Nivolumab After Induction Treatment in Triple-negative Breast Cancer (TNBC) Patients (TONIC)
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ClinicalTrials.gov Identifier: NCT02499367 |
Recruitment Status :
Active, not recruiting
First Posted : July 16, 2015
Last Update Posted : March 22, 2022
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This is a single center non-blinded randomized non-comparative phase II trial. The first stage of the trial consists of five arms ( with induction treatment followed by nivolumab, 1 with no induction treatment before nivolumab).
For the second stage, the number of arms will be reduced based on the results obtained in the first stage.
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Breast Cancer | Drug: Nivolumab Radiation: Radiation therapy Drug: Low dose doxorubicin Drug: Cyclophosphamide Drug: Cisplatin | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 84 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | Adaptive Phase II Randomized Non-comparative Trial of Nivolumab After Induction Treatment in Triple-negative Breast Cancer (TNBC) Patients: TONIC-trial |
Study Start Date : | August 2015 |
Estimated Primary Completion Date : | December 2023 |
Estimated Study Completion Date : | August 2025 |

Arm | Intervention/treatment |
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Active Comparator: Radiation therapy
Radiotherapy on metastatic lesion
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Drug: Nivolumab
nivolumab 3 mg/kg, every 2 weeks after induction treatment Radiation: Radiation therapy 20 Gy to metastatic lesion |
Active Comparator: Low dose doxorubicin
15mg flat dose, once weekly for 2 weeks
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Drug: Nivolumab
nivolumab 3 mg/kg, every 2 weeks after induction treatment Drug: Low dose doxorubicin 15 mg flat dose, once weekly for 2 weeks |
Active Comparator: Cyclophosphamide
metronomic schedule, 50mg daily orally for 2 weeks
|
Drug: Nivolumab
nivolumab 3 mg/kg, every 2 weeks after induction treatment Drug: Cyclophosphamide metronomic schedule, 50 mg daily orally for 2 weeks |
Active Comparator: Cisplatin
40mg/m2, weekly for 2 weeks
|
Drug: Nivolumab
nivolumab 3 mg/kg, every 2 weeks after induction treatment Drug: Cisplatin 40 mg/m2, weekly for 2 weeks |
Active Comparator: No induction treatment |
Drug: Nivolumab
nivolumab 3 mg/kg, every 2 weeks after induction treatment |
- Progression free survival [ Time Frame: assessed monthly until progression; median 12 months ]Time from randomization todate of first tumor progression
- Overall response rate [ Time Frame: At 12 weeks and 6 months ]complete response or partial response at 12 weeks and 6 months
- Clinical benefit rate [ Time Frame: At 6 months ]Beneficial response (complete response, partial response or stable disease) at 6 months
- Toxicity of all study regimens [ Time Frame: assessed until 100 days after of treatment end ]adverse events will be graded according to NCI Common Toxicity Criteria v 4.0

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Metastatic triple negative breast cancer with confirmation of Estrogen Receptor (ER) and HER2 negativity on a histological biopsy of a metastatic lesion
- 18 years or older
- Metastatic lesion accessible for histological biopsy (Mandatory biopsies: pre-induction treatment, post-induction treatment, 6-weeks. Optional biopsies: 12-weeks, at progression, of irradiated site). The pre-induction treatment biopsy has to contain sufficient tumor content (≥100 tumor cells); subjects with samples that have insufficient tumor content will require re-biopsy prior to induction treatment. Interval between last treatment and pre-induction biopsy has to be at least 14 days
- One, two or three line(s) of chemotherapy for metastatic disease and with progression of disease on last treatment regimen
- Evaluable disease according to RECIST 1.1
- Metastatic lesion accessible for radiation with 1x20 Gray or 3x8 Gray
- Subjects with brain metastases are eligible if these are not symptomatic. 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.
- WHO performance status of 0 or 1
- Adequate bone marrow function
- Adequate hepatic function
- Adequate renal function
- Signed written informed consent
Exclusion Criteria:
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris.
- known history of leptomeningeal disease localization
- history of having received other anticancer therapies within 2 weeks of start of the study drug
- history of immunodeficiency, autoimmune disease, conditions requiring immunosuppression (>10 mgl daily prednisone equivalents) or chronic infections.
- prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody
- 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
- history of uncontrolled serious medical or psychiatric illness
- any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
- current pregnancy or breastfeeding.

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02499367
Netherlands | |
Antoni van Leeuwenhoek | |
Amsterdam, Netherlands, 1066 CX |
Principal Investigator: | Marleen Kok, MD | Antoni van Leeuwenhoek |
Responsible Party: | The Netherlands Cancer Institute |
ClinicalTrials.gov Identifier: | NCT02499367 |
Other Study ID Numbers: |
N15TON |
First Posted: | July 16, 2015 Key Record Dates |
Last Update Posted: | March 22, 2022 |
Last Verified: | March 2022 |
triple negative metastatic |
Breast Neoplasms Triple Negative Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Cyclophosphamide Cisplatin Doxorubicin Nivolumab Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |
Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists Antibiotics, Antineoplastic Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Antineoplastic Agents, Immunological Immune Checkpoint Inhibitors |