18F- Fluorothymidine to Evaluate Treatment Response in Lymphoma

A Pilot Study of 18F Fluorothymidine (FLT) PET/CT in Lymphoma

Background:

• Positron emission tomography (PET) uses radioactive substances called radiotracers to locate areas of cancer in the body. For this test, the patient is given an injection of the radiotracer and lies in a large donut-shaped scanner that detects where in the body the radioactivity accumulates. Computed tomography (CT) scans use low dose x-rays that help to better localize where the radioactive tracer is concentrating. PET/CT scans are usually done in lymphoma patients before treatment starts and at the end of treatment to evaluate the response to therapy.
• PET scans typically use a sugar-like radioactive tracer called fluorodeoxyglucose (FDG) and low-dose x-rays. Sometimes, however, FDG PET scans show what looks like active disease and presence of a mass after chemotherapy even when there are no live cancer cells. Doctors have particular problems in evaluating response to treatment when this happens because they can't tell if the mass is active cancer or just dead tumor cells.
• An experimental radiotracer called 18F- Fluorothymidine (FLT) has high uptake in active tumor cells and may be better able to evaluate treatment response.

Objectives:

- To test the use of FLT PET/CT imaging in assessing treatment response in patients with lymphoma.

Eligibility:

- Patients 18 years of age or older who are enrolled in a lymphoma therapy study at the National Institutes of Health (NIH) Clinical Center or in the Cancer and Leukemia Group B (CALGB) 50330 study at another location.

Design:

- There are two arms in this study:

• The first arm evaluates FLT as an early predictor of tumor response to therapy. Patients are imaged with FLT and FDG PET before starting treatment, following two cycles of therapy and after treatment ends.
• The second arm evaluates the ability of FLT to distinguish if a mass that remains after treatment has viable cancer or dead tissue. Patients who have completed treatment and in whom FDG PET shows a remaining tumor mass are imaged with FLT PET. Following the scan, the tumor is biopsied for verification.

Study Overview

• Status: Terminated
• Conditions: Lymphoma
• Intervention / Treatment: Diagnostic test: fluorodeoxyglucose F 18 Positron Emission Tomography and computed tomography; Other: [3'-deoxy-3'-[F-18] fluorothymidine; Procedure: computed tomography; Procedure: Biopsy; Procedure: fine-needle aspiration

Detailed Description

Background:

• 3-deoxy-3-18F-fluorothymidine (FLT) positron emission tomography (FLT PET)/Compute tomography (CT) has been shown to correlate with the rate of cellular/tumor proliferation.
• The Imaging Subcommittee of the International Harmonization Project in Lymphoma recommends performing fluorodeoxyglucose (FDG) positron emission tomography (PET) at least 3 weeks, and preferably 6-8 weeks after chemotherapy or chemoimmunotherapy and 8-12 weeks after radiation or chemoradiation therapy due to high FDG accumulation in inflammatory tissues.
• FLT uptake in inflammatory lesions is less prominent than FDG and it is likely that FLT PET/CT can better differentiate inflammation from tumor.
• FLT PET/CT imaging is expected to better differentiate between treatment induced inflammation and malignancy and should enable early prediction of therapeutic response.
• FLT PET/CT imaging is expected to differentiate between residual inflammatory residual masses from residual malignancy and therefore guide appropriate treatment.

Primary Objectives:

• To estimate the diagnostic accuracy of FLT PET/CT as an early indicator of complete response to therapy in B and T cell lymphoma.
• To estimate the diagnostic accuracy of FLT PET/CT in the evaluation of residual masses after therapy.

Eligibility:

• Participant must be enrolled in a lymphoma therapy study at the National Institutes of Health (NIH) Clinical Center OR be enrolled in the CALGB 50303 study at another site OR undergoing a new course of treatment of lymphoma at another facility. The National Cancer Institute (NCI) Laboratory of Pathology will confirm diagnosis for subjects enrolled at all CALGB study sites.
• Participants must have a clinical course consistent with lymphoma and have available documentation of lymphoma from either the NCI or from an outside pathology laboratory.
• Subjects enrolling in the early response arm must undergo baseline FLT PET prior to receiving a new course of lymphoma therapy.
• Subjects enrolling in the residual mass evaluation arm can be enrolled at the time the FDG avid residual mass is discovered (i.e. no pre-therapy FLT image is required).
• Subjects can enroll in both arms of the study.
• Participant must be 18 years or older.
• Eastern Cooperative Oncology Group (ECOG) Performance score of 0 or 1.
• Serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT) less than 5 times upper limit of normal (ULN).
• bilirubin less than or equal to 2 times ULN.

