Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02499367
Recruitment Status : Active, not recruiting
First Posted : July 16, 2015
Last Update Posted : September 22, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
The Netherlands Cancer Institute

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.


Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Nivolumab Radiation: Radiation therapy Drug: Low dose doxorubicin Drug: Cyclophosphamide Drug: Cisplatin Phase 2

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.

Layout table for study information
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 : March 2021
Estimated Study Completion Date : August 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Nivolumab

Arm Intervention/treatment
Active Comparator: Radiation therapy
Radiotherapy on metastatic lesion
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
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




Primary Outcome Measures :
  1. Progression free survival [ Time Frame: assessed monthly until progression; median 12 months ]
    Time from randomization todate of first tumor progression


Secondary Outcome Measures :
  1. Overall response rate [ Time Frame: At 12 weeks and 6 months ]
    complete response or partial response at 12 weeks and 6 months

  2. Clinical benefit rate [ Time Frame: At 6 months ]
    Beneficial response (complete response, partial response or stable disease) at 6 months

  3. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

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


Locations
Layout table for location information
Netherlands
Antoni van Leeuwenhoek
Amsterdam, Netherlands, 1066 CX
Sponsors and Collaborators
The Netherlands Cancer Institute
Bristol-Myers Squibb
Investigators
Layout table for investigator information
Principal Investigator: Marleen Kok, MD Antoni van Leeuwenhoek
Layout table for additonal information
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: September 22, 2020
Last Verified: September 2020
Keywords provided by The Netherlands Cancer Institute:
triple negative
metastatic
Additional relevant MeSH terms:
Layout table for MeSH terms
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
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