ACRIN6682: Phase II Trial of 64Cu-ATSM PET/CT in Cervical Cancer

• Sponsor: American College of Radiology Imaging Network (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00794339
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 73
• Locations: 2
• Arm: 1
• Actual Duration (Months): 29.1
• Patients Per Site: 36.5
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

RATIONALE: Diagnostic procedures, such as 64Cu-labeled diacetyl-bis[N4-methylthiosemicarbazone] (copper Cu 64-ATSM) PET/CT scans, may help doctors predict how patients will respond to treatment.

PURPOSE: This phase II trial is studying how well copper Cu 64-ATSM PET/CT scans work in predicting disease progression in patients undergoing standard of care treatment with cisplatin and radiation therapy (external beam and brachytherapy) per National Comprehensive Cancer Network (NCCN) guidelines for newly-diagnosed stage IB, stage II, stage III, or stage IVA cervical cancer via the Federation of Gynecology and Obstetrics (FIGO) staging systems.

Condition or Disease	Intervention/Treatment	Phase
Cervical Cancer	Drug: 64Cu-ATSM; Drug: FDG	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To define the role of pre-therapy ^64Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone) (copper Cu 64-ATSM) in predicting prognosis and determining the behavior of an invasive squamous cell cervical cancer in patients with newly-diagnosed stage IB2-IVA cervical squamous cell carcinoma.

• To determine whether higher copper Cu 64-ATSM uptake is associated with lower progression-free survival of these patients after chemoradiotherapy.

Secondary

• To determine if higher copper Cu 64-ATSM uptake is associated with lower overall survival of these patients.

• To determine if higher copper Cu 64-ATSM uptake is associated with earlier primary cervical tumor recurrence and a higher rate of development of distant metastatic disease in these patients.

• To determine if higher copper Cu 64-ATSM uptake is associated with a lower frequency of complete metabolic response on 2-Deoxy-2-[18F]fluoroglucose (FDG) -PET/CT scan performed 3 months after completion of radiotherapy and chemotherapy.

• To estimate the accuracy of copper Cu 64-ATSM uptake as a predictor of progression-free survival, overall survival, primary tumor recurrence, and future development of distant metastatic disease in these patients.

• To evaluate the performance of copper Cu 64-ATSM uptake as a predictor of lymph node metastasis at study entry.

• To evaluate whether copper Cu 64-ATSM uptake correlates with tumor volume at study entry.

• To examine the relationship between tumor uptake of copper Cu 64-ATSM and other markers of tumor hypoxia, including Vascular endothelial growth factor (VEGF) , Glucose transporter 1 (GLUT1), Carbonic anhydrase IX (CA9/CA IX), and Osteopontin (OPN).

• To compare the predictive ability of pre-therapy copper Cu 64-ATSM-PET to that of post-therapy FDG-PET/CT scan.

• To assess whether pre-therapy FDG-PET/CT findings are predictive of progression-free survival.

OUTLINE: This is a multicenter study.

Patients receive copper Cu 64-ATSM IV and undergo PET/CT scan over 30 minutes 30-40 minutes later. Within 4 weeks after copper Cu 64-ATSM-PET/CT scan, patients begin planned concurrent standard of care chemoradiotherapy comprising 6 weeks of radiotherapy (external beam and brachytherapy)and weekly cisplatin administration per NCCN guidelines. Patients then undergo FDG-PET/CT scan 3 months after completion of chemoradiotherapy.

Tissue samples from previously collected cervical biopsy (obtained for diagnosis) are used for detecting hypoxic markers by immunohistochemistry analysis.

After completion of study intervention, patients are followed for every 3 months for 2 years and then every 6 months for 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 73 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Copper Cu 64-ATSM and PET/CT Scan in Predicting Disease Progression in Patients With Newly-Diagnosed Stage IB, Stage II, Stage III, or Stage IVA Cervical Cancer Who Are Undergoing Chemoradiotherapy Per NCCN Guidelines
• Actual Study Start Date: Jul 29, 2009
• Actual Primary Completion Date: Dec 31, 2011
• Actual Study Completion Date: Dec 31, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Copper ATSM pre-therapy pelvic 64Cu-ATSM-PET/CT with Pre- and post- therapy FDG PET/CT	Drug: 64Cu-ATSM; Other Names: copper 64 64Cu Diacetyl-bis(N4-methylthiosemicarbazone) ; Drug: FDG; Other Names: fludeoxyglucose F 18 Fluorodeoxyglucose (18F) 18F-FDG 18F-fluorodeoxyglucose

