Adaptive phase II randomized non-comparative trial of nivolumab after induction treatment in triple-negative breast cancer (TNBC) patients: TONIC-trial

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, we hypothesize that short-term induction treatment with
radiation, doxorubicin, cyclophosphamide or cisplatin induces an anticancer
immune response resulting in synergistic activity with nivolumab.

This study has been transitioned to CTIS with ID 2025-520487-18-00 check the CTIS register for the current data.

To determine the activity of nivolumab after four different immune response
induction treatments in TNBC patients with metastatic disease. We hypothesize
that short-term induction treatment induces an anticancer immune response
resulting in increased activity of nivolumab as compared to unprimed, single
agent nivolumab.

This is a single center non-blinded randomized non-comparative phase II trial
with a Simon two-stage design.The first stage of the trial consists of five
arms (4 with induction treatment followed by nivolumab, 1 with no induction
treatment before nivolumab), all with a Simon two-stage design. For the second
stage, the number of arms will be reduced based on the results obtained in the
first stage.

Protocol version 4.0 dd 07 march 2018;
In stage II of the trial, doxorubicin and the no induction treatment cohorts
will be expanded. In both cohorts, an additional 17 evaluable patients will be
accrued. In the no induction treatment cohort, a two-week waiting period with
an additional biopsy before the start of anti-PD1 (nivolumab) will be optional.

protocol version 5.0 dd 04 july 2018;
Two week waiting period in the no induction cohort is removed, additional
biopsy after 1 cycle of nivolumab in this cohort

Protocol version 6.0 dd 19aug2019;
Disease Free Interval (defined as time between first diagnosis or local
recurrence and first metastasis) longer than 1 year added to inclusion criteria
After 26 weeks, nivolumab will be administered every 4 weeks.

Treatment arms part I;
1. Radiation therapy, followed by nivolumab 3 mg/kg one week later, every 2
weeks
2. Low dose doxorubicin 15mg flat dose, once weekly for 2 weeks, after 2 weeks
followed by nivolumab 3 mg/kg, every 2 weeks
3. Cyclophosphamide, metronomic schedule, 50mg daily orally, after 2 weeks
followed by nivolumab 3 mg/kg, every 2 weeks
4. Cisplatin 40mg/m2, weekly, after 2 weeks followed by nivolumab 3 mg/kg,
every 2 weeks
5. No induction treatment, nivolumab 3 mg/kg, every 2 weeks

For the second stage, the number of arms will be reduced based on the results
obtain in the first stage.

Protocol version 4.0 dd 07 march 2018;
In stage II of the trial, doxorubicin and the no induction treatment cohorts
will be expanded. In both cohorts, an additional 17 evaluable patients will be
accrued. In the no induction treatment cohort, a two-week waiting period with
an additional biopsy before the start of anti-PD1 (nivolumab) will be optional.

Protocol version 6.0 dd 19aug2019;
After 26 weeks, nivolumab will be administered every 4 weeks.

The risks involved in treatment with nivolumab are low. There is a lot of
experience with this agent in patients with melanoma, lung cancer, Hodgkin's
disease and other cancers. There is a small chance (<5%) of pneumonia by the
nivolumab but that can often be treated. Serious side effects are rare. In a
Phase 1 study with anti-PDL1 in breast cancer patients was shown that 11% of
the patients have moderate or sometimes serious side effect, which are often
treatable or resolve after cessation of anti-PDL1. As the patient population
that will participate in the TONIC study do not have a good anti-cancer
treatment option more and we expect that we will see an anti-tumor effect in
1/3 of the participants, thus creating an extended lifetime, we consider the
risk / burden acceptable compared to the potential profits of the treatment
with nivolumab.