Metastatic Breast CancerPhase 2TONIC-2NCT04159818
Immune Induction Strategies to Improve Response to Immune Checkpoint Blockade in Triple Negative Breast Cancer (TNBC) Patients
A Phase 2 study testing Nivolumab, Cisplatin and Low dose doxorubicin in people with Metastatic Breast Cancer, run by The Netherlands Cancer Institute at 1 site in Netherlands.
Trial summary
This is a single center non-blinded randomized multi-cohort non-comparative phase II trial with a Simon's two-stage design. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Breast Cancer
- What is being tested?
- Nivolumab, Cisplatin and Low dose doxorubicin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- 1 siteNetherlands
- Study dates
- 21 Feb 2020to 15 Dec 2026
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
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 or incurable locally advanced triple negative breast cancer (ER < 10%, HER2 IHC 0,1+ or 2+ with no amplification)
- Metastatic lesion accessible for histological biopsy
- 18 years or older
- Maximum of three lines of chemotherapy for metastatic disease and with evidence of progression of disease. Treatment with low-dose doxorubicin in the palliative setting is not allowed.
- WHO performance status of 0 or 1
- Measurable or evaluable disease according to RECIST 1.1
Show all 10Show fewer
- Disease Free Interval (defined as time between first diagnosis or locoregional recurrence and first metastasis) longer than 1 year
- Subjects with brain metastases are eligible if these are not symptomatic and free of progression of at least 4 weeks
- A maximum dosage of 360 mg/m2 of anthracyclines and no previous anthracycline-related cardiac toxicity. In case of radiation in the cardiac area, hypertension, diabetes mellitus or hypercholesterolemia, the left ventricular ejection fraction must be 50% or higher.
- Adequate bone marrow, kidney and liver function
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 immune checkpoint inhibitors.
- active other cancer
- history of uncontrolled serious medical or psychiatric illness
- current pregnancy or breastfeeding
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Netherlands1 site, 1 recruiting
- Recruiting
Antoni van Leeuwenhoek
Amsterdam, 1066 CX
Marleen Kok, MD, +3120512 ext. 9111, m.kok@nki.nl
Ingrid AM Mandjes, MSc, +3120512 ext. 9111, i.mandjes@nki.nl
About this study
Official title: Immune Induction Strategies to Improve Response to Immune Checkpoint Blockade in Triple Negative Breast Cancer (TNBC) Patients: the TONIC-2 Trial
This is a single center non-blinded randomized multi-cohort non-comparative phase II trial with a Simon's two-stage design.
Read the detailed description
In the first stage, 13 evaluable patients will be accrued per cohort. Evaluable is defined as: at least one administration of nivolumab and availability of paired biopsies for immunohistochemistry (for induction treatment cohorts pre-induction and pre-nivolumab biopsies).
If there are 1 or no responses observed in these 13 patients, the cohort will be stopped. Otherwise, 21 additional patients will be accrued for a total of 34.
- Conditions
- Metastatic Breast Cancer
- Keywords
- Triple negative, Metastatic disease
- 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
240 mg flat-dose, every 2 weeks. From 20 weeks onwards, nivolumab will be administered every 4 weeks with a flat-dose of 480 mg starting from week 20 onwards
CisplatinDrug
40mg/m2, weekly for two weeks
Low dose doxorubicinDrug
15mg flat dose, weekly for 8 weeks
| Study group | Role | What they receive |
|---|---|---|
| Control group | Experimental | no induction treatment, nivolumab 240 mg flat-dose, every 2 weeks Receives: Drug: Nivolumab |
| Cisplatin induction | Experimental | Cisplatin 40mg/m2, weekly for two weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks Receives: Drug: Nivolumab; Drug: Cisplatin |
| Low dose doxorubicin induction | Experimental | Low dose doxorubicin 15mg flat dose, weekly for 8 weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks Receives: Drug: Nivolumab; Drug: Low dose doxorubicin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression free survival
Time from randomization to date of first tumor progression
Measured: assessed monthly until progression or date of death; median 12 months
Secondary outcomes (5)
Overall response rate
complete response or partial response according to iRECIST and RECIST1.1
Measured: assessed at week 6, 12 and 20 and every 8 weeks thereafter; assessed up to 120 months
Clinical benefit rate
Beneficial response (complete response, partial response or stable disease) according to RECIST 1.1 and iRECIST
Measured: assessed at week 6, 12 and 20 and every 8 weeks thereafter; assessed up to 120 months
Overall survival
time from nivolumab initiation to death from any cause
Measured: assessed monthly until date of death; median 12 months
Toxicity of all study regimens
adverse events will be graded according to NCI Common Toxicity Criteria v 5.0
Measured: assessed until 100 days after of treatment end
Progression Free Survival after 6 cycles
the number of patients free of progression after 6 cycles of nivolumab
Measured: time from nivolumab initiation to tumor progression or death from any cause; assessed up to 120 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Nov 2019
- Study start21 Feb 2020
- Primary completion15 Dec 2022 (estimated)
- Study completion15 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastatic 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
- Model description
- Patients are randomized between experimental cohorts and a control cohort.