Outcome Measures

Primary Outcome Measures

1. Relationship Between Copper Cu 64-ATSM Uptake in the Primary Tumor and Progression-free Survival 3 Years After Chemoradiotherapy [every 3 months for first 2 years and every 6 months during year 3, up to 3 years]

   Progression-free survival (PFS) evaluated every 3 months for first 2 years and every 6 months during year 3 to determine PFS at 3years. Cu64-ATSM Uptake measured within 14 days of baseline Uptake is a measure of activity within a tumor the maximum standardized uptake value (SUVmax = tracer uptake in ROI / (injected activity / patient weight)) Tumor-to-Muscle uptake ratio (T/M, An FDG-PET/CT-guided circular region of interest of 1.0-1.5 cm in diameter is drawn around the most intense region of the primary tumor to calculate the maximum uptake within the region. In addition, regions of interest are drawn on bilateral gluteal muscle groups on at least 3 slices, and the mean uptake is calculated. The T/M is the ratio of these measurements.)

Secondary Outcome Measures

1. Copper Cu 64-ATSM T/M Uptake and Overall Survival [every 3 months for first 2 years and every 6 months during year 3, up to 3 years]

   To determine if higher 64Cu-ATSM uptake on PET/CT is associated with lower Overall survival (OS) T/M Uptake measured within 14 days of baseline; Overall survival (OS) is measured every 3 months for first 2 years and every 6 months during year 3,until time of death or 3 years from baseline.

2. Relationship Between Copper Cu 64-ATSM Uptake and Complete Metabolic Response [3 months after completion of chemoradiation]

   Complete metabolic response determined by FDG PET/CT performed 3 months after completion of chemoradiation By definition, metabolic response (as defined by NCI Concept ID: C3897320. https://www.ncbi.nlm.nih.gov/medgen/856914) is "the disappearance of metabolic tumor activity in target and non-target lesions, marked by a decrease in tumor standardized uptake value to the level of surrounding normal tissue (tumor uptake/normal uptake = ~1)"

3. Primary Tumor Recurrence [every 3 months for first 2 years and every 6 months during year 3, up to 3 years]

   To determine if higher 64Cu ATSM uptake is associated with earlier primary cervical tumor recurrence images were taken every 3 months for first 2 years and every 6 months during year 3, up to 3 years and evaluated for primary cervical tumor recurrence

4. Lymph Node Metastasis at Baseline [Two weeks]

   Lymph nodes were evaluated at 5 locations: Pelvic, Common Iliac, Para Aortic, Mediastinal, and Supraclavicular This outcome looks at the Association of Ratio of Tissue to Muscle (T/M) uptake with Lymph Node Metastases at Baseline

5. Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and Carbonic Anhydrase IX (CA-IX) Percentage of Tumor Cells Staining Score as a Marker of Tumor Hypoxia [baseline]

   The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with Carbonic anhydrase IX (CA-IX) markers using the Percentage of Tumor Cells Staining Score: 0=<1% tumor cells; 1=1 33% tumor cells; 2=34 66% tumor cells; and 3=>66% tumor cells.

6. Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and CA-IX Staining Intensity Score: as a Marker of Tumor Hypoxia [baseline]

   The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with CA-IX markers using the Staining Intensity Score: 0=No staining; 1=Weak staining; and 2=Moderate to strong staining.

7. Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and CA-IX Composite Score as a Marker of Tumor Hypoxia [Baseline]

   The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with CA-IX markers using the Composite Score (range 0-6): Computed by using the coded values of Percentage of Tumor Cells Staining Score (0-3) multiplied by the coded value of Staining Intensity Score (0-2).

8. Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and VEGF Percentage of Tumor Cells Staining Score as a Marker of Tumor Hypoxia [baseline]

   The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with VEGF markers using the Percentage of Tumor Cells Staining Score: 0=<1% tumor cells; 1=1 33% tumor cells; 2=34 66% tumor cells; and 3=>66% tumor cells.

9. Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and Vascular Endothelial Growth Factor (VEGF) Staining Intensity Score: as a Marker of Tumor Hypoxia [baseline]

   The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with Vascular endothelial growth factor (VEGF) markers using the Staining Intensity Score: 0=No staining; 1=Weak staining; and 2=Moderate to strong staining.

10. Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and Vascular Endothelial Growth Factor (VEGF) Composite Score as a Marker of Tumor Hypoxia [Baseline]

    The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with Vascular endothelial growth factor (VEGF) markers using the Composite Score (range 0-6): Computed by using the coded values of Percentage of Tumor Cells Staining Score (0-3) multiplied by the coded value of Staining Intensity Score (0-2).

11. Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and Glucose Transporter 1 (GLUT1) Percentage of Tumor Cells Staining Score as a Marker of Tumor Hypoxia [baseline]

    The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with Glucose transporter 1 (GLUT1) markers using the Percentage of Tumor Cells Staining Score: 0=<1% tumor cells; 1=1 33% tumor cells; 2=34 66% tumor cells; and 3=>66% tumor cells.

12. Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and Glucose Transporter 1 (GLUT1) Staining Intensity Score: as a Marker of Tumor Hypoxia [baseline]

    The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with GLUT-1 markers using the Staining Intensity Score: 0=No staining; 1=Weak staining; and 2=Moderate to strong staining.

13. Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and Glucose Transporter 1 (GLUT1) Composite Score as a Marker of Tumor Hypoxia [Baseline]

    The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with Glucose transporter 1 (GLUT1) markers using the Composite Score (range 0-6): Computed by using the coded values of Percentage of Tumor Cells Staining Score (0-3) multiplied by the coded value of Staining Intensity Score (0-2).

14. Relationship Between Copper Cu 64-ATSM Uptake and Development of Distant Metastasis [every 3 months for first 2 years and every 6 months during year 3, up to 3 years]

    Existence of distant metastasis was evaluated every 3 months for first 2 years and every 6 months during year 3 Copper Cu 64-ATSM Uptake (T/M) measured within 14 days of baseline;

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed primary invasive cervical squamous cell carcinoma

• Newly diagnosed disease

• Stage IB2 - IVA disease based on FIGO staging system

• Plan to receive standard of care treatment with concurrent cisplatin and radiation therapy (external beam and brachytherapy) per NCCN guidelines

• Must be scheduled to receive 6 weekly courses of cisplatin

• Meets 1 of the following criteria:

• Pelvic nodal (or no nodal) disease only by FDG-PET/CT scan within 4 weeks of enrollment

• Para-aortic nodal metastasis by FDG-PET/CT scan within 4 weeks of enrollment, and patient will undergo radiotherapy to para-aortic nodes

• FDG-PET/CT scan at baseline if not meeting any of the above criteria

• No stage IVB disease (distant metastases or supraclavicular metastasis) confirmed by FDG-PET/CT scan

• No recurrent invasive carcinoma of the uterine cervix regardless of previous treatment

• No know metastases to lungs, supraclavicular lymph nodes, or other organs outside of the pelvis or abdominal lymph nodes at time of diagnosis

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Able to lie flat for the duration of the PET/CT scan

• No septicemia or severe infection

• No uncontrolled or poorly controlled diabetes

• No circumstances that would prevent completion of imaging studies or required clinical follow-up

• No other prior or concurrent invasive malignancies, with the exception of non-melanoma skin cancer, within the past 5 years

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior pelvic or abdominal lymphadenectomy

• No prior pelvic radiation therapy

• No previous cancer treatment contraindicates this protocol therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California	United States	90089-9181
2	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• American College of Radiology Imaging Network
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Farrokh Dehdashti, MD, Mallinckrodt Institute of Radiology at Washington University Medical Center
• Study Chair: David A. Mankoff, MD, PhD, University of Washington

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• National Cancer Institute's Clinical trial database

Publications

None provided.

• Responsible Party: American College of Radiology Imaging Network
• ClinicalTrials.gov Identifier: NCT00794339
• Other Study ID Numbers: CDR0000624407; ACRIN-6682; U01CA080098; U01CA079778
• First Posted: Nov 20, 2008
• Last Update Posted: Feb 23, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by American College of Radiology Imaging Network: cervical squamous cell carcinoma; stage IIB cervical cancer; stage III cervical cancer; stage IV cervical cancer; stage IVA cervical cancer; stage IB cervical cancer; stage IIA cervical cancer
• Additional relevant MeSH terms: Uterine Cervical Neoplasms; Fluorodeoxyglucose F18

Study Results

Participant Flow

Recruitment Details	Study funding source changed (from National Cancer Institutes to American College of Radiology Imaging Network foundation) after accrual of 28 individuals

Arm/Group Title	Copper ATSM
Arm/Group Description	pre-therapy pelvic [64Cu][Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)] (64Cu-ATSM) PET/CT exam with Pre- and post- therapy (18)F-fluorodeoxyglucose (FDG) PET/CT exams
Period Title: Overall Study
STARTED	73
Eligible	69
Evaluable	59
COMPLETED	59
NOT COMPLETED	14

