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

Adaptive Phase II Randomized Non-comparative Trial of Nivolumab After Induction Treatment in Triple-negative Breast Cancer (TNBC) Patients: TONIC-trial

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Nivolumab; Radiation: Radiation therapy; Drug: Low dose doxorubicin; Drug: Cyclophosphamide; Drug: Cisplatin

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.

• Study Type: Interventional
• Enrollment (Anticipated): 84
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Antoni van Leeuwenhoek

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 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.

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

5

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	complete response or partial response at 12 weeks and 6 months	At 12 weeks and 6 months
Clinical benefit rate	Beneficial response (complete response, partial response or stable disease) at 6 months	At 6 months
Toxicity of all study regimens	adverse events will be graded according to NCI Common Toxicity Criteria v 4.0	assessed until 100 days after of treatment end

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Marleen Kok, MD, Antoni van Leeuwenhoek

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): August 1, 2025

Study Registration Dates

• First Submitted: July 6, 2015
• First Submitted That Met QC Criteria: July 13, 2015
• First Posted (Estimate): July 16, 2015

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: metastatic; triple negative
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Immune Checkpoint Inhibitors; Cyclophosphamide; Cisplatin; Nivolumab; Doxorubicin
• Other Study ID Numbers: N15TON