Breast CancerPhase 2TONICNCT02499367
Nivolumab After Induction Treatment in Triple-negative Breast Cancer (TNBC) Patients
A Phase 2 study testing Nivolumab, Radiation therapy and Low dose doxorubicin in people with Breast Cancer, run by The Netherlands Cancer Institute at 1 site in Netherlands.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Nivolumab, Radiation therapy and Low dose doxorubicin
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 84 participants
- Where
- 1 siteNetherlands
- Study dates
- Aug 2015to Aug 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Adaptive Phase II Randomized Non-comparative Trial of Nivolumab After Induction Treatment in Triple-negative Breast Cancer (TNBC) Patients: TONIC-trial
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.
Read the detailed description
Triple negative breast cancer (TNBC) patients have a relatively high relapse rate and upon relapse the median overall survival is less than a year. No targeted therapies are currently available for this subgroup. Compared to other breast cancer subtypes, the percentage of tumor-infiltrating lymphocytes (TILs) is significantly higher in TNBC. Given the durable responses induced by the immune checkpoint inhibitor nivolumab in other advanced solid cancers, immunotherapeutic approaches, such as blockade of PD-1 by nivolumab may be the key to treat TNBC. Moreover, since classical anticancer agents can stimulate immune effector cells, the investigators hypothesize that short-term induction treatment with radiation, doxorubicin, cyclophosphamide or cisplatin induces an anticancer immune response resulting in synergistic activity with nivolumab.
- Conditions
- Breast Cancer
- Being tested
- Nivolumab, Radiation therapy, Low dose doxorubicin, Cyclophosphamide, Cisplatin
- Keywords
- triple negative, metastatic
- Medical subject headings
- Breast Neoplasms, Neoplasm Metastasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NivolumabDrug
nivolumab 3 mg/kg, every 2 weeks after induction treatment
Radiation therapyRadiation
20 Gy to metastatic lesion
Low dose doxorubicinDrug
15 mg flat dose, once weekly for 2 weeks
CyclophosphamideDrug
metronomic schedule, 50 mg daily orally for 2 weeks
CisplatinDrug
40 mg/m2, weekly for 2 weeks
| Study group | Role | What they receive |
|---|---|---|
| Radiation therapy | Active comparator | Radiotherapy on metastatic lesion Receives: Drug: Nivolumab; Radiation: Radiation therapy |
| Low dose doxorubicin | Active comparator | 15mg flat dose, once weekly for 2 weeks Receives: Drug: Nivolumab; Drug: Low dose doxorubicin |
| Cyclophosphamide | Active comparator | metronomic schedule, 50mg daily orally for 2 weeks Receives: Drug: Nivolumab; Drug: Cyclophosphamide |
| Cisplatin | Active comparator | 40mg/m2, weekly for 2 weeks Receives: Drug: Nivolumab; Drug: Cisplatin |
| No induction treatment | Active comparator | Not described Receives: Drug: Nivolumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression free survival
Time from randomization todate of first tumor progression
Measured: assessed monthly until progression; median 12 months
Secondary outcomes (3)
Overall response rate
complete response or partial response at 12 weeks and 6 months
Measured: At 12 weeks and 6 months
Clinical benefit rate
Beneficial response (complete response, partial response or stable disease) at 6 months
Measured: At 6 months
Toxicity of all study regimens
adverse events will be graded according to NCI Common Toxicity Criteria v 4.0
Measured: assessed until 100 days after of treatment end
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jul 2015 (estimated)
- Study startAug 2015
- Primary completionDec 2023 (estimated)
- Study completionAug 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by The Netherlands Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 84 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Netherlands Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Responsible party
- Sponsor
- Investigators
- Marleen Kok, MD, Principal investigator, Antoni van Leeuwenhoek
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02499367
- Sponsor's protocol ID
- N15TON
- Acronym
- TONIC
- Status last verified
- Mar 2022
- First submitted
- 6 Jul 2015
- Last updated
- 22 Mar 2022
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Lin AY, Isaeva OI, Deger T, Geurts VCM, Vessies DCL, Voorwerk L, Slagter M, Moore KS, van der Leest P, Martens JWM, van den Broek D, Wessels LFA, Kok M. CfDNA-based copy-number dynamics during anti-PD1 treatment in metastatic triple negative breast cancer. Cell Rep Med. 2025 Dec 16;6(12):102512. doi: 10.1016/j.xcrm.2025.102512.
