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

• ClinicalTrials.gov Identifier: NCT03815890
• Recruitment Status: Recruiting
• First Posted: January 24, 2019
• Last Update Posted: January 22, 2021
• Sponsor: The Netherlands Cancer Institute
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): The Netherlands Cancer Institute

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: Nivolumab; Drug: Ipilimumab	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 80 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Separate cohorts will be opened in this trial. LumB and TNBC tumors will be divided in separate cohorts.More cohorts, e.g. combining nivolumab and novel IO, can open after the start of this trial.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pre-operative Phase II Trial for Breast Cancer With Nivolumab in Combination With Novel IO (BELLINI Trial)
• Actual Study Start Date: October 4, 2019
• Estimated Primary Completion Date: January 7, 2023
• Estimated Study Completion Date: January 7, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1A; LumB; Nivolumab	Drug: Nivolumab; 2 courses 3mg/kg
Experimental: 1B; TNBC; Nivolumab	Drug: Nivolumab; 2 courses 3mg/kg
Experimental: 2A; LUMB; Nivolumab and ipilimumab	Drug: Nivolumab; 2 courses 3mg/kg; Drug: Ipilimumab; single dose ipilimumab (1mg/kg) at day 1
Experimental: 2B; TNBC; Nivolumab and ipilimumab	Drug: Nivolumab; 2 courses 3mg/kg; Drug: Ipilimumab; single dose ipilimumab (1mg/kg) at day 1

Outcome Measures

Primary Outcome Measures :

1. Immune activation after pre-operative nivolumab [ Time Frame: through study completion, an average of 1 year ]
   measuring the tumor-associated CD8 and expression of genes induced by IFNy after pre-operative immunotherapy

Secondary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events according to NCI Common Toxicity Criteria version 5.0 [ Time Frame: up to 3 weeks after surgery, an average of 6 months ]
   Adverse events in all regimens will be graded according to NCI Common Toxicity Criteria version 5.0.
2. Radiological response rate [ Time Frame: At 4 weeks ]
   The percentage of patients having a complete response, partial response or stable disease per cohort assessed by MRI
3. Pathological response rate [ Time Frame: up to 3 weeks after surgery, an average of 6 months ]
   The percentage of patients having a complete response or residual cancer burden per cohort

Eligibility Criteria

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

Criteria

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 grade 3 or Ki67≥20%. HER2 negative is defined as an IHC score of <2 or 2+ with a negative ISH.

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;

Contacts and Locations

Contacts

Contact: M Kok, MD; 3120512 ext 9111; m.kok@nki.nl

Contact: I Nederlof; 3120512 ext 9111; i.nederlof@nki.nl

Locations

Netherlands

NKI-AVL; Recruiting

Amsterdam, Netherlands, 1066CX

Contact: M Kok, MD m.kok@nki.nl

Contact: I Nederlof i.nederlof@nki.nl

Principal Investigator: M Kok, MD

Sponsors and Collaborators

The Netherlands Cancer Institute

Bristol-Myers Squibb

Investigators

• Principal Investigator: M Kok, MD; NKI-AvL

More Information

• Responsible Party: The Netherlands Cancer Institute
• ClinicalTrials.gov Identifier: NCT03815890
• Other Study ID Numbers: M18BEL
• First Posted: January 24, 2019
• Last Update Posted: January 22, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: to be determined

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by The Netherlands Cancer Institute:

pre-operative; triple negative and Luminal B; resectable, stage I-III

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Nivolumab; Ipilimumab; Antineoplastic Agents, Immunological; Antineoplastic Agents