Baseline Characteristics

Arm/Group Title	Copper ATSM
Arm/Group Description	pre-therapy pelvic 64Cu-ATSM-PET/CT with Pre- and post- therapy FDG PET/CT 64Cu-ATSM FDG
Overall Participants	59
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	51.2
Sex: Female, Male (Count of Participants)
Female	59 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	13 22%
Not Hispanic or Latino	46 78%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.7%
Asian	2 3.4%
Native Hawaiian or Other Pacific Islander	1 1.7%
Black or African American	5 8.5%
White	39 66.1%
More than one race	0 0%
Unknown or Not Reported	11 18.6%
FIGO stage (Count of Participants)
IB2	15 25.4%
IIA	5 8.5%
IIB	21 35.6%
III	1 1.7%
IIIA	2 3.4%
IIIB	12 20.3%
IVA	3 5.1%

Outcome Measures

1. Primary Outcome

Title	Relationship Between Copper Cu 64-ATSM Uptake in the Primary Tumor and Progression-free Survival 3 Years After Chemoradiotherapy
Description	Progression-free survival (PFS) evaluated every 3 months for first 2 years and every 6 months during year 3 to determine PFS at 3years. Cu64-ATSM Uptake measured within 14 days of baseline Uptake is a measure of activity within a tumor the maximum standardized uptake value (SUVmax = tracer uptake in ROI / (injected activity / patient weight)) Tumor-to-Muscle uptake ratio (T/M, An FDG-PET/CT-guided circular region of interest of 1.0-1.5 cm in diameter is drawn around the most intense region of the primary tumor to calculate the maximum uptake within the region. In addition, regions of interest are drawn on bilateral gluteal muscle groups on at least 3 slices, and the mean uptake is calculated. The T/M is the ratio of these measurements.)
Time Frame	every 3 months for first 2 years and every 6 months during year 3, up to 3 years

Outcome Measure Data

Analysis Population Description

As a fully paired analysis, all participants were evaluated in each group. 21 participants progressed by year 3 and 38 participants were progression free at year 3.

Arm/Group Title	64 CU-ATSM SUVmax @ Baseline	64 CU-ATSM T/M Ratio @ Baseline
Arm/Group Description	The maximum standardized uptake value (SUVmax) is the Cu64-ATSM Uptake measured within 14 days of baseline is defined as SUVmax = tracer uptake in ROI / (injected activity / patient weight))	Cu64-ATSM uptake measured using the Tumor-to-Muscle uptake ratio within 14 days of baseline The tumor uptake is measured by selecting an FDG-PET/CT-guided circular region of interest of 1.0-1.5 cm in diameter around the most intense region of the primary tumor to calculate the maximum uptake within the region. The Muscle uptake is measured by selecting regions of interest on bilateral gluteal muscle groups on at least 3 slices, and calculating the mean uptake. The T/M uptake is the ratio of these 2 measurements.
Measure Participants	59	59
Progression within 3 years	4.4 (1.3)	8.2 (4.1)
No progression within 3 years	4.2 (1.3)	8.0 (3.1)

2. Secondary Outcome

Title	Copper Cu 64-ATSM T/M Uptake and Overall Survival
Description	To determine if higher 64Cu-ATSM uptake on PET/CT is associated with lower Overall survival (OS) T/M Uptake measured within 14 days of baseline; Overall survival (OS) is measured every 3 months for first 2 years and every 6 months during year 3,until time of death or 3 years from baseline.
Time Frame	every 3 months for first 2 years and every 6 months during year 3, up to 3 years

Outcome Measure Data

Analysis Population Description

Participants were divided into two groups by whether their T/M Ratio fell at or above vs. below the observed median of 7.3.

Arm/Group Title	T/M Below Median	T/M at or Above Median
Arm/Group Description	Tumor-to-muscle ratio (T/M) below the observed median value of 7.3	Tumor-to-muscle ratio (T/M) at or above the observed median value of 7.3
Measure Participants	28	31
Median (Full Range) [days]	773.5	786.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	64 CU-ATSM SUVmax @ Baseline, 64 CU-ATSM T/M Ratio @ Baseline
	Comments	Participants were divided into two groups by whether their T/M Ratio fell at or above vs. below the observed median of 7.3 and the the median survival was compared between the 2 groups.
	Type of Statistical Test	Equivalence
	Comments	equivalence margin=0
Statistical Test of Hypothesis	p-Value	0.4883
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Relationship Between Copper Cu 64-ATSM Uptake and Complete Metabolic Response
Description	Complete metabolic response determined by FDG PET/CT performed 3 months after completion of chemoradiation By definition, metabolic response (as defined by NCI Concept ID: C3897320. https://www.ncbi.nlm.nih.gov/medgen/856914) is "the disappearance of metabolic tumor activity in target and non-target lesions, marked by a decrease in tumor standardized uptake value to the level of surrounding normal tissue (tumor uptake/normal uptake = ~1)"
Time Frame	3 months after completion of chemoradiation

