Sentimag Highlights of Instructions for Use Issue 1.0 July 2018

INSTRUCTIONS FOR USE: CONTENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS TM 5.1 Magtrace is for use ONLY with the Sentimag System 5.2 Interference with Magnetic Resonance Imaging 5.3 Anaphylaxis and Cardiovascular Reactions 6 POSSIBLE ADVERSE EVENTS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies 14.2 Sentinel lymph node detection 16 HOW SUPPLIED/STORAGE AND HANDLING 17 MRI SAFETY INFORMATION 18 PATIENT COUNSELING INFORMATION 19 SUMMARY OF SAFETY AND EFFECTIVENESS DATA

FULL INSTRUCTIONS FOR USE 1 INDICATIONS AND USAGE TM

®

The Magtrace and Sentimag Magnetic Localization System is indicated to assist in localizing lymph nodes draining a tumor site, as part of a sentinel lymph node biopsy procedure, in patients with breast cancer undergoing a mastectomy. Magtrace

TM

®

is intended and calibrated for use ONLY with the Sentimag system.

2 DOSAGE AND ADMINISTRATION Recommended dose is 2 ml with the equivalent iron content of circa 56 mg per dose. Inspect the seal of the vial before use to ensure it is unbroken. Do not use if the vial cap is broken, the vial is leaking, or if the expiration date has passed. Do not reuse, sterility cannot be guaranteed if the rubber seal on the vial has already been punctured. TM

TM

Draw 2 ml of Magtrace via a sterile needle and check the quantity. Administer Magtrace by subcutaneous injection into interstitial breast tissue and follow with 5 minutes vigorous massage at the injection site. Surgeons should wait at least 20 minutes before attempting transcutaneous measurement of the axilla. In patients where a transcutaneous signal cannot be obtained, continue the surgery as planned and continue to assess the location of the nodes in the tissue using the device. A signal may be found subcutaneously. Migration may be slower in older or larger patients (BMI >30) and may make it more difficult to obtain a transcutaneous signal. 3 DOSAGE FORMS AND STRENGTHS Magtrace is available in single use vials. A 2ml vial volume contains ~56 mg of iron and ~64mg carboxydextran combined in the form of carboxydextran-coated superparamagnetic iron oxide. 4 CONTRAINDICATIONS   

Known hypersensitivity to iron oxide or dextran compounds. Iron overload disease A metal implant in the axilla or in the chest.

5 WARNINGS AND PRECAUTIONS 5.1 General TM

®

®

Magtrace is intended ONLY for use with the Sentimag device, and is therefore subject to the Warnings and Precautions of the Sentimag device including the precaution that the system should not be used in patients with pacemakers. The Magtrace TM

Magtrace

TM

®

and Sentimag Magnetic Localization System should only be used by physicians experienced in sentinel lymph node biopsy, and who have been trained in its use.

is not intended for treatment of iron deficiency anemia in patients or any other medicinal applications.

The safety and effectiveness of the system have not been established in pregnant or lactating women, or in patients less than 18 years of age. For injection into interstitial tissue ONLY. 5.2 Interference with Magnetic Resonance Imaging TM

TM

Magtrace can alter magnetic resonance imaging (MRI) studies of the injection and drainage site. Some amount of alteration may be long-term. Because of this, surgeons should consider whether Magtrace appropriate for a patient on a case by case basis.

is

MagtraceTM may travel to regions away from the injection site such as liver, spleen etc if injected directly into the blood stream. In such cases the presence of MagtraceTM may cause image artefacts during Magnetic Resonance Imaging (MRI). Some manipulation of scan parameters may be required to compensate for the artefact. MagtraceTM residues have not been reported to produce artifacts affecting imaging in X-ray, PET, PET/CT, CT or ultrasound studies.

5.3 Anaphylaxis and Cardiovascular Reactions If Magtrace

TM

is inadvertently administered intravenously, anaphylaxis or cardiovascular reactions may occur.

5.4 Skin Staining Magtrace

TM

may produce temporary or longer-term skin discoloration near the injection site.

6 POSSIBLE ADVERSE EVENTS Magtrace™ is intended for injection into the breast ONLY (interstitial injection). When similar material to that used in Magtrace™ has been injected directly into the bloodstream (intravenously), the following undesirable effects have been reported:   

Common (<2%) – pain at the injection site, vasodilation, paresthesia Uncommon (≥0.1% to <1%) – asthenia, back pain, injection site reactions, chest pain, nausea, vomiting, headache, taste changes, itching, rash, inflammatory response (localized redness and swelling) with intradermal injection. Rare (≥0.01% to <0.1%) - Hypersensitivity and anaphylaxis, hypertension, phlebitis, hyperesthesia, anxiety, dizziness, convulsion, parosmia, dyspnea, increased cough, rhinitis, eczema, urticaria.

