PET Imaging of Solid Tumors by a Novel Tracer, 68Ga-FAPI

Official title

PET Imaging of Tumors in Pancreas, Bile Ducts, Stomach and Ovaries by a Novel Tracer, 68Ga-FAPI-46 = Fibroblast Activation Protein Inhibitor

Overview

Cancers of the pancreas, bile ducts, stomach and ovaries are dismal diseases with most patients being diagnosed in advanced stages leading to a bad prognosis. These cancers can be difficult to diagnose and sometimes impossible to differentiate from underlying benign conditions. Establishing the correct diagnosis of primary cancer lesions and possible spread to other organs in time is pivotal for choosing the right therapy. Routinely applied staging procedures are however not always reliable. The main aim in this study is to evaluate the diagnostic accuracy of PET/CT with a novel radiotracer, FAPI, in the primary diagnosis of cancers in the pancreas, stomach and bile ducts as well as in patients with primary and recurrent epithelial ovarian cancer (EOC).

Detailed description

Malignant tumors exceeding 1-2 mm in size require formation of a supporting stroma, which includes vascular cells, inflammatory cells and fibroblasts . Several organs in the upper gastro-intestinal tract are known to develop tumors with strong desmoplastic reaction characterized by pervasive growth of tumor stroma. The pancreas, stomach, bile ducts and ovaries are all organs with this property. Within tumor stroma, a subpopulation of fibroblasts called cancer-associated fibroblasts (CAFs) are known to be involved in growth, migration and progression of the tumor.

The Fibroblast Activation Protein (FAP) is one of the more prominent stroma markers and was the focus in the development of an agent for imaging and, eventually, even targeted radionuclide therapy. FAP is a type II membrane bound glycoprotein absent or only expressed at insignificant levels, in normal tissues in adults. The FAP inhibitor, FAPI, gets selectively enriched in tissues where its target protein is expressed and there is no or very limited FAPI uptake in all normal organs. This opens new possibilities for the detection of malignant lesions with higher stromal content based on the high contrast positron emission tomography (PET) images obtained with a 68-Gallium (68Ga) radiolabeled - FAPI compound. As cancers in pancreas, stomach, bile ducts and ovaries are all characterized by abundant desmoplasia that constitutes up to 90% of the total tumor volume and contains extracellular matrix, immune cells, vasculature and CAFs, it would be suitable for targeted imaging with FAPI.

Preliminary studies show elevated FAPI uptake in many tumors rich in fibroblasts along with low background uptake. The main objective of this prospective study is to improve non-invasive diagnostics of malignancy in tumors of pancreas, stomach, bile ducts and ovaries, all known for a strong desmoplastic reaction by evaluating the diagnostic accuracy of PET/CT with a novel radiotracer, FAPI in the primary diagnosis and staging of such cancers.

Interventions

• Drug 68Ga-FAPI-46
  * \[68Ga\] Ga-FAPI-46 Solution for Injection is manufactured at the Karolinska University Hospital Radiopharmacy facilities, for imaging studies with Positron Emission Tomography (PET). * It is a radiolabelled Fibroblast Activation Protein Inhibitor (FAPI) used for PET of a number of different cancer entities. * Depending on the labelling yield 50 - 370 megabecquerel (MBq) of \[68Ga\] Ga-FAPI-46 Solution for Injection will be administered intravenously 60 minutes prior to whole-body PET image ac
• Device PET/CT
  * Combined PET and computed tomography (CT) imaging with 68Ga-FAPI-46 will be performed using the same protocol on a "Biograph 6" PET/CT scanner (Siemens, Erlangen, Germany) and "General Electrics" (GE) Discovery 710, Milwaukee, Wisconsin, USA at the Department of Nuclear Medicine, Karolinska Huddinge within 2 weeks before surgery. * PET/CT imaging will be performed in dynamic mode at one bed position centered over the primary tumor for 45 minutes. * At 60 minutes post injection, a whole-body PE

Primary outcome measures

• Diagnostic accuracy of FAPI-PET/CT in primary tumors [Time frame: up to 18 months]

Secondary outcome measures (6)

