[68Ga]Ga-ABY-025 PET for Quantification of HER2-status in Solid Tumors

Phase II Study of [68Ga]Ga-ABY-025 PET for Non-invasive Quantification of HER2-status in Solid Tumors

The goal of this phase II clinical trial is to improve the selection of patients with solid tumors who would benefit from effective treatment with HER2 targeted drugs. This will be achieved by examining patients with HER2 positive tumors in the esophagus or stomach or patients with advanced breast cancer with low HER2 expression (HER2low) with the HER2 specific positron emission tomography (PET) tracer ABY-025 (HER2-PET) and compare the imaging results with HER2 expression in tumor tissue derived from biopsies (reference standard).

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Esophageal Neoplasms; HER2-positive Gastric Cancer; Gastric Neoplasms Malignant
• Intervention / Treatment: Diagnostic test: [68Ga]Ga-ABY-025 PET; Diagnostic test: Biopsy and analysis of HER2 expression

Detailed Description

The goal of this phase II interventional clinical trial is to evaluate the HER2-status in tumor lesions measured by Gallium-68-ABY-025-uptake on PET/CT with HER2-status defined by reference standard (laboratory analyses) in patients with gastroesophageal cancer (GEAC) and metastatic breast cancer with low HER2 expression (HER2-low mBC).

The participants in GEAC cohort of the study will undergo two sessions of HER2 PET and one 18-Fluorodeoxyglucose (18F-FDG) PET/CT for study purposes. The first HER2 PET is performed within 21 days before initiation of the systemic oncological treatment and is followed by tumor biopsies. A second HER2 PET and a second 18F-FDG PET will be performed adjacent to response evaluation after 3 courses of oncological therapy. Data from the PET investigations will be compared to HER2 expression analyses of the biopsy specimen and correlated to disease and survival data at follow up one year after inclusion. Within the pilot study, participants with HER2 low mBC will undergo one HER2 PET followed by biopsies.

• Study Type: Interventional
• Enrollment (Anticipated): 72
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rimma Axelsson, Prof., MD; Phone Number: +46 8 585 800 00; Email: rimma.axelsson@ki.se
• Study Contact Backup: Name: Siri af Burén, MD; Phone Number: +46739099570; Email: siri.afburen@regionstockholm.se

Study Locations

• Sweden
  • Stockholm, Sweden, 14186
    • Recruiting
    • Department of Radiation Physics and Nuclear Medicine, Karolinska University Hospital
    • Contact: Siri af Burén, MD; Phone Number: +46739099570; Email: siri.afburen@regionstockholm.se
    • Contact: Rimma Axelsson, Prof; Phone Number: +46858580000; Email: rimma.axelsson@ki.se
    • Principal Investigator: Rimma Axelsson, Professor
    • Sub-Investigator: Renske Althena, MD, PhD
    • Sub-Investigator: Magnus Nilsson, Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18 years.
2. The subject has given written consent to participate in the study.
3. Patients with metastatic disease because of gastroesophageal adenocarcinoma or HER2-low breast cancer. Cohort 1: Histologically confirmed HER2-positive primary gastroesophageal adenocarcinoma, scheduled for palliative HER2-targeted therapy; Cohort 2: HER2-low metastatic breast cancer first within a pilot study (of which five patients with de novo HER2-low mBC and five patients with pre-treated HER2-low mBC). Later, within a post-pilot study. Definition of HER2 positivity (ASCO College of American Pathologist 2018. HER2 Testing for Breast Cancer Guidelines.) HER2-low mBC is defined as IHC 1+ or IHC 2+ but ISH negative.
4. At least one metastatic lesion ≥ 10 mm is available for biopsy defined on CT.
5. At least one (and up to five) additional metastatic index lesion/s ≥ 10 mm for evaluation of treatment effect
6. World Health Organization (WHO) performance status ≤ 2.
7. Expected survival > 12 weeks.

Exclusion Criteria:

1. Significantly impaired renal function (GFR <30 ml/min/1.73 m2)
2. Allergy to iodinated contrast media
3. Subjects that for some reason are unable to exercise their rights, such as cognitive function impairment.
4. Other manifest malignancy except for basal cell carcinoma of the skin.
5. The patient presenting any contraindication for the use of HER2 targeted therapy for metastatic disease: congestive heart failure, baseline left ventricular ejection fraction (LVEF) less than 50%, transmural myocardial infarction, uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg), angina pectoris requiring medication, clinically significant valvular heart disease, high-risk arrhythmias, lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome, active gastrointestinal bleeding.
6. Inadequate organ function, suggested by the following laboratory results: absolute neutrophil count <1,500 cells/mm3, haemoglobin <90 g/L, total bilirubin ≥1.5 x Upper Limit of Normal (ULN) (unless the patient has documented Gilbert's syndrome), Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or Alanine aminotransferase (ALT)/ serum glutamic pyruvic transaminase (SGPT) >5.0 x ULN.
7. Positive pregnancy test in women of childbearing potential (premenopausal or <12 months of amenorrhea post-menopause and who have not undergone surgical sterilization), or lactation.
8. Female patients of childbearing potential and sexually active and not willing to use a highly effective contraceptive. Examples of highly effective contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone releasing intrauterine devices (IUDs), and copper IUDs. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Women must refrain from donating eggs during this same period.