7 DRUG INTERACTIONS No interactions with other medications have been observed. Formal drug interaction studies have not been carried out. 8 USE IN SPECIFIC POPULATIONS Intravenously delivered carboxydextran-coated superparamagnetic iron oxide showed no effects on fertility and general reproductive performance of male and female rats and was non-teratogenic in rats and rabbits. Some reproductive toxicity was seen at doses far beyond the recommended dose. The potential risk for humans is unknown. 8.1 Pregnancy Risk Summary There are no available clinical data to establish whether or not Magtrace

TM

poses a risk to pregnancy outcomes.

In animal reproductive studies in rats and rabbits no evidence of prenatal toxicity was found at daily intravenous doses of 0.01 and 0.03 mmol Fe/kg/day (rats) or 0.01, 0.03, 0.1 and 0.4 mmol Fe/kg/day (rabbits). At the maximum dose of 0.5 mmol Fe/kg/day in the rat study and at 0.8 mmol Fe/kg/day in the rabbit study, evidence of toxicity in pregnant females was accompanied by a slightly increased post-implantational/prenatal loss (rats) or increased values of death/resorption rates with a lower number of living foetuses (rabbits). 8.2 Lactation Risk Summary There are no available clinical data to establish whether or not Magtrace

TM

poses a risk during lactation.

When delivered intravenously, no transfer of carboxydextran-coated superparamagnetic iron oxide or metabolized iron into breast milk was observed in lactating rats, within 24 h. It is not known if Magtrace TM excreted into breast milk in humans. Magtrace should only be given during lactation after special consideration. 8.3 Females and Males of Reproductive Potential Infertility Females In animal studies when a similar material to that used in Magtrace

TM

has been injected intravenously no effect on fertility at normal levels was seen.

TM

has been injected intravenously no effect on fertility at normal levels was seen.

Males In animal studies when a similar material to that used in Magtrace 8.4 Pediatric Use Safety and effectiveness of Magtrace

TM

have not been established in patients less than 18 years in age.

TM

is

8.5 Geriatric Use TM

There is no upper age limit for the use of Magtrace . 10 OVERDOSAGE TM

Overdose is unlikely if used as specified with a single 2 ml volume of Magtrace

administered as an interstitial injection.

11 DESCRIPTION TM

Magtrace , a magnetic tracer, contains carboxydextran-coated superparamagnetic iron oxide. The iron oxide is in the form of maghaemiteγ-Fe2O3, and the chemical formula of the carboxydextran is C6H11O6(C6H10O5)n-C6H11O5. TM

Magtrace is an aqueous suspension of carboxydextran-coated superparamagnetic iron oxide formulated with 0.3% (w/v) sodium chloride. It is a black to reddish-brown liquid, supplied in single-use vials, for a 2ml TM injection, with each milliliter of Magtrace contains ~28 milligrams of iron and ~32 mg of carboxydextran. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action TM

Magtrace consists of superparamagnetic iron oxide coated with a carboxydextran shell. The particles are sized for uptake into the lymphatics along with normal lymph flow draining from the injection site tissue. The ® TM particles are physically filtered in the draining lymph nodes where they accumulate, allowing them to be magnetically detected by the Sentimag system. When the Magtrace material is exposed to the excitation ® TM field of the Sentimag the Magtrace material responds with a temporarily induced magnetic field. 12.2 Pharmacodynamics Magtrace

TM

is a combination product with a device primary mode of action. Pharmacodynamic studies of Magtrace

TM

were not conducted.

12.3 Pharmacokinetics Magtrace

TM

TM

is a combination product with a device primary mode of action. Human pharmacokinetic studies of Magtrace

In clinical studies, Magtrace

TM

were not conducted.

has been detectable in lymph nodes within 20 minutes after injection.

Studies in mice and pigs show that Magtrace

TM

transits from the site of injection to the draining lymph nodes within 10 minutes of administration.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis TM

No animal studies for Carcinogenesis were conducted for Magtrace . Mutagenesis TM

No animal studies for mutagenesis were conducted for Magtrace . Impairment of Fertility TM

No animal studies for impairment of fertility were conducted for Magtrace . In silico studies for the carboxydextran indicate no carcinogenicity. 13.2 Animal Toxicology and/or Pharmacology Magtrace

TM

has been tested for intracutaneous sensitization according to the requirements of ISO 10993-1:2009 based on the specified site of injection and duration. These studies revealed no sensitization.

In animal studies when carboxydextran-coated superparamagnetic iron oxide has been injected intravenously the data suggested no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Intravenously administered carboxydextran-coated superparamagnetic iron oxide showed no effects on fertility and general reproductive performance of male and female rats and was non-teratogenic in rats and rabbits. Only at high multiples of the diagnostic dose given daily over the period of organogenesis, carboxydextran-coated superparamagnetic iron oxide caused post-implantation and prenatal losses and delays in development of pups in rats (at 0.5mmol Fe/kg/day representing about 50 times the diagnostic dose) and increased resorption rate and reduced the number of live fetuses in rabbits (at 0.8mmol Fe/kg/day representing about 80 times the diagnostic dose.)