• Diagnostic accuracy of FAPI-PET/CT in metastases [Time frame: up to 18 months]
• Immunohistochemistry [Time frame: up to 18 months]
• FAPI-PET/CT and stroma markers as prognostic factors for Disease Free Survival (DFS) [Time frame: up to 5 years]
• FAPI-PET/CT and stroma markers as prognostic factors for Overall Survival (OS) [Time frame: up to 5 years]
• Correlation between FAPI-PET/CT imaging results and those of conventional radiology [Time frame: up to 18 months]
• Safety of 68Ga-FAPI-46 [Time frame: up to 1 month]

Eligibility criteria

Inclusion criteria

• Consecutive patients scheduled for surgical removal of either a pancreatic, biliary or gastric lesion.

\- Consecutive patients scheduled for primary surgical removal of early stage epithelial ovarian cancer (EOC), interval debulking surgery of EOC or surgical removal or tissue biopsy of recurrent EOC

• Signed informed consent.

Common Exclusion Criteria for all study populations:

• Age ≤18 year
• Pregnancy and lactation
• Significantly reduced renal function
• Allergy to iodinated contrast media
• Subjects that for some reason are unable to exercise their own rights, such as cognitive function impairment.

Additional Exclusion Criteria for study populations with either pancreatic-, gastric or bile duct cancer:

• Known metastatic disease

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Diagnostic

Study locations

Sweden · 1 center

• Karolinska University Hospital Huddinge — Stockholm

Publications

• Davidson B, Goldberg I, Kopolovic J. Inflammatory response in cervical intraepithelial neoplasia and squamous cell carcinoma of the uterine cervix. Pathol Res Pract. 1997;193(7):491-5. doi: 10.1016/s0344-0338(97)80102-1. PMID 9342755
• Whatcott CJ, Posner RG, Von Hoff DD, Han H. Desmoplasia and chemoresistance in pancreatic cancer. In: Grippo PJ, Munshi HG, editors. Pancreatic Cancer and Tumor Microenvironment. Trivandrum (India): Transworld Research Network; 2012. Chapter 8. Available from http://www.ncbi.nlm.nih.gov/books/NBK98939/ PMID 22876390
• Moon SB, Hur JM, Koo HH, Suh YL, Shin HB, Seo JM, Lee SK. Desmoplastic small round cell tumor of the stomach mimicking a gastric cancer in a child. J Korean Surg Soc. 2011 Jun;80 Suppl 1(Suppl 1):S80-4. doi: 10.4174/jkss.2011.80.Suppl1.S80. Epub 2011 Jun 17. PMID 22066092
• Baba AI, Câtoi C. TUMORS OF THE ALIMENTARY SYSTEM [Internet]. The Publishing House of the Romanian Academy; 2007 [cited 2020 Apr 1]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9565/
• Fiori ME, Di Franco S, Villanova L, Bianca P, Stassi G, De Maria R. Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Mol Cancer. 2019 Mar 30;18(1):70. doi: 10.1186/s12943-019-0994-2. PMID 30927908
• Ham IH, Lee D, Hur H. Role of Cancer-Associated Fibroblast in Gastric Cancer Progression and Resistance to Treatments. J Oncol. 2019 Jun 9;2019:6270784. doi: 10.1155/2019/6270784. eCollection 2019. PMID 31281359
• Ma Y, Zhu J, Chen S, Li T, Ma J, Guo S, Hu J, Yue T, Zhang J, Wang P, Wang X, Chen G, Liu Y. Activated gastric cancer-associated fibroblasts contribute to the malignant phenotype and 5-FU resistance via paracrine action in gastric cancer. Cancer Cell Int. 2018 Jul 20;18:104. doi: 10.1186/s12935-018-0599-7. eCollection 2018. PMID 30038550
• Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, Corbo V, Oni TE, Hearn SA, Lee EJ, Chio II, Hwang CI, Tiriac H, Baker LA, Engle DD, Feig C, Kultti A, Egeblad M, Fearon DT, Crawford JM, Clevers H, Park Y, Tuveson DA. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017 Mar 6;214(3):579-596. doi: 10.1084/jem.20162024. Ep PMID 28232471

Identifiers

NCT: NCT05172310 · H035-FAPI · 2020-002568-30

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