9. Patients with increased risk of complications from biopsies, i.e. increased risk of bleeding, defined as

   • prothrombin time test (INR value) >1.4, platelet count <70 (109/l), activated partial thromboplastin time (APTT) >30s.
   • known bleeding disorder such as hemophilia, von Willebrand disease or platelet disorders.
   • any anticoagulants or antiplatelet treatment (except for low-dose acetyl-salicylic acid (ASA), i. e 75 mg daily).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Patients with HER2 positive GEAC or HER2 low cancer (pilot); The participants of the study will undergo two sessions of HER2 PET and one 18F-FDG PET/CT for study purposes. The first HER2 PET is performed within 21 days before initiation of the systemic oncological treatment including HER2-targeted drugs, and is followed by tumor biopsies. A second HER2 PET and a second 18F-FDG PET will be performed adjacent to response evaluation after 3 courses of oncological therapy. Data from the PET investigations will be compared to HER2 expression analyses of the biopsy specimen and correlated to disease and survival data at follow up one year after inclusion. Within the pilot study, participants with HER2 low mBC will undergo one HER2 PET followed by biopsies.

Diagnostic test: [68Ga]Ga-ABY-025 PET; [68Ga]Ga-ABY-025 PET: Each patient in Cohort 1 will be imaged with a PET/CT twice using the radiolabeled investigational product ABY-025 as a tracer. At the time of injection, a 45-minutes long dynamic scan will take place over a pre specified region of interest. Three hours after injection a full body PET scan followed by a CT scan will be performed.; Other Names: HER2 PET; Diagnostic test: Biopsy and analysis of HER2 expression; Biopsy: Within 3 days after the first ABY-025-PET a tissue sample from at least one metastasis >10 mm available for biopsy, preferably shallow lymph nodes, will be analyzed for HER2 expression through immunohistochemistry- (IHC) and in situ hybridization- (ISH) analysis in patients with GEAC and HER2low mBC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of HER2-positive lesions	Percentage of HER2-positive lesions (primary tumors and/or metastases) measured by tracer uptake on PET/CT which are also positive regarding HER2-status defined by reference biopsy-based standard used in clinical routine in patients with GEAC	up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SUV	Optimal Standardized Uptake Values (SUVs) cut-off values for separating HER2-positive/or HER2-low from HER2-negative lesions by reference standard methods.	up to 24 months
TBR	Tumor-to-Background Ratio (TBR) cut-off values for separating HER2-positive/or HER2-low from HER2-negative lesions by reference standard methods.	up to 24 months
Intra-individual heterogeneity of HER2-positivity	Percentage of tracer uptake sites on whole-body HER2 PET compared to all known cancer-related lesions, determined on the routine radiological investigation with CT as an estimation of intra-individual heterogeneity of HER2-positivity.	up to 24 months
Feasibility in HER2low	Percentage of false-negative findings on HER2 PET compared to results from immunohistochemistry testing (IHC) from at least one index lesion in patients with HER2-low mBC.	up to 24 months
HER2 positive cancer burden	Percentage of tracer uptake in sites, not previously determined on the routine radiological investigation with CT, as a measure of cancer burden determined on the whole body HER2 PET in tumor lesions.	up to 24 months
Safety aspects of ABY-025	Frequency of Adverse Events (AEs), Adverse Reactions (ARs), Serious Adverse Events (SAEs), and Suspected Unexpected Serious Adverse Reactions (SUSARs).	up to 36 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment response 1	To examine the change in HER2 expression measured by tracer uptake on PET/CT (SUVs and TBR) performed after 3 courses of chemotherapy/HER2 targeted drugs compared to pre-treatment values and in which proportion of the examined patients this occur.	up to 36 months
Treatment response 2	Changes in SUVs in index lesions, as well as in the total HER2-positive tumor volume at HER2 PET (percentage) before and after treatment with systemic therapy including HER2 targeted drugs to evaluate treatment response.	up to 36 months
Comparison between HER2 PET and FDG PET	Comparison of treatment response evaluation performed by HER2 PET versus 18F-FDG PET/CT defined as percentage of complete and partial response, stable and progressive disease (percentage of concordant results).	up to 24 months
HER2 PET as a prognostic tool	The correlation between HER2 expression measured by a total HER2-positive tumor volume at HER2 PET before treatment and progression-free survival (PFS), overall (or clinical) response rate to systemic therapy (ORR) at 12 months after inclusion.	up to 36 months
HER2 PET as a marker for treatment related cardiotoxicity	The presence and frequency of myocardial uptake of [68Ga]Ga-ABY-025 and relation to treatment-related cardiotoxicity determined by echocardiography.	up to 36 months
Dynamic PET parameters	The agreement between whole body static imaging and kinetic parameters in the determination of HER2-status.	up to 36 months