- Masking
- None (open label)
- Enrolment
- 52 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, The Netherlands Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04159818
- Sponsor's protocol ID
- N19TON
- Acronym
- TONIC-2
- Status last verified
- Mar 2022
- First submitted
- 23 Oct 2019
- Last updated
- 22 Mar 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
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
- Immune Induction Strategies to Improve Response to Immune Checkpoint Blockade in Triple Negative Breast Cancer (TNBC) Patients: the TONIC-2 Trial
- ClinicalTrials.gov ID
- NCT04159818
- Acronym / sponsor ID
- TONIC-2 / N19TON
- Conditions
- Metastatic Breast Cancer
- Keywords
- Triple negative, Metastatic disease
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 52 participants (estimated)
- Lead sponsor
- The Netherlands Cancer InstituteUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Study start
- 21 Feb 2020 (actual)
- Primary completion
- 15 Dec 2022 (estimated)
- Study completion
- 15 Dec 2026 (estimated)
- First posted
- 12 Nov 2019 (actual)
- 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 multi-cohort non-comparative phase II trial with a Simon's two-stage design.
Detailed description
In the first stage, 13 evaluable patients will be accrued per cohort. Evaluable is defined as: at least one administration of nivolumab and availability of paired biopsies for immunohistochemistry (for induction treatment cohorts pre-induction and pre-nivolumab biopsies).
If there are 1 or no responses observed in these 13 patients, the cohort will be stopped. Otherwise, 21 additional patients will be accrued for a total of 34.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Patients are randomized between experimental cohorts and a control cohort.
| Arm | Type | Receives |
|---|---|---|
| Control group | Experimental | Drug: Nivolumabno induction treatment, nivolumab 240 mg flat-dose, every 2 weeks |
| Cisplatin induction | Experimental | Drug: Nivolumab, Drug: CisplatinCisplatin 40mg/m2, weekly for two weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks |
| Low dose doxorubicin induction | Experimental | Drug: Nivolumab, Drug: Low dose doxorubicinLow dose doxorubicin 15mg flat dose, weekly for 8 weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Metastatic or incurable locally advanced triple negative breast cancer (ER < 10%, HER2 IHC 0,1+ or 2+ with no amplification)
- Metastatic lesion accessible for histological biopsy
- 18 years or older
- Maximum of three lines of chemotherapy for metastatic disease and with evidence of progression of disease. Treatment with low-dose doxorubicin in the palliative setting is not allowed.
- WHO performance status of 0 or 1
Key exclusion criteria (8 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 immune checkpoint inhibitors.
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 |
|---|---|---|
| Nivolumab240 mg flat-dose, every 2 weeks. From 20 weeks onwards, nivolumab will be administered every 4 weeks with a flat-dose of 480 mg starting from week 20 onwards | Drug | Cisplatin induction, Control group, Low dose doxorubicin induction |
| Cisplatin40mg/m2, weekly for two weeks | Drug | Cisplatin induction |
| Low dose doxorubicin15mg flat dose, weekly for 8 weeks | Drug | Low dose doxorubicin induction |
Primary outcome
Progression free survival
Time frame: assessed monthly until progression or date of death; median 12 months
Time from randomization to date of first tumor progression
5 secondary outcomes
Overall response rate
Time frame: assessed at week 6, 12 and 20 and every 8 weeks thereafter; assessed up to 120 months
Clinical benefit rate
Time frame: assessed at week 6, 12 and 20 and every 8 weeks thereafter; assessed up to 120 months
Overall survival
Time frame: assessed monthly until date of death; median 12 months
Toxicity of all study regimens
Time frame: assessed until 100 days after of treatment end
Progression Free Survival after 6 cycles
Time frame: time from nivolumab initiation to tumor progression or death from any cause; assessed up to 120 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Mar 2022.
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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.
Marleen Kok, MD principal investigator
The Netherlands Cancer Institute
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, Cisplatin and Low dose doxorubicin in people with Metastatic 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 10 inclusion and 8 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: looking for participants now, 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Marleen Kok, MD (+3120 512 ext. 9111, m.kok@nki.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression free survival (time frame: assessed monthly until progression or date of death; median 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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.