No evidence of a sensitizing (contact-allergenic) potential was seen using the maximization test in guinea-pigs. It has been observed that intravenously delivered carboxydextran-coated superparamagnetic iron oxide induces anaphylactic (hypersensitivity) reactions in dextran-sensitized dogs. 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies TM

The safety and effectiveness of Magtrace

was assessed in two paired comparison clinical trials. TM

®

Study 1 was a pivotal, open-label, multicenter paired comparison of the Magtrace (carboxydextran-coated superparamagnetic iron oxide) and Sentimag Magnetic Localization System and the combined radioisotope and blue dye for sentinel lymph node detection in patients with breast cancer or ductal carcinoma in-situ (DCIS) scheduled for sentinel node biopsy. Radioisotope (Technetium sulfur colloid) was injected TM according to the standard of care protocol at each site, and blue dye was injected shortly prior to surgery according to the site protocol. Magtrace was injected at least 20 minutes prior to initiating sentinel lymph node mapping. ®

Lymph node detection was performed intraoperatively using the Sentimag probe to identify magnetic nodes, followed by the use of a handheld gamma probe to identify radioactive ('hot') nodes. Any blue or black/brown stained nodes, and any nodes judged to be highly clinically suspicious by the surgeon were also excised. The excised nodes were evaluated using histopathology. The detection rate in confirmed lymph nodes for the magnetic technique and the standard of care technique was determined. In Study 1, 147 female patients underwent sentinel lymph node biopsy (SLNB). The median age was 61 years. ®

Study 2 was an open-label, multicenter, paired comparison of Sentimag and Sienna+ (carboxydextran-coated superparamagnetic iron oxide) and radioisotope with or without blue dye for sentinel lymph node detection in patients with breast cancer scheduled for sentinel node biopsy. Sienna+ is an earlier formulation of carboxydextran-coated superparamagnetic iron oxide requiring dilution with saline prior to injection. Radioisotope (Technetium albumin colloid) was injected according to the standard of care protocol at each site. 45/108 (42%) of patients also received a blue dye injection shortly prior to surgery at sites where blue dye was standard protocol. Sienna+ was injected at least 20 minutes prior to initiating sentinel lymph node mapping. ®

Lymph node detection was performed intraoperatively using the Sentimag probe to identify magnetic nodes, followed by the use of a handheld gamma probe to identify radioactive ('hot') nodes. Any blue or black/brown stained nodes, and any nodes judged to be highly clinically suspicious by the surgeon were also excised. The excised nodes were evaluated using histopathology. In Study 2, 108 female patients underwent SLNB. The median age was 58 years. 14.2 Sentinel lymph node detection In Studies 1 and 2 efficacy analyses were based on the nodal detection rate per patient and per node. Table 1 shows the per patient detection rates for the magnetic technique and the standard of care control TM techniques, and Table 2 shows the per node detection rates. Additional analyses were conducted to evaluate the presence or absence of Magtrace in nodes excised from patients determined by pathologic staging TM to have cancer spread to at least one lymph node. In Study 1 Magtrace identified 21/22 node positive breast cancer patients and in Study 2, Sienna+ identified 45/46 node positive breast cancer patients. TM

Table 1. Per patient lymph node detection rates for Magtrace Study

Study 1

Study 2

Number of Patients (N)

147

108

(or Sienna+) and Radioisotope with or without blue dye in patients with breast cancer or DCIS. TM

Active Comparator present

Magtrace

(95% CI)

Present

Only Active Comparator present (95% CI)

Only MagtraceTM present (95% CI)

Neither Active Comparator nor MagtraceTM present

Radiopharmaceutical

Either Blue Dye and/or Radiopharmaceutical

(95% CI)

79.6% (117/147)

95.2% (140/147)

98.0% (144/147)

98.6% (145/147)

0.0% (0/147)

0.0% (0/147)

0.0% (0/147)

0.7% (1/147)

0.7% (1/147)

(72.2%, 85.8%)

(90.4%, 98.1%)

(94.2%, 99.6%)

(95.2%, 99.8%)

(0.0%, 2.5%)

(0.0%, 2.5%)

(0.0%, 2.5%)

(0.0%, 3.7%)

(0.0%, 3.7%)

81.0% (34/42)

95.4% (103/108)

95.4% (103/108)

97.2% (105/108)

0.0% (0/108)

0.9% (1/108)

2.8% (3/108)

1.9% (2/108)

(65.9%, 91.4%)

(89.5%, 98.5%)

(89.5%, 98.5%)

(92.1%, 99.4%)

(0.0%, 3.4%)

(0.0%, 5.1%)

(0.6%, 7.9%)

(0.2%, 6.5%)

Blue Dye

Only Blue Dye

Only RadioBoth Comparators pharmaceutical

(95% CI)

Table 2. Per node lymph node detection rates for Magtrace Study

Number of Nodes (N)

Study 1

369

Study 2

214

TM

(or Sienna+) and Radioisotope with or without blue dye in patients with breast cancer or DCIS.