Design:

There are 2 arms in this study

• The first arm will assess FLT as an early predictor of tumor response to therapy (treatment naive or recurrent disease). Subjects are imaged with FLT and FDG PET pre-therapy, following 2 cycles of therapy and post therapy.

• The second arm will assess lymphoma patients with FDG PET positive residual mass. Subjects are imaged with FLT PET prior to standard of care biopsy of residual mass. If initial FDG PET data is not available in Digital Imaging and Communications in Medicine (DICOM) format or is of suboptimal image quality, a repeat FDG PET/CT at the study site may be required.

  • We will accrue 70 participants (40 in the early response arm and 30 in the residual mass arm) to this study.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike
    • Bethesda, Maryland, United States, 20301
      • Walter Reed National Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

Participant must be enrolled in a lymphoma therapy study at the National Institutes of Health (NIH) Clinical Center OR be enrolled in the Cancer and Leukemia Group B (CALGB) 50303 study at another site OR undergoing a new course of treatment of lymphoma at another facility.

Participants must have a clinical course consistent with lymphoma and have available documentation of lymphoma from either the National Cancer Institute (NCI) or from an outside pathology laboratory.

Participant must be 18 years or older.

Eastern Cooperative Oncology Group (ECOG) Performance score of 0 or 1.

Ability to provide informed consent. All patients must sign a document of informed consent indicating their understanding of the investigational nature and risks of the study before any protocol related studies are performed.

For subjects enrolling in early response arm

• Must be enrolled in CALGB 50303 or a lymphoma therapy study at the NIH Clinical Center or undergoing a new course of treatment of lymphoma at another facility
• Must not have begun lymphoma therapy for this tumor occurrence/ relapse
• Prior completed therapy does NOT affect eligibility

For subjects enrolling in the residual FDG avid mass arm

• Must have a residual (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) positive mass greater than equal to 1cm, with uptake greater than that of mediastinal blood pool.
• Participant will undergo a repeat FDG PET/CT scan if the original FDG/PET imaging performed at an outside institution is not of adequate imaging quality for subjects enrolling in the residual FDG mass arm.

EXCLUSION CRITERIA:

Known allergy to fluorothymidine.

Participants for whom enrollment would significantly delay (greater than 2 weeks) the scheduled standard of care therapy.

Participants with any coexisting medical or psychiatric condition that is likely to interfere with study procedures and/or results are excluded.

Participants with severe claustrophobia not relieved by oral anxiolytic medication or patients weighing greater than 136 kg (weight limit for scanner table).

Other medical conditions deemed by the Principal Investigator (PI) or associates to make the patient ineligible for protocol procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Group A - Participants Scanned at Baseline & After Chemotherapy; Patients undergo 3'-deoxy-3'-[18F] fluorothymidine (FLT) and fluorodeoxyglucose F 18 (FDG) PET/CT scans at baseline, after 2 courses of chemotherapy, and after completion of chemotherapy. Patients with residual FDG-positive mass after completion of therapy may be enrolled in group B.	Diagnostic test: fluorodeoxyglucose F 18 Positron Emission Tomography and computed tomography; Imaging; Other: [3'-deoxy-3'-[F-18] fluorothymidine; Undergo scans; Procedure: computed tomography; Undergo scans
EXPERIMENTAL: Group B - Participants Scanned in the Evaluation of Residual Masses After Therapy; Patients who have completed treatment in whom FDG-PET shows a remaining tumor mass undergo an FLT PET/CT scan . Patients also undergo a biopsy or fine-needle aspiration, if clinically indicated.	Diagnostic test: fluorodeoxyglucose F 18 Positron Emission Tomography and computed tomography; Imaging; Other: [3'-deoxy-3'-[F-18] fluorothymidine; Undergo scans; Procedure: computed tomography; Undergo scans; Procedure: Biopsy; Biopsy taken; Procedure: fine-needle aspiration; sample collected

