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

Netherlands Cancer Institute (NKI)

Status and phase: Enrolling; Phase 2

Conditions: Metastatic Breast Cancer

Treatments: Drug: Nivolumab; Drug: Low dose doxorubicin; Drug: Cisplatin

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT04159818

N19TON

Details and patient eligibility

About

This is a single center non-blinded randomized multi-cohort non-comparative phase II trial with a Simon's two-stage design.

Full 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.

Enrollment: 52 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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52 participants in 3 patient groups

Control group

Experimental group

Description:

no induction treatment, nivolumab 240 mg flat-dose, every 2 weeks

Treatment:

Drug: Nivolumab

Cisplatin induction

Experimental group

Description:

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

Treatment:

Drug: Nivolumab

Drug: Cisplatin

Low dose doxorubicin induction

Experimental group

Description:

Low dose doxorubicin 15mg flat dose, weekly for 8 weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks

Treatment:

Drug: Nivolumab

Drug: Low dose doxorubicin