Back to resultsImmune Induction Strategies to Improve Response to Immune Checkpoint Blockade in Triple Negative Breast Cancer (TNBC) Patients (TONIC-2)
Primary Purpose
Metastatic Breast Cancer
Status
Recruiting
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Nivolumab
Cisplatin
Low dose doxorubicin
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Breast Cancer focused on measuring Triple negative, Metastatic disease
Eligibility Criteria
Inclusion Criteria:
- 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
- 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
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 immune checkpoint inhibitors.
- active other cancer
- history of uncontrolled serious medical or psychiatric illness
- current pregnancy or breastfeeding
Sites / Locations
- Antoni van LeeuwenhoekRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Control group
Cisplatin induction
Low dose doxorubicin induction
Arm Description
no induction treatment, nivolumab 240 mg flat-dose, every 2 weeks
Cisplatin 40mg/m2, weekly for two weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks
Low dose doxorubicin 15mg flat dose, weekly for 8 weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks
Outcomes
Primary Outcome Measures
Progression free survival
Time from randomization to date of first tumor progression
Secondary Outcome Measures
Overall response rate
complete response or partial response according to iRECIST and RECIST1.1
Clinical benefit rate
Beneficial response (complete response, partial response or stable disease) according to RECIST 1.1 and iRECIST
Overall survival
time from nivolumab initiation to death from any cause
Toxicity of all study regimens
adverse events will be graded according to NCI Common Toxicity Criteria v 5.0
Progression Free Survival after 6 cycles
the number of patients free of progression after 6 cycles of nivolumab
Full Information
NCT ID
NCT04159818
First Posted
October 23, 2019
Last Updated
March 21, 2022
Sponsor
The Netherlands Cancer Institute
Collaborators
Bristol-Myers Squibb
1. Study Identification
Unique Protocol Identification Number
NCT04159818
Brief Title
Immune Induction Strategies to Improve Response to Immune Checkpoint Blockade in Triple Negative Breast Cancer (TNBC) Patients
Acronym
TONIC-2
Official Title
Immune Induction Strategies to Improve Response to Immune Checkpoint Blockade in Triple Negative Breast Cancer (TNBC) Patients: the TONIC-2 Trial
Study Type
Interventional
2. Study Status
Record Verification Date
March 2022
Overall Recruitment Status
Recruiting
Study Start Date
February 21, 2020 (Actual)
Primary Completion Date
December 15, 2022 (Anticipated)
Study Completion Date
December 15, 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Netherlands Cancer Institute
Collaborators
Bristol-Myers Squibb
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Breast Cancer
Keywords
Triple negative, Metastatic disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Patients are randomized between experimental cohorts and a control cohort.
Masking
None (Open Label)
Masking Description
Patients are randomized between experimental cohorts and a control cohort.
Allocation
Randomized
Enrollment
52 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Control group
Arm Type
Experimental
Arm Description
no induction treatment, nivolumab 240 mg flat-dose, every 2 weeks
Arm Title
Cisplatin induction
Arm Type
Experimental
Arm Description
Cisplatin 40mg/m2, weekly for two weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks
Arm Title
Low dose doxorubicin induction
Arm Type
Experimental
Arm Description
Low dose doxorubicin 15mg flat dose, weekly for 8 weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Cisplatin
Intervention Description
40mg/m2, weekly for two weeks
Intervention Type
Drug
Intervention Name(s)
Low dose doxorubicin
Intervention Description
15mg flat dose, weekly for 8 weeks
Primary Outcome Measure Information:
Title
Progression free survival
Description
Time from randomization to date of first tumor progression
Time Frame
assessed monthly until progression or date of death; median 12 months
Secondary Outcome Measure Information:
Title
Overall response rate
Description
complete response or partial response according to iRECIST and RECIST1.1
Time Frame
assessed at week 6, 12 and 20 and every 8 weeks thereafter; assessed up to 120 months
Title
Clinical benefit rate
Description
Beneficial response (complete response, partial response or stable disease) according to RECIST 1.1 and iRECIST
Time Frame
assessed at week 6, 12 and 20 and every 8 weeks thereafter; assessed up to 120 months
Title
Overall survival
Description
time from nivolumab initiation to death from any cause
Time Frame
assessed monthly until date of death; median 12 months
Title
Toxicity of all study regimens
Description
adverse events will be graded according to NCI Common Toxicity Criteria v 5.0
Time Frame
assessed until 100 days after of treatment end
Title
Progression Free Survival after 6 cycles
Description
the number of patients free of progression after 6 cycles of nivolumab
Time Frame
time from nivolumab initiation to tumor progression or death from any cause; assessed up to 120 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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
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
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 immune checkpoint inhibitors.
active other cancer
history of uncontrolled serious medical or psychiatric illness
current pregnancy or breastfeeding
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Marleen Kok, MD
Phone
+3120 512
Ext
9111
Email
m.kok@nki.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Leonie Voorwerk, MD
Phone
+3120 512
Ext
9111
Email
l.voorwerk@nki.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marleen Kok, MD
Organizational Affiliation
NKI-AvL
Official's Role
Principal Investigator
Facility Information:
Facility Name
Antoni van Leeuwenhoek
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marleen Kok, MD
Phone
+3120512
Ext
9111
Email
m.kok@nki.nl
First Name & Middle Initial & Last Name & Degree
Ingrid AM Mandjes, MSc
Phone
+3120512
Ext
9111
Email
i.mandjes@nki.nl
First Name & Middle Initial & Last Name & Degree
Marleen kok, MD
12. IPD Sharing Statement
Learn more about this trial
Immune Induction Strategies to Improve Response to Immune Checkpoint Blockade in Triple Negative Breast Cancer (TNBC) Patients
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