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Immune Induction Strategies to Improve Response to Immune Checkpoint Blockade in Triple Negative Breast Cancer (TNBC) Patients (TONIC-2)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04159818
Recruitment Status : Recruiting
First Posted : November 12, 2019
Last Update Posted : February 28, 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 multi-cohort non-comparative phase II trial with a Simon's two-stage design.

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

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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.
Primary Purpose: Treatment
Official Title: Immune Induction Strategies to Improve Response to Immune Checkpoint Blockade in Triple Negative Breast Cancer (TNBC) Patients: the TONIC-2 Trial
Actual Study Start Date : February 21, 2020
Estimated Primary Completion Date : December 15, 2022
Estimated Study Completion Date : December 15, 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Control group
no induction treatment, nivolumab 240 mg flat-dose, every 2 weeks
Drug: Nivolumab
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

Experimental: Cisplatin induction
Cisplatin 40mg/m2, weekly for two weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks
Drug: Nivolumab
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

Drug: Cisplatin
40mg/m2, weekly for two weeks

Experimental: Low dose doxorubicin induction
Low dose doxorubicin 15mg flat dose, weekly for 8 weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks
Drug: Nivolumab
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

Drug: Low dose doxorubicin
15mg flat dose, weekly for 8 weeks




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Overall response rate [ Time Frame: assessed at week 6, 12 and 20 and every 8 weeks thereafter; assessed up to 120 months ]
    complete response or partial response according to iRECIST and RECIST1.1

  2. Clinical benefit rate [ Time Frame: assessed at week 6, 12 and 20 and every 8 weeks thereafter; assessed up to 120 months ]
    Beneficial response (complete response, partial response or stable disease) according to RECIST 1.1 and iRECIST

  3. Overall survival [ Time Frame: assessed monthly until date of death; median 12 months ]
    time from nivolumab initiation to death from any cause

  4. 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 5.0

  5. 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 ]
    the number of patients free of progression after 6 cycles of nivolumab



Information from the National Library of Medicine

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

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): NCT04159818


Contacts
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Contact: Marleen Kok, MD +3120 512 ext 9111 m.kok@nki.nl
Contact: Leonie Voorwerk, MD +3120 512 ext 9111 l.voorwerk@nki.nl

Locations
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Netherlands
Antoni van Leeuwenhoek Recruiting
Amsterdam, Netherlands, 1066 CX
Contact: Marleen Kok, MD    +3120512 ext 9111    m.kok@nki.nl   
Contact: Ingrid AM Mandjes, MSc    +3120512 ext 9111    i.mandjes@nki.nl   
Principal Investigator: Marleen kok, MD         
Sponsors and Collaborators
The Netherlands Cancer Institute
Bristol-Myers Squibb
Investigators
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Principal Investigator: Marleen Kok, MD NKI-AvL
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Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT04159818    
Other Study ID Numbers: N19TON
First Posted: November 12, 2019    Key Record Dates
Last Update Posted: February 28, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by The Netherlands Cancer Institute:
Triple negative
Metastatic disease
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Doxorubicin
Nivolumab
Antineoplastic Agents
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological