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

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

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

Study Overview

• Status: Recruiting
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Nivolumab; Drug: Cisplatin; Drug: Low dose doxorubicin

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.

• Study Type: Interventional
• Enrollment (Anticipated): 52
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Marleen Kok, MD; Phone Number: 9111 +3120 512; Email: m.kok@nki.nl
• Study Contact Backup: Name: Leonie Voorwerk, MD; Phone Number: 9111 +3120 512; Email: l.voorwerk@nki.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Recruiting
    • Antoni van Leeuwenhoek
    • Contact: Marleen Kok, MD; Phone Number: 9111 +3120512; Email: m.kok@nki.nl
    • Contact: Ingrid AM Mandjes, MSc; Phone Number: 9111 +3120512; Email: i.mandjes@nki.nl
    • Principal Investigator: Marleen Kok, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	Time from randomization to date of first tumor progression	assessed monthly until progression or date of death; median 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	complete response or partial response according to iRECIST and RECIST1.1	assessed at week 6, 12 and 20 and every 8 weeks thereafter; assessed up to 120 months
Clinical benefit rate	Beneficial response (complete response, partial response or stable disease) according to RECIST 1.1 and iRECIST	assessed at week 6, 12 and 20 and every 8 weeks thereafter; assessed up to 120 months
Overall survival	time from nivolumab initiation to death from any cause	assessed monthly until date of death; median 12 months
Toxicity of all study regimens	adverse events will be graded according to NCI Common Toxicity Criteria v 5.0	assessed until 100 days after of treatment end
Progression Free Survival after 6 cycles	the number of patients free of progression after 6 cycles of nivolumab	time from nivolumab initiation to tumor progression or death from any cause; assessed up to 120 months

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Marleen Kok, MD, NKI-AVL

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2020
• Primary Completion (Anticipated): December 15, 2022
• Study Completion (Anticipated): December 15, 2026

Study Registration Dates

• First Submitted: October 23, 2019
• First Submitted That Met QC Criteria: November 7, 2019
• First Posted (Actual): November 12, 2019

Study Record Updates

• Last Update Posted (Actual): March 22, 2022
• Last Update Submitted That Met QC Criteria: March 21, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Triple negative; Metastatic disease
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Immune Checkpoint Inhibitors; Nivolumab; Doxorubicin
• Other Study ID Numbers: N19TON

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No