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With the Presence/Absence of Abnormal 18F- Fluorothymidine (FLT) Uptake, and Positive/Negative Biopsy	A positive malignant residual mass was defined as focal 18F- Fluorothymidine (FLT) uptake within the residual mass greater than the normal mediastinal background uptake. FLT uptake within the mass lower than the mediastinal was considered non-malignant. The positive/negative FLT uptake was correlated with biopsy results within the residual mass (presence or absence of malignant tumor cells).	Up to 3.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
18F- Fluorothymidine (FLT) Uptake Within the Tumor(s) Between Baseline vs Completion of Therapy Scans	FLT uptake within the tumor(s) using standard uptake value (SUVmax) was compared between baseline and completion of therapy scans.	up to 4.5 years
Tumor(s) Maximum Standard Uptake Value (SUVmax) at Baseline Scan and SUVmax After Completion Scan in Responders and Non-responders' Patients	The SUVmax (defined as radiotracer uptake in a region of interest normalized by the injected activity and body weight) was measured within the tumor(s). The SUVmax was defined as the uptake value of the hottest pixels, within a volume of interest containing the entire tumor(s). SUVmax was calculated at baseline and after completion of therapy.	up to 4.5 years
Tumor Uptake With Fluorothymidine (FLT) - Maximum Standard Uptake Value (SUVmax)	The maximum standard uptake value (SUVmax) (defined as radiotracer uptake in a region of interest normalized by the injected activity and body weight) was measured within the tumor(s). The SUVmax was defined as the uptake value of the hottest pixels, within a volume of interest containing the entire tumor(s).	Up to 4.5 years
18F-fluorodeoxyglucose (18FDG) Standardized Uptake Values (SUV) Estimated Maximum and Tumor: Blood Pool Ratio at 1-hour Post-injection	After 1 hour post-injection of fluorodeoxyglucose (FDG), the maximum uptake value (SUVmax) (defined as radiotracer uptake in a region of interest normalized by the injected activity and body weight) was calculated was calculated within the residual mass. The ratio between SUVmax within the residual mass and SUVmean in the pool blood was measured.	up to 3.5 years
3'-Deoxy-3'-[18F]-Fluorothymidine (FLT) Dynamic Influx Parameter (Ki) Standardized Uptake Values (SUV) Estimated Maximum at 1- and 2-hours Post-injection	The maximum uptake value (SUVmax) (defined as radiotracer uptake in a region of interest normalized by the injected activity and body weight) was calculated within the residual mass at 1 h and at 2 hours post-injection of FLT.	up to 3.5 years
Tumor(s) Maximum Standard Uptake Value (SUVmax) at Baseline and at Mid-treatment (Post-2 Cycles) Scan	The SUVmax (defined as radiotracer uptake in a region of interest normalized by the injected activity and body weight) was measured within the tumor(s). The SUVmax was defined as the uptake value of the hottest pixels, within a volume of interest containing the entire tumor(s). SUVmax was calculated at baseline and after 2-cycles of therapy.	Up to 4.5 years
Time to Progression	The time to progression (defined as time in months from 3'-deoxy-3'-[18F] fluorothymidine (FLT)-scan until patient progressed) was compared between the two groups (patients with higher Maximum Standard Uptake Value (SUVmax) vs lower SUVmax, using the median SUV value).	up to 4.5 years
18F- Fluorothymidine (FLT) Uptake, Positron-emission Tomography (PET) Standard Uptake Value (SUV)Max in Malignant Residual Tumors Versus Benign Lesions After Therapy	FLT uptake was calculated within malignant residual tumors versus benign lesions using maximum standard uptake value (SUVmax).	up to 4.5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Here is the number of participants with non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Date treatment consent signed to date off study, approximately 4 years, 7 months and 9 days.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Esther Mena, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. doi: 10.3322/canjclin.57.1.43.
• Spaepen K, Stroobants S, Dupont P, Vandenberghe P, Thomas J, de Groot T, Balzarini J, De Wolf-Peeters C, Mortelmans L, Verhoef G. Early restaging positron emission tomography with ( 18)F-fluorodeoxyglucose predicts outcome in patients with aggressive non-Hodgkin's lymphoma. Ann Oncol. 2002 Sep;13(9):1356-63. doi: 10.1093/annonc/mdf256.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 29, 2008
• Primary Completion (ACTUAL): October 23, 2014
• Study Completion (ACTUAL): October 23, 2014

Study Registration Dates

• First Submitted: October 17, 2008
• First Submitted That Met QC Criteria: October 17, 2008
• First Posted (ESTIMATE): October 20, 2008

Study Record Updates

• Last Update Posted (ACTUAL): March 11, 2021
• Last Update Submitted That Met QC Criteria: February 18, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: PET/CT; Lymphoma; FDG; FLT; 18F-Fluorothymidine
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals; Fluorodeoxyglucose F18
• Other Study ID Numbers: 080200; 08-C-0200

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: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No