Active Comparator present

MagtraceTM

Only Active Comparator present

(95% CI)

Present

(95% CI)

Radiopharmaceutical

Either Blue Dye and/or Radiopharmaceutical

(95% CI)

48.8% (180/369)

91.6% (338/369)

93.5%* (345/369)

(43.6%,54.0%)

(88.3%, 94.2%)

(90.5%, 95.8%)

68.4% (54/79)

90.2% (193/214)

N/R

(57.0%, 78.4%)

(85.4%, 93.8%)

Blue Dye

*p ≤ 0.01 for main efficacy endpoint, Magtrace

TM

Only MagtraceTM present

Neither Active Comparator nor MagtraceTM present

Only Blue Dye

Only RadioBoth Comparators pharmaceutical

94.3%* (348/369)

0.0% (0/369)

3.8% (14/369)

1.4% (5/369)

6.0% (22/369)

0.5% (2/369)

(91.4%, 96.4%)

(0.0%,1.0%)

(2.1%, 6.3%)

(0.4%, 3.1%)

(3.8%, 8.9%)

(0.1%, 1.9%)

97.2% (208/214)

0.0% (0/214)

2.3% (5/214)

9.3% (20/214)

0.5% (1/214)

(94.0%, 99.0%)

(0.0%, 1.7%)

(0.8%, 5.4%)

(5.8%, 14.1%)

(0.0%, 2.6%)

(95% CI)

(95% CI)

non-inferiority to Control.

16 HOW SUPPLIED/STORAGE AND HANDLING Magtrace

TM

is supplied in single-use vials. TM

Each vial contains 2ml Magtrace . Storage o

o

Store between +2 C and +30 C (36˚F and 86˚F) DO NOT FREEZE. 17 MRI SAFETY INFORMATION Non-clinical testing has demonstrated that Magtrace

TM

is MR Conditional. A patient who has been injected with this solution can be safely scanned in an MR system meeting the following conditions:



Static magnetic field of 1.5-Tesla (1.5 T) or 3-Tesla (3 T).



Maximum spatial field gradient of 4,000 G/cm (40 T/m).



Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 4.0 W/kg (First Level Controlled Operating Mode) at 1.5 T and 3 T. TM

Under the scan conditions defined above, Magtrace

is expected to produce a maximum temperature rise of less than 4.0˚C after 15 minutes of continuous scanning.

Caution: The RF heating behavior does not scale with static field strength. Devices that do not exhibit detectable heating at one field strength may exhibit high values of localized heating at another field strength. In non-clinical testing, the image artifact caused by Magtrace

TM

extends approximately 4.7 cm from the injected solution when imaged with a gradient-echo pulse sequence in a 3 T MRI system.

18 PATIENT COUNSELING INFORMATION    

Question patient regarding any prior history of iron overload disease, reactions to iron oxide or dextran products. Inform patient to report any signs and symptoms of hypersensitivity that may develop during and/or following administration, such as rash, itching, dizziness, lightheadedness. Advise patient that some long-term brownish skin coloration may occur. Advise patient that Magtrace® may alter post-operative magnetic resonance imaging (MRI) scans. Some alteration may be long-term.

Symbols Single Use

Store between temperatures indicated

Expiration Date specified on vial

Manufacturer

Lot or batch number specified on vial

CE mark for Medical Device as specified by the Medical Device Directive 93/42/EEC

Aseptically Filled For Use by, or on the Order of, a Physician Read Instructions Manufactured by: Endomagnetics Limited Warnings and Cautions specified in instructions

The Jeffreys Building Cowley Road, Cambridge

MR Conditional

Do not use if vial is open or damaged

CB4 0WS, United Kingdom Endomagnetics, Inc., 1701 Trinity Street, Mail Code Z1400 Austin, TX, 78712-1885, USA

19. SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I.

SUMMARY OF PRIMARY CLINICAL STUDIES TM

®

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of the Magtrace and Sentimag Magnetic Localization System for localizing lymph nodes draining a tumor site in patients with breast cancer, as part of a sentinel lymph node biopsy procedure in the US (IDE #G140208, NCT02336737). An additional supporting study was conducted in France (NCT01790399) which was an open-label, multicenter, paired comparison of Sentimag and Sienna+ and radioisotope with or without blue dye for sentinel TM lymph node detection in patients with breast cancer scheduled for sentinel node biopsy. Sienna+ is an earlier formulation of Magtrace requiring dilution with saline prior to injection. Note: The French Sentimag Feasibliity Trial is discussed in the Summary of Supplemental Clinical Information section (Section III) because it was only supporting clinical data. Table 1: Clinical Studies Study

Products used

U.S. Sentimag trial G140208, NCT02336737

Magtrace , Sentimag

French Sentimag Feasibility Trial, NCT01790399

Sienna+, Sentimag Multi-center paired comparison with Radioisotope ± Blue dye

TM

Study design

Location

Number of subjects (sites)

