Clinical trial NCT05619016: [68Ga]Ga-ABY-025 PET for Quantification of HER2-status in Solid Tumors
Official title: Phase II Study of [68Ga]Ga-ABY-025 PET for Non-invasive Quantification of HER2-status in Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Esophageal Neoplasms
Gastric Neoplasms Malignant
Breast Cancer
HER2-positive Gastric Cancer
Keywords: 68-Ga ABY-025
HER2 PET
PET/CT
Gastroesophageal cancer
Metastatic breast cancer
HER2 low
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
First posted: 2022-11-16
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Prospective, single-center, single-blinded, diagnostic explorative phase II basket trial.

Investigators select subjects that are scheduled for anti-HER2 treatment due to

* metastatic HER2 positive gastroesophageal cancer (GEAC)
* metastatic breast cancer with low HER2 expression (HER2low mBC).

All patients undergo a PET/CT with the interventional drug/radiotracer 68Ga-ABY-025 before starting treatment. GEAC patients will undergo an additional ABY-025-PET after 3 cycles of treatment. Results will be compared to HER2 analysis of tissue samples.
Primary purpose: DIAGNOSTIC

Brief summary: 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).

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Percentage of HER2-positive lesions
timeFrame: up to 24 months
Secondary outcomes:
measure: SUV
timeFrame: up to 24 months
measure: TBR
timeFrame: up to 24 months
measure: Intra-individual heterogeneity of HER2-positivity
timeFrame: up to 24 months
measure: Feasibility in HER2low
timeFrame: up to 24 months
measure: HER2 positive cancer burden
timeFrame: up to 24 months
measure: Safety aspects of ABY-025
timeFrame: up to 36 months
Other outcomes:
measure: Treatment response 1
timeFrame: up to 36 months
measure: Treatment response 2
timeFrame: up to 36 months
measure: Comparison between HER2 PET and FDG PET
timeFrame: up to 24 months
measure: HER2 PET as a prognostic tool
timeFrame: up to 36 months
measure: HER2 PET as a marker for treatment related cardiotoxicity
timeFrame: up to 36 months
measure: Dynamic PET parameters
timeFrame: up to 36 months
Locations:
city: Stockholm
country: Sweden
facility: Department of Radiation Physics and Nuclear Medicine, Karolinska University Hospital
Study officials:
affiliation: Karolinska University Hospital
name: Rimma Axelsson, Prof., MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
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citation: 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.
citation: 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.
citation: 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.
citation: 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.