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Nivolumab After Induction Treatment in Triple-negative Breast Cancer (TNBC) Patients (TONIC)

Primary Purpose

Breast Cancer

Status
Active
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Nivolumab
Radiation therapy
Low dose doxorubicin
Cyclophosphamide
Cisplatin
Sponsored by
The Netherlands Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring triple negative, metastatic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Antoni van Leeuwenhoek

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

Radiation therapy

Low dose doxorubicin

Cyclophosphamide

Cisplatin

No induction treatment

Arm Description

Radiotherapy on metastatic lesion

15mg flat dose, once weekly for 2 weeks

metronomic schedule, 50mg daily orally for 2 weeks

40mg/m2, weekly for 2 weeks

Outcomes

Primary Outcome Measures

Progression free survival
Time from randomization todate of first tumor progression

Secondary Outcome Measures

Overall response rate
complete response or partial response at 12 weeks and 6 months
Clinical benefit rate
Beneficial response (complete response, partial response or stable disease) at 6 months
Toxicity of all study regimens
adverse events will be graded according to NCI Common Toxicity Criteria v 4.0

Full Information

First Posted
July 6, 2015
Last Updated
March 21, 2022
Sponsor
The Netherlands Cancer Institute
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT02499367
Brief Title
Nivolumab After Induction Treatment in Triple-negative Breast Cancer (TNBC) Patients
Acronym
TONIC
Official Title
Adaptive Phase II Randomized Non-comparative Trial of Nivolumab After Induction Treatment in Triple-negative Breast Cancer (TNBC) Patients: TONIC-trial
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 2015 (undefined)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
August 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Netherlands Cancer Institute
Collaborators
Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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). 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer
Keywords
triple negative, metastatic

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
84 (Anticipated)

8. Arms, Groups, and Interventions

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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marleen Kok, MD
Organizational Affiliation
Antoni van Leeuwenhoek
Official's Role
Principal Investigator
Facility Information:
Facility Name
Antoni van Leeuwenhoek
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands

12. IPD Sharing Statement

Learn more about this trial

Nivolumab After Induction Treatment in Triple-negative Breast Cancer (TNBC) Patients

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