pCR prediction by I-VAB after NAC

SAKK - SWISS GROUP FOR
CLINICAL CANCER RESEARCHCTU Hirslanden
Klinik Hirslanden
Witellikerstrasse 408032 Zürich
Phone: +41 387 95 45
ClinicalTrialUnit@hirslanden.ch

TRIAL OVERVIEW VISION I
Sponsor:

Hirslanden AG

Trial Title:

Intelligent Vacuum assisted biopsy Immediately before Surgery as an
Intra- or pre-Operative surrogate for patient response to Neoadjuvant
chemotherapy for breast cancer (VISION I). A multicenter prospective
feasibility trial

Short Title / Trial ID:

pCR prediction by I-VAB after NAC

Protocol Version andDate:

Version 2.1, 18.05.2022

Trial registration:

The trial has been registered at www.clinicaltrials.gov and on the
Swiss National Clinical Trials Portal (SNCTP) at www.kofam.ch.

Trial category andRationale:

Clinical trial with health intervention. The health-intervention is aroutine procedure in Switzerland and in the EU. According to the
Swiss HRA and its corresponding Ordinance ClinO on clinical trials,
this trial is classified as category A.

Clinical Phase:

N/A

Background andRationale:

Neoadjuvant chemotherapy (NAC), initially indicated to downstage
tumors to achieve the option of breast conserving surgery, has lately
become common practice in the primary treatment of breast cancer.
The use of modern NAC regimens leads to a complete pathologic
remission (pCR) of the tumor in more than 50% in aggressive tumor
types.
In general, it is difficult to predict pCR in the absence of invasive
surgical techniques, as it depends on several factors such as
biological subtype, the used chemotherapy regimen and anatomic
stage. The most common imaging methods beside clinicalexamination are breast ultrasound, mammography and breast
magnetic resonance imaging (MRI). As NAC induces different
response patterns, radiologic imaging is not sufficiently accurate inpredicting residual disease. Because of this uncertainty, surgery(and the standardized assessment of resected tissue) is so far theonly valid option to either ascertain complete response or to remove
the complete residual disease.
Vacuum-assisted biopsy (VAB) with the possibility of obtaining tissueof the former tumor center could contribute more reliably to detect any
residual tumor or respectively, rule out residual disease. Ultrasound(US) or mammographically (MG) guided VAB will be used in this trial
in order to detect residual tumor lesions in patients with radiologicalcomplete response (rCR) after NAC.

pCR prediction by I-VAB after NAC

We have learned from similar previous trials that VAB alone fails toaccurately predict pCR in the breast. More promising results havebeen shown using a combination of multiple clinical, radiological andpathological variables (including VAB)- these variables have been
trained and validated to predict pCR using standard machine learning(ML) tools. This more advanced ML-algorithm which includes theresult from VAB is termed intelligent VAB (I-VAB).
In this trial we aim to prospectively evaluate the diagnostic accuracyof I-VAB using the full pathologic specimen evaluation obtained after
open surgery as the gold standard to detect residual tissue.
Objective(s):The main objective of the trial is to determine the diagnostic accuracyof I-VAB in determining pCR compared to open surgery.

Endpoints:

The primary endpoint of the trial is:Sensitivity of I-VAB to predict pCR (breast)

Secondary endpoints of the trial are:

Sensitivity of the I-VAB to predict pCR in the breast and axilla
Specificity, positive predictive value (PPV), negative predictivevalue (NPV), and accuracy (ACC) of I-VAB to predict pCR (breast)
Sensitivity of “representative” VAB to predict pCR (breast)
Adverse events (AE)

Explorative endpoints of the trial are:

Trial design:Page 2 of 5

Estimation of the differences in sensitivity between VAB (breast)and I-VAB (breast) per center
Estimation of the generalizability of the I-VAB (breast) and of theI-VAB (axilla)
Sensitivity of the I-VAB retrained on the combined VISION andRESPONDER data (for both breast and breast + axillaseparately).

Multicenter, prospective, single arm, feasibility trial

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VISION I

pCR prediction by I-VAB after NAC

Inclusion / Exclusion
criteria:

Inclusion criteria
1. Written informed consent according to ICH/GCP regulations before
registration and prior to any trial specific procedures
2. Unifocal, histologically confirmed invasive breast cancer with IHC
luminal B (with or without overexpression or amplification of the HER2receptor) and all ER negative (ER < 10%) breast cancers
Notes:- Multifocal lesions are allowed if they fit into the following definitionof satellite lesions: Every tumor close to the main tumor within adistance ≤ the shortest diameter of the main tumor (measured onMRI) (see Appendix 1)- Surrounding non-mass enhancement (NME) next to the primarycancer and ≤ 2 cm in size is considered as unifocal breast cancer
independently of histologically confirmed or not as ductal carcinoma
in situ (DCIS)
3. Initial tumor size larger than 1 and less than 5 cm (cT1c to cT2),
any N, M0
4. Clipping of the primary tumor center prior to the start of neoadjuvant chemotherapy
5. Neoadjuvant chemotherapy resulting in a radiological complete
response or near complete response on MR-Imaging (confirmedwithin 28 days before or on registration) as described in the trial
specific MR-Imaging instructions (available on the welcome page ofthe study specific SecuTrial link (hirslanden.ch/vision))
Notes:- Bilateral breast cancer is allowed, however in case of full remission
in both sides, one side will be selected by the investigator for the trial
intervention- NAC is administered in accordance with the standard guidelines forthe respective tumor subtypes
6. Former tumor bed must be accessible for biopsy
7. Female or male aged ≥ 18 years
8. Adequate condition for breast cancer surgery
9. Patients with a previously treated malignancy are eligible, when therisk of the prior malignancy interfering with either safety or efficacy
endpoints is very low
Exclusion criteria
1. Metastatic breast cancer
2. Multifocal/Multicentric breast cancer- Surrounding NME next to the primary cancer and > 2cm in size
respectively extending to more than 2 cm (measured from theborder of the primary cancer), which is either histologicallyconfirmed as DCIS or suspicious of DCIS is considered as unifocal
cancer with extensive intraductal component (EIC). This
constellation unifocal cancer + EIC is not allowed.
3. Inflammatory breast cancer
4. Luminal-A types of breast cancers (ER ≥ 10% and PgR ≥ 10 %and G1 or 2, and/or Ki-67 ≤ 20%, HER2 negative) or low risk if
assessed by a validated genomic prognostic test (e.g. Mammaprint,VISION I