Multi-center paired comparison with Radioisotope + Blue dye

US

160 (6)

France

115 (4)

A. Study Design Patients were treated between 9 January 2015 and 16 December 2015. The database for this PMA reflected data collected through 16 December 2015 and included 160 patients. There were 6 investigational sites in the United States. TM

®

The study was a pivotal prospective open label multicenter, paired comparison study of The Magtrace and Sentimag Magnetic Localization System with the standard of care (Tc-99m radioisotope with blue dye) for the detection of lymph nodes in patients with breast cancer undergoing a sentinel lymph node biopsy (G140208). The trial was designed to provide powered evidence that the lymph node detection rate of The TM ® Magtrace and Sentimag Magnetic Localization System is non-inferior to the standard of care in patients with breast cancer and to summarize measures of product safety and performance. The active control was Technetium 99 labelled sulfur colloid radioisotope in combination with isosulfan blue dye. The control was administered according to the standard of care at each site. All subjects underwent TM simultaneous lymph node mapping using Magtrace , and with radioisotope with blue dye. TM

The trial sought to reject a null hypothesis that the true per lymph node detection rate for Magtrace was worse than or equal to the true lymph node detection rate for standard of care by more than the non-inferiority TM margin δ, and support the alternative hypothesis that the true lymph node detection rate of Magtrace was no worse than the true lymph node detection rate for standard of care less the non-inferiority margin δ, i.e., H0: PT – PC ≤ –δ (inferior) Ha: PT – PC > –δ (non-inferior), where PT and PC are the lymph node detection rates for Magtrace

TM

and standard of care Control, respectively, and δ is the non-inferiority margin.

The sample size calculation for the primary endpoint was performed using PASS 2008 and was based on a non-inferiority (one-sided) test of correlated proportions and the method of Nam with the following assumptions:



TM

®

Expected Magtrace /Sentimag (test) rate = 95%

    

Expected standard of care (Control) rate = 95% Non-inferiority margin (δ) = 5% Assumed discordance rate = 8% Test significance level (α) = 0.05 (1-sided) Power (1-β) ≈ 0.85

A minimum of 265 nodes were required for each method. Given that ~2 lymph nodes were expected per subject, it was anticipated that a total of 140 subjects would be required. The expected per node detection rate for the standard of care combined technique was 94.6% based on the NSABP B-32 trial (Krag et al., Sentinel-lymph-node resection compared with conventional axillary-lymphnode dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial., Lancet Oncol. 2010 Oct;11(10):927-33.). 1.

Clinical Inclusion and Exclusion Criteria TM

®

Enrollment in the Magtrace /Sentimag study (G140208) was limited to patients who met the following inclusion criteria 

Subjects with a diagnosis of primary breast cancer or subjects with pure ductal carcinoma in situ (DCIS)



Subjects scheduled for surgical intervention, with a sentinel lymph node biopsy procedure being a part of the surgical plan



Subjects aged 18 years or more at the time of consent



Subjects with an ECOG performance status of Grade 0 – 2



Subject has a clinical negative node status (i.e. T0-3, N0, M0) ®

Patients were not permitted to enroll in the Sentimag study if they met any of the following exclusion criteria:

2.



The subject is pregnant or lactating



The subject has clinical or radiological evidence of metastatic cancer including palpably abnormal or enlarged lymph nodes



The subject has a known hypersensitivity to Isosulfan blue dye



The subject has participated in another investigational drug study within 30 days of scheduled surgery



Subject has had either a) previous axilla surgery, b) reduction mammoplasty, or c) lymphatic function that is impaired in the surgeon’s judgment



Subject has had preoperative radiation therapy to the affected breast or axilla



Subject has received a Feraheme (ferumoxytol) Injection within the past 6 months



Subject has intolerance or hypersensitivity to iron or dextran compounds or to Magtrace



Subject has an iron overload disease



Subject has pacemaker or other implantable device in the chest wall

®

Study Procedure and Follow-up Schedule

The study procedure flow is depicted in figure 1 below. Figure 1 : Sentinel Node Biopsy Procedure Flow

TM

Start of Procedure

Incision

Radioisotope injection

SLN localization with SentiMag

Anaesthesia

SLN localization with gamma probe

Sienna+ injection > 20 mins before incision

SLN excision (also excise any blue nodes or highly clinically suspicious nodes)

5 mins massage of injection site Patient preparation

Ex-vivo SLN ‘count’ measured on SentiMag

Blue dye injection Ex-vivo SLN ‘count’ measured on gamma probe

Transcutaneous SLN localization using gamma probe

Lymph node sent for histological analysis

Transcutaneous SLN localization using SentiMag

Document data

Lumpectomy or mastectomy procedure with or without breast reconstruction

Standard of care Conclusion of Procedure

Additional for clinical trial

®

Each SLN identified by Sentimag and/or gamma probe or stained blue or black was excised and additional counts, with the excised node on the end of the probe, were taken with each detection system (Sentimag and gamma probe) and recorded. In addition, nodes that were deemed highly clinically suspicious nodes (e.g. very hard and firm, or, white colored consistent with gross tumor in the lymph node) were excised as sentinel nodes. Sentinel lymph node biopsy (SLNB) was stopped when the residual count/signal in the axilla was less than 10% of the largest ex-vivo reading from an already excised node using that detection method. All patients were scheduled to return for follow-up examinations at between 6 and 22 days post-procedure for a safety assessment postoperatively. The study visits and assessments are summarized in Table 2. Table 2: Study Visits and Data Collection Overview

