Neoplasms

Digestive System Diseases

All Conditions

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

After checking the eligibility for the study entry, patients will be scheduled to perform \[18F\]FLT-PET scans before and on 21st day from the administration of regorafenib. Regorafenib will be administered 160 mg/day given orally on day 1 to days 21 following 7 days break, which consists of 4 weeks as 1 cycle. Treatment will be repeated every 4 weeks and continued until disease progression, unacceptable toxicity or the patient's refusal. Standard anatomical response evaluation will be performed every 8 weeks (without regard to the cycles or schedules of chemotherapy). Additional \[18F\]FDG-PET will be performed before treatment and at 8 weeks (just once at the point of first response evaluation).

After checking the eligibility for the study entry, patients will be scheduled to perform \[18F\]FLT-PET scans before and on 21st day from the administration of regorafenib. Regorafenib will be administered 160 mg/day given orally on day 1 to days 21 following 7 days break, which consists of 4 weeks as 1 cycle. Treatment will be repeated every 4 weeks and continued until disease progression, unacceptable toxicity or the patient's refusal. Standard anatomical response evaluation will be performed every 8 weeks (without regard to the cycles or schedules of chemotherapy).

Regorafenib

Yong Sang Hong, M.D., Ph.D.

Regorafenib is approved in the treatment for metastatic colorectal cancer patients who have been progressed after standard therapies, however, there has not been a predictive biomarker. The investigators designed this study to investigate whether \[18F\]FLT-PET might paly a role as a predictive imaging biomarker of treatment responses to regorafenib.

Recent advances have been made in the treatments for the patients with metastatic colorectal cancer (mCRC) owing to the introductions of targeted agents, which included bevacizumab, cetuximab, panitumumab, and aflibercept. And in addition, regorafenib, a newer tyrosine kinase inhibitor (TKI), has been approved in the treatment for the mCRC patients.

Regorafenib (BAY 73-4506) is an orally available multikinase inhibitor with activity against multiple targets, including tumor angiogenesis (VEGFR-1, -2, -3 and TIE-2), oncogenesis (KIT, RET, RAF-1, BRAF, and BRAFV600E), and tumor microenvironment (PDGF and FGFR). Regorafenib has shown antitumor activities in multiple solid tumors, and demonstrated significant efficacy outcomes in patients with advanced gastrointestinal stromal tumors and colorectal cancers.

The CORRECT study, which compared regorafenib vs placebo in mCRC patients who have been treated with all standard treatment, showed survival improvements with statistical significances; median OS 6.4 vs 5.0 months, HR 0.77, p=0.0052; median PFS 1.9 vs 1.7 months, HR 0.49, p\<0.000001. Above these results, regorafenib monotherapy has been recently approved for the treatment of mCRC patients who have been refractory to all of standard therapies.

However, there are still only a few biomarkers which have been established as predictive of treatment responses in the fields of treatments for mCRC patients; KRAS or BRAF mutations for the lack of responses to anti-EGFR agents, cetuximab or panitumumab. There still has not been any biomarker which would be predictive of treatment responses to bevacizumab, aflibercept or regorafenib. The difficulties in search for biomarkers for these agents might come from the facts as following; either bevacizumab or aflibercept does not act directly against tumor itself and should be combined with cytotoxic agents to show efficacy; regorafenib is a multikinase inhibitor which has too many potential targets.

Above these reasons, imaging modalities can be fascinating and alternative candidates for predictive biomarkers of treatment responses. Conventional anatomic imaging studies such as computed tomography (CT) scans can hardly predict the treatment responses earlier, and the RECIST using CT scans, which is widely used for measurement of treatment responses, might have several limitations for measurement of efficacy from targeted agents such as cystic necrosis without tumor shrinkage. In the CORRECT study, overall response rate by RECIST was only 1%, although the rates for disease stabilization was up to 40%, which might be a good example for the limitations of the RECIST using conventional anatomical imaging studies for the response evaluation of regorafenib.

Among imaging studies, PET scans are useful tools for the noninvasive measurement of functional changes after treatment with targeted agents, and \[18F\]FLT-PET is potentially useful tool for earlier prediction of treatment responses because it can detect earlier changes of cellular proliferation using \[18F\]FLT (fluorothymidine), a radiotraceable substitute for thymidine which is essential for DNA synthesis. Several studies have been reported that \[18F\]FLT-PET may allow an early assessment of the response to chemotherapy including targeted agents. There also has been a report that \[18F\]FLT-PET could predict treatment responses of BRAF inhibitors in the colorectal cancer xenograft model; regorafenib also has an inhibitory effect on BRAF.

Therefore, the investigators have planned this study with hypothesis that \[18F\]FLT-PET could be useful for identifying a subgroup of mCRC patients with clinical responsiveness to regorafenib.