PubMed 41406937
Study at a glance
From the registry record, last updated by the sponsor on 22 Mar 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Adaptive Phase II Randomized Non-comparative Trial of Nivolumab After Induction Treatment in Triple-negative Breast Cancer (TNBC) Patients: TONIC-trial
- ClinicalTrials.gov ID
- NCT02499367
- Acronym / sponsor ID
- TONIC / N15TON
- Conditions
- Breast Cancer
- Keywords
- triple negative, metastatic
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 84 participants (estimated)
- Lead sponsor
- The Netherlands Cancer InstituteUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Study start
- Aug 2015
- Primary completion
- Dec 2023 (estimated)
- Study completion
- Aug 2025 (estimated)
- First posted
- 16 Jul 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Triple negative breast cancer (TNBC) patients have a relatively high relapse rate and upon relapse the median overall survival is less than a year. No targeted therapies are currently available for this subgroup. Compared to other breast cancer subtypes, the percentage of tumor-infiltrating lymphocytes (TILs) is significantly higher in TNBC. Given the durable responses induced by the immune checkpoint inhibitor nivolumab in other advanced solid cancers, immunotherapeutic approaches, such as blockade of PD-1 by nivolumab may be the key to treat TNBC. Moreover, since classical anticancer agents can stimulate immune effector cells, the investigators hypothesize that short-term induction treatment with radiation, doxorubicin, cyclophosphamide or cisplatin induces an anticancer immune response resulting in synergistic activity with nivolumab.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Radiation therapy | Active comparator | Drug: Nivolumab, Radiation: Radiation therapyRadiotherapy on metastatic lesion |
| Low dose doxorubicin | Active comparator | Drug: Nivolumab, Drug: Low dose doxorubicin15mg flat dose, once weekly for 2 weeks |
| Cyclophosphamide | Active comparator | Drug: Nivolumab, Drug: Cyclophosphamidemetronomic schedule, 50mg daily orally for 2 weeks |
| Cisplatin | Active comparator | Drug: Nivolumab, Drug: Cisplatin40mg/m2, weekly for 2 weeks |
| No induction treatment | Active comparator | Drug: Nivolumab |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nivolumabnivolumab 3 mg/kg, every 2 weeks after induction treatment | Drug | Cisplatin, Cyclophosphamide, Low dose doxorubicin, No induction treatment, Radiation therapy |
| Radiation therapy20 Gy to metastatic lesion | Radiation | Radiation therapy |
| Low dose doxorubicin15 mg flat dose, once weekly for 2 weeks | Drug | Low dose doxorubicin |
| Cyclophosphamidemetronomic schedule, 50 mg daily orally for 2 weeks | Drug | Cyclophosphamide |
| Cisplatin40 mg/m2, weekly for 2 weeks | Drug | Cisplatin |
Primary outcome
Progression free survival
Time frame: assessed monthly until progression; median 12 months
Time from randomization todate of first tumor progression
3 secondary outcomes
Overall response rate
Time frame: At 12 weeks and 6 months
Clinical benefit rate
Time frame: At 6 months
Toxicity of all study regimens
Time frame: assessed until 100 days after of treatment end
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Mar 2022.
- Derived from this study: PubMed 41406937Lin AY, Isaeva OI, Deger T, Geurts VCM, Vessies DCL, Voorwerk L, Slagter M, Moore KS, van der Leest P, Martens JWM, van den Broek D, Wessels LFA, Kok M. CfDNA-based copy-number dynamics during anti-PD1 treatment in metastatic triple negative breast cancer. Cell Rep Med. 2025 Dec 16;6(12):102512. doi: 10.1016/j.xcrm.2025.102512.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marleen Kok, MD principal investigator
Antoni van Leeuwenhoek
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nivolumab, Radiation therapy and Low dose doxorubicin in people with Breast Cancer, run by The Netherlands Cancer Institute at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 22 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression free survival (time frame: assessed monthly until progression; median 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02499367, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Mar 2022.