Procedure/ Assessment

Inclusion / Exclusion Criteria

Screening / Enrollment

X

Visit 1

Visit 2

Baseline / Medical History

Sentinel Node Biopsy Procedure

Visit 3 Post-procedure Evaluation (14 days +/- 8 days)

Unscheduled Visit

®

Screening / Enrollment

Procedure/ Assessment

Informed Consent

Visit 1

Visit 2

Baseline / Medical History

Sentinel Node Biopsy Procedure

Visit 3 Post-procedure Evaluation

Unscheduled Visit

(14 days +/- 8 days)

X

Demographics, Medical / Surgical History

X

Pregnancy test

X

Lymph node mapping and sentinel node biopsy procedure

X

Excised nodes sent for histological analysis & pathology evaluation

X

SLN Biopsy results

X

Adverse Event Assessment

X

X

X

X

Medications

X

X

X

X

Device Deficiency Assessment

X

Study Completion

3.

X

Clinical Endpoints

Primary Safety Endpoint: TM

To provide evidence of the safety of the Magtrace procedure.

®

and Sentimag Magnetic Localization System as indicated by adverse events and serious adverse events and their relatedness to the detection method or

Primary Effectiveness Endpoint: TM

®

The primary effectiveness endpoint was the lymph node detection rate, which is defined as the number of lymph nodes identified by a specific method (Magtrace /Sentimag or Control) divided by the total number of lymph nodes detected. Success/Failure Criteria: TM

®

The study was considered a success if the Magtrace and Sentimag Magnetic Localization System demonstrated a statistically significantly non-inferior lymph node detection rate compared to the Control, with a 5% non-inferiority margin. If the lower bound of the one-sided 95% confidence interval for the difference between detection rates at the nodal level was greater than -5%, then the study was considered a success. B.

Accountability of PMA Cohort

At the time of database lock, of 160 patients enrolled in the PMA study, 147 patients completed the study and are available for analysis. Patient accountability is shown in Figure 4. Thirteen patients withdrew from the study prior to sentinel lymph node biopsy procedure as follows: 5 patients withdrew themselves, and 8 patients were withdrawn by investigators for the following reasons:

     

2 received the incorrect isotope injection (Lymphoseek (technetium Tc 99m tilmanocept) instead of Tc-99m sulfur colloid) 2 were found not to meet the inclusion/exclusion criteria 1 was withdrawn due to concerns regarding her history of thalassemia 1 was found to have axillary metastasis on a PET scan 1 was withdrawn as there was no study coordinator on site to record the study data 1 patient opted for chemotherapy prior to surgery

The primary analysis set was the modified intent to treat (mITT) cohort comprising all subjects who completed the study procedures (n=147). Figure 2: Sentimag IC trial patient accountability tree

Consented N=160

Withdrew prior to SLNB procedure N=13 8 Investigator withdrawal

Completed study

5 Withdrawal by subject

N=147

Modified intent to treat (mITT) cohort. Primary Analysis set

Per Protocol (PP) cohort N=133

Protocol deviations N=14

C.

Study Population Demographics and Baseline Clinicopathological Characteristics

Patient demographic characteristics are shown in Table 3 with the patient baseline clinicopathological characteristics given in Table 4. Table 3: Study Population Demographics Overall (N=147) Race (not mutually exclusive, %) American Indian or Alaska Native

0.0%

Asian

4.8 %

Black or African American

7.5%

Pacific Islander

0.0%

White

82.3%

Other

6.1%

Ethnicity (n/N (%)) Hispanic or Latino

11.6%

Not Hispanic or Latino

88.4%

Mean Age (SD)

61.1 (12.3)

Mean Weight in lbs (SD)

167.1 (38.5)

Mean Height in inches (SD)

63.7 (2.6) 2

Mean Body Mass Index (BMI Kg/m (SD))

29.0 (6.9)

Menopausal status Premenopausal

19.0%

Perimenopausal

3.4%

Postmenopausal

77.6%

Table 4: Baseline Patient Clinicopathological Characteristics Type of surgery * Wide Local Excision/Lumpectomy

103/147 (70.1)

Mastectomy

43/147 (29.3)

Tumor location Upper Outer Quadrant (UOQ)

74/147 (50.3)

Upper Inner Quadrant (UIQ)

28/147 (19)

Lower Inner Quadrant (LIQ)

10/147 (6.8)

Lower Outer Quadrant (LOQ)