Collaborators and Investigators

• Sponsor: Karolinska University Hospital
• Investigators: Principal Investigator: Rimma Axelsson, Prof., MD, Karolinska University Hospital

Publications and helpful links

General Publications

• Velikyan I, Schweighofer P, Feldwisch J, Seemann J, Frejd FY, Lindman H, Sorensen J. Diagnostic HER2-binding radiopharmaceutical, [68Ga]Ga-ABY-025, for routine clinical use in breast cancer patients. Am J Nucl Med Mol Imaging. 2019 Feb 15;9(1):12-23. eCollection 2019.
• Alhuseinalkhudhur A, Lubberink M, Lindman H, Tolmachev V, Frejd FY, Feldwisch J, Velikyan I, Sorensen J. Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer. EJNMMI Res. 2020 Mar 23;10(1):21. doi: 10.1186/s13550-020-0603-9.
• Ahlgren S, Orlova A, Wallberg H, Hansson M, Sandstrom M, Lewsley R, Wennborg A, Abrahmsen L, Tolmachev V, Feldwisch J. Targeting of HER2-expressing tumors using 111In-ABY-025, a second-generation affibody molecule with a fundamentally reengineered scaffold. J Nucl Med. 2010 Jul;51(7):1131-8. doi: 10.2967/jnumed.109.073346. Epub 2010 Jun 16.
• Sandstrom M, Lindskog K, Velikyan I, Wennborg A, Feldwisch J, Sandberg D, Tolmachev V, Orlova A, Sorensen J, Carlsson J, Lindman H, Lubberink M. Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule 68Ga-ABY-025 in Breast Cancer Patients. J Nucl Med. 2016 Jun;57(6):867-71. doi: 10.2967/jnumed.115.169342. Epub 2016 Feb 9.
• Sorensen J, Sandberg D, Sandstrom M, Wennborg A, Feldwisch J, Tolmachev V, Astrom G, Lubberink M, Garske-Roman U, Carlsson J, Lindman H. First-in-human molecular imaging of HER2 expression in breast cancer metastases using the 111In-ABY-025 affibody molecule. J Nucl Med. 2014 May;55(5):730-5. doi: 10.2967/jnumed.113.131243. Epub 2014 Mar 24.
• Sorensen J, Velikyan I, Sandberg D, Wennborg A, Feldwisch J, Tolmachev V, Orlova A, Sandstrom M, Lubberink M, Olofsson H, Carlsson J, Lindman H. Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [68Ga]ABY-025 Affibody PET/CT. Theranostics. 2016 Jan 1;6(2):262-71. doi: 10.7150/thno.13502. eCollection 2016.
• Tolmachev V, Velikyan I, Sandstrom M, Orlova A. A HER2-binding Affibody molecule labelled with 68Ga for PET imaging: direct in vivo comparison with the 111In-labelled analogue. Eur J Nucl Med Mol Imaging. 2010 Jul;37(7):1356-67. doi: 10.1007/s00259-009-1367-7. Epub 2010 Feb 4.
• Sandberg D, Tolmachev V, Velikyan I, Olofsson H, Wennborg A, Feldwisch J, Carlsson J, Lindman H, Sorensen J. Intra-image referencing for simplified assessment of HER2-expression in breast cancer metastases using the Affibody molecule ABY-025 with PET and SPECT. Eur J Nucl Med Mol Imaging. 2017 Aug;44(8):1337-1346. doi: 10.1007/s00259-017-3650-3. Epub 2017 Mar 6.

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2022
• Primary Completion (Anticipated): December 31, 2025
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: November 7, 2022
• First Submitted That Met QC Criteria: November 15, 2022
• First Posted (Actual): November 16, 2022

Study Record Updates

• Last Update Posted (Actual): November 30, 2022
• Last Update Submitted That Met QC Criteria: November 25, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: PET/CT; Metastatic breast cancer; HER2 low; Gastroesophageal cancer; 68-Ga ABY-025; HER2 PET
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms; Stomach Neoplasms; Esophageal Neoplasms
• Other Study ID Numbers: K 2020-9716; 2022-500448-39-00 (Other Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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