[18F]FLT-PET as a Predictive Imaging Biomaker of Treatment Responses to Regorafenib

3'-Deoxy-3'-18F-fluorothymidine Positron Emission Tomography ([18F] FLT-PET) for the Prediction of Response to Regorafenib in the Metastatic Colorectal Cancer Patients Who Progressed After All Standard Therapies

Quantitative image analysis of \[18F\]FLT uptake includes Maximum Standardized Uptake Value (SUV_MAX) of all target lesions.

All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline and every 8 weeks.

Asan Medical Center

Assistant Professor

Carcinoma

Carcinoma, Squamous Cell

Head and Neck Neoplasms

All Drugs and Chemicals

Radiopharmaceuticals

F-18 Fluorothymidine

Yusuf Menda, MD

Kenneth J Dornfeld, MD, PhD

Timothy Tewson, PhD

Preliminary observations suggest positron emission tomography (PET) imaging with an F-18 labeled thymidine analog (FLT) can selectively identify proliferating and non-proliferating tissues, including tumors. FLT uptake in the tumor appears to reflect the level of cells undergoing DNA synthesis. This is clinically important because cell proliferation markers have significant prognostic value, both prior to initiating radiotherapy and as they change during the course of therapy. In the proposed study, the researchers assess the biodistribution and radiation dosimetry of FLT to obtain the necessary data to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA). The information collected under Radioactive Drug Research Committee (RDRC) approval will not be used for diagnostic purposes, to assess the subject's response to therapy, or for clinical management of the subject.

There are approximately 40,000 new cases of head and neck cancer each year in the United States. Worldwide more than 500,000 individuals will develop head and neck cancer each year, ranking as the sixth most common cancer. These cancers are predominately squamous cell cancers. Approximately two thirds of subjects will present with locally advanced disease with either large disease at the primary site and/or spread to regional lymph node levels.

Despite aggressive treatment, 5-year survival remains poor (overall, approximately 50%). The major site of treatment failure is within the head and neck region, with distant metastases occurring in approximately 25% of subjects and usually after local and/or regional (nodal) failure.

Current treatment options for locally advanced head and neck cancer include combinations of surgery, radiation therapy, and chemotherapy. It is currently difficult to predict which combination will be best suited for any particular individual. Rapid methods of assessing the response of subjects to chemo-radiotherapy would be a useful tool, as it would permit the oncologist to change therapies, either in type or degree, in cases when the subject does not respond to the initial therapy regimen. Current best methods of evaluating tumor response are either serial CT examinations, so that changes in tumor size can be estimated or a fluorodeoxyglucose (FDG) positron emission tomography (PET) study in which changes in the metabolic status of the tumor are evaluated. Unfortunately, the anatomic information afforded by CT examinations often require months after treatment to allow the full effects of therapy to take place. Even after this time, the metabolic activity of any remaining tissue is nearly impossible to assess by CT scan, making it difficult to distinguish between fibrosis and viable tissue. Generally the FDG studies require 3-4 weeks after the end of the therapeutic regime before the relevant information is available, with more reliable information obtained at 3-4 months after treatment.

It is predictable that the most immediate signal of an anti-tumor therapeutic regime that has been successful is that the tumor cells will stop dividing (proliferating) after the therapy is initiated. Therefore, a tracer which is taken up into and retained in cells as a function of their proliferative activity should provide rapid information as to the effectiveness of the treatment. It is the objective of this study to determine the biodistribution and radiation dosimetry of tracer F-18 3'-deoxy-3'-fluorothymidine. This distribution data is essential before an Investigational New Drug (IND) application can be filed with the FDA that would allow the use of this tracer in clinical trials.

Study to Calculate the Radiation Dosimetry in Subjects With Head and Neck Cancer

Biodistribution and Radiation Dosimetry of F-18 Fluorothymidine (FLT) Imaged With Positron Emission Tomography (PET) in Patients With Head and Neck Cancer: A Radioactive Drug Research Committee (RDRC) Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
[18F]FLT-PET as a Predictive Imaging Biomaker of Treatment Responses to Regorafenib	NCT02175095	Colorectal Canc...	Regorafenib	20 Years -	Asan Medical Center
Study to Calculate the Radiation Dosimetry in Subjects With Head and Neck Cancer	NCT00245349	Head and Neck C...	F-18 Fluorothym...	21 Years -	University of Iowa
[18F]FLT-PET as a Predictive Imaging Biomaker of Treatment Responses to Regorafenib	NCT02175095	Colorectal Canc...	Regorafenib	20 Years -	Asan Medical Center
Study to Calculate the Radiation Dosimetry in Subjects With Head and Neck Cancer	NCT00245349	Head and Neck C...	F-18 Fluorothym...	21 Years -	University of Iowa

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