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pCR prediction by I-VAB after NAC

Measurements andprocedures:Endopredict, Oncotype or Nanostring)
5. Distinct radiological sign of residual disease in the breast after
neo-adjuvant chemotherapy in MRI
6. Intra-/peritumoral microcalcifications larger than 2 cm at time ofdiagnosis
7. Any local therapy (irradiation or surgery) to the currently treatedbreast prior to the trial intervention
8. Contraindication for MRI
9. Any other serious underlying medical, psychiatric, psychological,
familial or geographical condition, which in the judgment of theinvestigator may interfere with the planned staging, trial intervention
and follow-up, affect patient compliance or place the patient at highrisk from trial intervention-related complications
The trial intervention consists of a diagnostic interventional
procedure, US-guided or mammographically guided VAB post-NAC,
prior to the standard breast surgery.
In patients scheduled for NAC, the center of the tumor will bemarked with a clip under US-guidance as part of site standard
operating procedure. NAC is administered in accordance with thestandard guidelines for the respective tumor subtypes. Aftercompletion of NAC, a final MRI will be performed to evaluate theradiological response. Patients with either rCR or near-rCR on MRI
are allowed to enter the study and will undergo US-guided VAB,
provided the clip was sonographically detectable during priorexamination. If the clip cannot be visualized in ultrasound,investigators will use stereotactic guidance (mammography).
The VAB has to be performed either concurrently to the surgicalexcision of the tumor bed or up to 1 week before surgery. Only
qualified surgeons or radiologists are allowed to perform or
supervise the VAB. Following VAB, conventional surgery isperformed, either in the form of breast conserving surgery or
mastectomy. Results obtained from the pathologist for both tissue
samples will be compared to determine whether VAB can reliably
predict pCR in patients who have undergone NAC.
Evaluations before registration
Mammography at time of diagnosis, histological confirmation ofbreast cancer, staging according to local standards, clip-control by
US, breast MRI (at diagnosis)
Evaluations within 4 weeks before or at registration
Medical history, vital signs (weight and height), mammography(limited to the clipped/affected breast), clinical examination of thebreast and the axilla, preoperative breast US and clip-control, breast
MRI (post-NAC)
Evaluations at trial intervention
Adverse events
Evaluations in the follow-up phase
Clinical examination of the breast and the axilla, adverse events

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VISION I

pCR prediction by I-VAB after NAC

IMP / Intervention:

VAB post-NAC followed by surgery (breast conserving surgery ormastectomy)

Control Intervention(if applicable):
Number ofParticipants withRationale:

Surgery is performed according to institutional routine practice in all
patients. This is a feasibility trial.
It is planned to enroll a total of 420 patients in the trial. See
statistical considerations for rationale.

Trial Duration:

Start of the trial: Q2 2020
End of accrual: Q2 2025
End of trial treatment: Q2 2025
Follow-up for 14 days after the conservative breast surgery ormastectomy
Trial termination (last patient last visit): Q2 2025

Schedule:

First-Participant-In: Q2 2020
Last-Participant-Out: Q2 2025

Coordinating
Investigator:

PD Dr. med. Christoph Tausch

Investigator(s):The Investigator List can be downloaded from the welcome page ofthe study specific SecuTrial link (hirslanden.ch/vision) and is listed inAppendix 2International and multicenter with 32 participating sites foreseen

Trial Site(s):StatisticalConsiderations:

GCP Statement:

VISION I

Brust-Zentrum, Zürich
Phone: +41 44 533 81 01
c.tausch@brust-zentrum.ch(Current status: Switzerland: 18; Germany 3; Austria: 5
The sample size is based on the primary endpoint sensitivity. With a
typeI error of 5% and a power of 80%, 179 patients in the primary
full analysis set (PFAS) with non pCR in surgical specimen will beneeded to show that the sensitivity is higher than 0.9. Consequently,
a total of 358 patients in PFAS have to be recruited to get therequired number of patients with non pCR in surgical specimen. To
account for patients who were excluded from the PFAS, the numberof patients need to be accrued will be increased to 420. The numberof patients excluded from the PFAS will be regularly checked fromthe time point where the accrual of 358 patients is reached and if
necessary the sample size will be adjusted. One interim analysis forefficacy is foreseen after 210 patients are recruited and have theirfollow-up assessment.
The primary endpoint will be analyzed based on the PFAS and otherefficacy endpoints will be analyzed based on the FAS.
This trial will be conducted in compliance with the protocol, the current
version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155(as far as applicable) as well as all national legal and regulatory
requirements.

Version 2.1, 18.05.2022

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