26/147 (17.7)

Central/Areolar

9/147 (6.1)

Pathological tumor size pTis

13/135 (9.6)

pT1a

19/135 (14.1)

pT1b

30/135 (22.2)

pT1c

33/135 (24.4)

pT2

33/135 (24.4)

pT3

7/135 (5.2)

Tumor grade I

45/135 (33.3)

II

51/135 (37.8)

III

37/135 (27.4)

IV

0/135 (0.0)

Not assessable

2/135 (1.5)

Estrogen Receptor (ER) Status (n/N (%)) Positive

113/135 (83.7)

Negative

13/135 (9.6)

Not performed

9/135 (6.7)

Progesterone Receptor (PR) Status (n/N (%)) Positive

87/135 (64.4)

Negative

39/135 (28.9)

Not performed

9/135 (6.7)

Human Epidermal Growth Factor Receptor (HER2) Status (n/N (%)) Positive

13/135 (9.6)

Negative

105/135 (77.8) 17/135 (12.6)

Not performed * One patient had SLNB only

D.

Safety and Effectiveness Results 1.

Safety Results

The analysis of safety was based on the cohort of 147 evaluable patients. The key safety outcomes for this study are presented below. Adverse effects are reported in Tables 5 and 6. Adverse events that occurred in the PMA clinical study: A total of 69 adverse events were reported in 56/147 (38.1%) subjects, and of these adverse events, 9 (13.0%) were considered serious (SAE). The most common adverse events were breast discoloration / hyperpigmentation, which occurred in 16.3% (24/147) of subjects and ecchymosis / bruising, which occurred in 6.8% (10/147) of subjects.

Table 5: Adverse events by type Events

Subjects

N

n (%)

Total Adverse Events

69

56 (38.1)

Breast Discoloration/Hyperpigmentation

24

24 (16.3)

Ecchymosis / Bruising

10

10 (6.8)

Pain

5

5 (3.4)

Other

5

5 (3.4)

Gastrointestinal Disorder

3

3 (2.0)

Cellulitis

3

3 (2.0)

Skin Ischemia

3

3 (2.0)

Cardiac Disorder

3

3 (2.0)

Rash

2

2 (1.4)

Erythema

2

2 (1.4)

Respiratory Disorder

1

1 (0.7)

Hypertension

1

1 (0.7)

Hypotension

1

1 (0.7)

Pulmonary Embolism

1

1 (0.7)

Musculoskeletal Disorder

1

1 (0.7)

Psychological Disorder

1

1 (0.7)

Allergic Reaction

1

1 (0.7)

Pleural Effusion

1

1 (0.7)

Inflammation

1

1 (0.7)

Adverse Event Type

TM

Table 6 shows Magtrace -related adverse events. If an adverse event was assessed as having an “undetermined” relationship, it was conservatively considered “related”. TM

TM

Twenty (20) events occurring in 20 subjects (13.6%) were related to Magtrace , and 6 events occurring in 6 subjects (4.1%) were assessed as having an undetermined relatedness in relation to Magtrace . There TM were 9 serious adverse events in the study. After data analysis, 7 out of the 9 SAEs were unrelated to the Magtrace , and 2 of the 9 SAEs were found to be undetermined ( Bradycardia and Anaphylaxis). TM

Table 6: Magtrace -Related Adverse Events TM

Magtrace -Related Adverse Events Adverse Event Type

Events N

Total Adverse Events

26

25 (16.3)

Breast Discoloration/Hyperpigmentation

23

23 (15.6)

Erythema

1

1 (0.7)

1

1 (0.7)

1

1 (0.7)

1

Anaphlaxis

2 3

Cardiac Disorder

Subjects n (%)

1

Breast Discoloration: The degree and duration of skin staining is unknown.

2

Anaphylaxis: During the procedure the patient developed tongue swelling, hypotension and tachycardia treated with epinephrine and steroids and the event resolved that day.

3

Cardiac Disorder: Thirty minutes after injection bradycardia followed by pulselessness treated with atropine, CPR with intubation and the event resolved.

2.

Effectiveness Results

The analysis of effectiveness was based on the 147 evaluable patients who completed the study. Key effectiveness outcomes are presented in Tables 7 to Table 13. Primary Endpoint Analysis The primary endpoint was the lymph node detection rate, which is defined as the number of lymph nodes identified by a specific method (Magtrace or Control) divided by the total number of lymph nodes detected TM ® (n=369). The Magtrace and Sentimag Magnetic Localization System had a detection rate 94.3% and the control detected 93.5% of the total nodes detected. The difference in detection rates between the methods TM (Magtrace - Control) was 0.8% with a 95% one-sided lower confidence bound of -2.1%.

