: Manon de Graaf, MD; Phone Number: 9111 +3120512; Email: tonic@nki.nl

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1066CX
      • Recruiting
      • Antoni van Leeuwenhoek
      • Contact: Marleen Kok, MD; Phone Number: +31205129111; Email: m.kok@nki.nl
      • Contact: Manon de Graaf, MD; Email: tonic@nki.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Metastatic or incurable locally advanced triple negative breast cancer with confirmation of Estrogen receptor (ER) and Human Epidermal growth factor Receptor 2 (HER2) negativity (ER <10%, HER2 IHC 0, 1+ or 2+ with no amplification) on a histological biopsy of a metastatic lesion
• Patients with PD-L1 negative disease determined using the Combined Positivity Score (CPS<10) (Dako 22C3 IHC) 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
• 18 years or older
• World Health Organisation (WHO) performance status of 0 or 1
• Maximum of three lines of chemotherapy, including antibody-drug conjugates and Poly-ADP Ribose Polymerase (PARP)-inhibitors, for metastatic disease and with evidence of progression of disease
• Measurable or evaluable disease according to RECIST1.1
• 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.
• Adequate bone marrow, kidney and liver function

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 if these are free of progression for at least 4 weeks)
• 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 hypersensitivy 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.
• 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, hepatitis C, HIV and/or Epstein Barr virus (EBV)
• History of uncontrolled serious medical or psychiatric illness
• Current pregnancy pregnancy or breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tiragolumab and atezolizumab; Tiragolumab 600mg and atezolizumab 1200 mg, both every three weeks	Drug: Tiragolumab; 600mg every 3 weeks (Q3W); Drug: Atezolizumab; 1200mg every 3 weeks (Q3W); Other Names: Tecentriq
Experimental: Tiragolumab and ipilimumab; Tiragolumab 600mg every 3 weeks and ipilimumab 1mg/kg every 3 weeks for the first 4 cycles	Drug: Tiragolumab; 600mg every 3 weeks (Q3W); Drug: Ipilimumab; 1 mg/kg, maximum of 4 cycles; Other Names: Yervoy
Experimental: Tiragolumab, atezolizumab and ipilimumab; Tiragolumab 600mg and atezolizumab 1200mg both every 3 weeks, plus ipilimumab 1mg/kg every 3 weeks for the first 4 cycles	Drug: Tiragolumab; 600mg every 3 weeks (Q3W); Drug: Atezolizumab; 1200mg every 3 weeks (Q3W); Other Names: Tecentriq; Drug: Ipilimumab; 1 mg/kg, maximum of 4 cycles; Other Names: Yervoy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS-12	Progression-free survival rate as measured by the proportion of patients free of progression after 12-weeks of treatment	Assessed at 12 weeks
Incidence of adverse events	Number of patients with adverse events as measured according to CTCAE v5.0	Assessed until 90 days after the last dose of study treatment or until initiation of new anti-cancer therapy, whichever occurs first

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	Complete response or partial response according to Response Evaluation Criteria in Solid Tumours in cancer immunotherapy trials (iRECIST) and Response Evaluation Criteria in Solid Tumours (RECIST version 1.1)	Assessed at week 6, week 12 and every 12 weeks thereafter; assessed up to 120 months
Clinical benefit rate	Complete response, partial response or stable disease for at least 24 weeks according to iRECIST and RECIST1.1	Assessed at week 6, week 12 and every 12 weeks thereafter; assessed up to 120 months
Progression-free survival	Time from randomization to data of first tumor progression	Assessed at week 6, week 12 and every 12 weeks thereafter; median 12 months
Overall survival	Time from therapy initiation to death from any cause	Assessed monthly until date of death; median 12 months

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Collaborators: Hoffmann-La Roche
• Investigators: Principal Investigator: Marleen Kok, MD, Antoni van Leeuwenhoek

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2024
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2030

Study Registration Dates

• First Submitted: March 7, 2024
• First Submitted That Met QC Criteria: March 25, 2024
• First Posted (Actual): April 2, 2024

Study Record Updates

• Last Update Posted (Actual): June 14, 2024
• Last Update Submitted That Met QC Criteria: June 13, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Triple negative breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Ipilimumab; Atezolizumab
• Other Study ID Numbers: N22TON

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No