Pre-operative Trial for Breast Cancer With Nivolumab in Combination With Novel IO (BELLINI)

Pre-operative Phase II Trial for Breast Cancer With Nivolumab in Combination With Novel IO (BELLINI Trial)

To determine whether short-term pre-operative nivolumab either as monotherapy or in combination with low dose doxorubicin or novel IO combinations can induce immune activation in early BC.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Nivolumab; Drug: Ipilimumab; Drug: Ipilimumab

Detailed Description

The investigators aim to test the activity of nivolumab monotherapy in primary breast tumors in a pre-operative window of opportunity trial. As the data of the investigators generated in the TONIC trial (metastatic TNBC) indicate that low dose doxorubicin may 'prime' the tumor microenvironment (TME) resulting in higher response rates on nivolumab, in addition, cohorts for treatment with nivolumab plus low dose doxorubicin will be opened. Given the emerging data on other immunomodulatory strategies, this platform study allows opening additional cohorts for promising novel immune-oncology (IO) drugs for which a strong efficacy signal has been seen without drug safety issues. The investigators will study the TME and systemic host factors with specific emphasis on immunosuppressive processes that can potentially be targeted by novel IO agents to further optimize BC immunotherapy.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: M Kok, MD; Phone Number: 9111 3120512; Email: m.kok@nki.nl
• Study Contact Backup: Name: I Nederlof; Phone Number: 9111 3120512; Email: i.nederlof@nki.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1066CX
    • Recruiting
    • NKI-AVL
    • Contact: M Kok, MD; Email: m.kok@nki.nl
    • Contact: I Nederlof; Email: i.nederlof@nki.nl
    • Principal Investigator: M Kok, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Signed written informed consent
• 18 years or older at moment of inclusion;
• Female gender;
• WHO performance status 0 or 1;
• Resectable primary breast cancer stage I-III. Nodal status must be examined by ultrasound, fine needle aspiration, sentinel node biopsy, or FDG-PET scan.

• The tumors must be:

  • at least 10 mm (minimum cT1c) as determined by MRI
  • TNBC defined as ER<10%, HER2-negative OR luminal B defined as ER≥10%, HER2-negative with either Ki67≥20% or PR =<20% OR grade 3. HER2 negative is defined as an IHC score of <2 or 2+ with a negative ISH.
  • For TNBC patients: TIL≥5%
  • For LumB breast cancer patients: TIL≥1%
  • For cohort 3B: N0 status, TN and TIL ≥50%
  • For cohort 4B: N0 status, TNBC and TIL 30-49%
  • For cohort 5B: N0 status, TNBC and TIL ≥50% ● Patients with multifocal/multicentric breast cancer are eligible if triple negative breast cancer histology as well as sufficient TIL percentages (30-49% in cohort 4B, ≥50% in cohort 5B) have been confirmed in all tumor lesions.

Exclusion Criteria:

• evidence or suspicion of metastatic disease. Evaluation of the presence of distant metastases may include chest X-ray, liver ultrasound, isotope bone-scan, CT-scan of chest and abdomen and/or FDG-PET scan, according to local procedures;
• evidence of a concurrent contralateral or ipsilateral second primary infiltrating breast cancer. Evaluation of the presence of a concurrent second primary breast cancer may include mammography, breast ultrasound and/or MRI breast;
• other malignancy except carcinoma in situ and basal-cell and squamous carcinoma of the skin, unless the other malignancy was treated ≥5 years ago with curative intent without the use of chemotherapy or radiotherapy
• previous radiation therapy or chemotherapy;
• prior treatment with checkpoint inhibitors (including anti- PD1, -PD-L1, -CTLA-4);
• concurrent anti-cancer treatment, neoadjuvant therapy or another investigational drug;

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1A; LumB; Nivolumab	Drug: Nivolumab; 2 courses 240 mg flat dose
Experimental: 1B; TNBC; Nivolumab	Drug: Nivolumab; 2 courses 240 mg flat dose
Experimental: 2A; LUMB; Nivolumab and ipilimumab	Drug: Nivolumab; 2 courses 240 mg flat dose; Drug: Ipilimumab; single dose ipilimumab (1mg/kg) at day 1; Drug: Ipilimumab; two courses ipilimumab (1mg/kg) at day 1 and 21
Experimental: 2B; TNBC; Nivolumab and ipilimumab	Drug: Nivolumab; 2 courses 240 mg flat dose; Drug: Ipilimumab; single dose ipilimumab (1mg/kg) at day 1; Drug: Ipilimumab; two courses ipilimumab (1mg/kg) at day 1 and 21
Experimental: 3B; TNBC, High TIL; Nivolumab and ipilimumab	Drug: Nivolumab; 2 courses 240 mg flat dose; Drug: Ipilimumab; single dose ipilimumab (1mg/kg) at day 1; Drug: Ipilimumab; two courses ipilimumab (1mg/kg) at day 1 and 21

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response rate per cohort,	number of patients with no residual invasively growing tumor cells detected by microscopic examination in breast and axilla	up to 3 weeks after surgery, an average of 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events according to NCI Common Toxicity Criteria version 5.0	Adverse events in all regimens will be graded according to NCI Common Toxicity Criteria version 5.0.	up to 3 weeks after surgery, an average of 6 months
Radiological response rate	The percentage of patients having a complete response, partial response or stable disease per cohort assessed by MRI	At 4 weeks
Immune activation after pre-operative nivolumab, either as monotherapy or in combination with ipilimumab or relatlimab or novel IO combinations.	Immune activation is defined as either a 2-fold increase in tumor-associated CD8 after pre-operative immunotherapy; and/or a 2-fold increase expression of genes induced by IFNy (determined using mRNA expression levels)	within 6 months after surgery

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2019
• Primary Completion (Estimated): January 1, 2031
• Study Completion (Estimated): January 1, 2033

Study Registration Dates

• First Submitted: December 13, 2018
• First Submitted That Met QC Criteria: January 22, 2019
• First Posted (Actual): January 24, 2019

Study Record Updates

• Last Update Posted (Actual): May 30, 2024
• Last Update Submitted That Met QC Criteria: May 28, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: pre-operative; triple negative and Luminal B; resectable, stage I-III
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab
• Other Study ID Numbers: M18BEL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: to be determined

Drug and device information, study documents

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