Table 7: Summary of Overall mITT Study Results G140208 Pivotal Study Breast Cancer Magtrace

TM

n = 147

Radioisotope with blue dye n = 147

Nodes detected (n)

348

345

Per node lymph node detection rate % (95% CI)

94.3%

93.5%

(91.9%, 96.7%)

(91.0%, 96.0%)

98.6%

98.0%

(95.2%, 99.8%)

(94.2%, 99.6%)

Per patient lymph node detection rate % (95% CI) Overall per patient concordance % (95% CI)

98.0%

Patients with at least one positive (metastatic) node (n)

22

Detection rate for patients with at least one metastatic node % (95% CI)

95.5%

95.5%

(86.8%, 100.0%)

(86.8%, 100.0%)

(94.2%, 99.6%)

Table 8: The nodal detection rates TM

Magtrace Control (Radioisotope and Blue Dye)

Detected

Not Detected

Total

Detected

326

19

345 (93.5%)

Not Detected

22

2

--

Total

348 (94.3%)

--

369 (100.0%)

1

1

Four sentinel lymph nodes are excluded due to missing data for Magnetic (Magtrace) count, Radioisotope count and/or Blue Dye.

There were 41 discordant nodes in 29 subjects; 19 were found by control only and 22 were found by Sentimag only.

Table 9: Findings of Discordant Lymph Nodes Overall discordant Nodes

Rate

Number of Nodes Detected by Test but not Control

Number of Nodes Detected by Control but not Test

41/369

11.1%

22 (in 16/29 patients)

19 (in 13/29 patients)

All of the discordant nodes had no clinical impact as:

 

All malignant SLNs were concordant All discordant SLNs were benign. (See Table 15 malignant nodes table)

Table 10: Sentinel Node per-Node Detection Rates by Radioisotope Alone Magtrace

TM

Radioisotope

Detected

Not Detected

Total

Detected

319 (86.4%)

19 (5.1%)

338 (91.6%)

Not Detected

29 (7.9%)

2 (0.5%)

--

Total

348 (94.3%)

--

369 (100.0%)

1

1

TM

Four sentinel lymph nodes are excluded due to missing data for Magnetic (Magtrace ) count, Radioisotope count and/or Blue Dye.

Table 11: Sentinel Node per-Node Detection Rates by Blue Dye Alone Magtrace

TM

Blue Dye

Detected

Not Detected

Total

Detected

175 (47.4%)

5 (1.4%)

180 (48.8%)

Not Detected

173 (46.9%)

16 (4.3%)

--

Total

348 (94.3%)

--

369 (100.0%)

1

1

TM

Four sentinel lymph nodes are excluded due to missing data for Magnetic (Magtrace ) count, Radioisotope count and/or Blue Dye.

Table 12: Sentinel Node per-Subject Detection Rates by Method Magtrace Control

TM

(Radioisotope and Blue Dye)

At Least 1 Node Detected

No Nodes Detected

Total

At Least 1 Node Detected

144/147 (98.0%)

0 (0.0%)

144 (98.0%)

No Nodes Detected

1/147 (0.7%)

1/147 (0.7%)

--

Total

145/147 (98.6%)

--

147 (100.0%)

Other Endpoint Analysis Table 13: Results of Other Per Node Endpoints Per Node Endpoints n/N Rate (95% CI) Overall Nodal Concordance Number of nodes identified by both test and Control out of all nodes identified Overall Nodal Discordance Number of nodes identified by either test or Control (but not by both) out of all nodes identified Nodal concordance Number of nodes identified by both test and Control out of nodes identified by Control Reverse nodal concordance Number of nodes identified by both test and Control out of nodes identified by test

326/369 (88.3%) CI (85.1%, 91.6%) 41/369 (11.1%) CI (7.9%, 14.3%) 326/345 (94.5%) CI (92.1%, 96.9%) 326/348 (93.7%) CI (91.1%, 96.2%)

Table 14: Number of Lymph Nodes Detected per Subject Assessed for Each Method. Mean (S.D)

Median

Magtrace,

2.4 (1.19)

2

0-6

Control

2.4 (1.34)

2

0-6

Radioisotope

2.3 (1.38)

2

0-6

Blue Dye

1.2 (0.93)

1

0-4

3.

Range

Subgroup Analysis

Per node endpoints for cancer positive (malignant) nodes The nodal status was reported as the percentage of histologically malignant nodes detected by a specific detection method (magnetic; combined radioisotope and blue dye; radioisotope alone; blue dye alone) on a per node and a per subject basis. TM

Of the 25 confirmed analyzable positive (malignant) nodes in the mITT analysis set, 96.0% (24/25) with a 95% CI of (88.3%, 100.0%) were identified by both the Control radioisotope or blue dye, and Magtrace . TM TM One (1) node was not identified by either Control or Magtrace , but was considered 'highly clinically suspicious' in the judgment of the investigator. All the nodes identified by either Magtrace or Control were TM identified by both Magtrace and Control. Blue dye detected 60.0% (15/25). TM

TM

Of the 24 malignant nodes identified by both Magtrace and Control, 19 contained macrometastasis, and 5 contained micrometastasis. The one node that was not identified by either Control or Magtrace considered clinically suspicious contained a macrometastasis.

but was