Outcome Measure Data

Analysis Population Description

52 observations were used for this analysis. 7 participants did not have FDG PET data available for analysis.

Arm/Group Title	Eligible Participants
Arm/Group Description	All eligible participants with evaluable pre-therapy pelvic 64Cu-ATSM-PET/CT within 14 days of baseline and with Pre- and post- therapy FDG PET/CT
Measure Participants	52
Complete metabolic response	23 39%
Partial response or progressive disease	29 49.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	64 CU-ATSM SUVmax @ Baseline
	Comments	Logistic Regression Modeling Complete Metabolic Response by T/M Ratio
	Type of Statistical Test	Equivalence
	Comments	no equivalence margin
Statistical Test of Hypothesis	p-Value	0.1924
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.1235
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.6988
	Estimation Comments

4. Secondary Outcome

Title	Primary Tumor Recurrence
Description	To determine if higher 64Cu ATSM uptake is associated with earlier primary cervical tumor recurrence images were taken every 3 months for first 2 years and every 6 months during year 3, up to 3 years and evaluated for primary cervical tumor recurrence
Time Frame	every 3 months for first 2 years and every 6 months during year 3, up to 3 years

Outcome Measure Data

Analysis Population Description

Two participants were off study before the follow up period began (one death and one withdrawal) and were not assessed for disease status - thus only 57 of the 59 participants were evaluated for this outcome.

Arm/Group Title	T/M Below Median	T/M at or Above Median
Arm/Group Description	Tumor-to-muscle ratio (T/M) below the observed median value of 7.3	Tumor-to-muscle ratio (T/M) at or above the observed median value of 7.3
Measure Participants	28	29
Median (Full Range) [days]	773.5	797.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	64 CU-ATSM SUVmax @ Baseline, 64 CU-ATSM T/M Ratio @ Baseline
	Comments	Participants were divided into two groups: those at or above the median for T/M Ratio (7.3) vs. those below, and the time to primary tumor recurrence was compared between the 2 goups.
	Type of Statistical Test	Equivalence
	Comments	equivalence margin = 0
Statistical Test of Hypothesis	p-Value	0.3090
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Lymph Node Metastasis at Baseline
Description	Lymph nodes were evaluated at 5 locations: Pelvic, Common Iliac, Para Aortic, Mediastinal, and Supraclavicular This outcome looks at the Association of Ratio of Tissue to Muscle (T/M) uptake with Lymph Node Metastases at Baseline
Time Frame	Two weeks

Outcome Measure Data

Analysis Population Description

one patient's scan could not evaluated for any lymph nodes, and three others could be evaluated only for pelvic lymph nodes.

Arm/Group Title	Eligible Participants
Arm/Group Description	All eligible participants with evaluable pre-therapy pelvic 64Cu-ATSM-PET/CT within 14 days of baseline and with Pre- and post- therapy FDG PET/CT
Measure Participants	58
Positive Nodes	31 52.5%
Negative Nodes	27 45.8%
Positive Nodes	14 23.7%
Negative Nodes	41 69.5%
Positive Nodes	7 11.9%
Negative Nodes	48 81.4%
Positive Nodes	0 0%
Negative Nodes	55 93.2%
Positive Nodes	0 0%
Negative Nodes	55 93.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	64 CU-ATSM SUVmax @ Baseline
	Comments	Logistic Regression Evaluating Tissue to Muscle (T/M) uptake ratio as a Predictor of PELVIC Lymph Node Metastases at Baseline
	Type of Statistical Test	Equivalence
	Comments	equivalence margin=0
Statistical Test of Hypothesis	p-Value	0.5291
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	64 CU-ATSM SUVmax @ Baseline
	Comments	Logistic Regression Evaluating Tissue to Muscle (T/M) uptake Ratio as a Predictor of COMMON ILIAC Lymph Node Metastases at Baseline
	Type of Statistical Test	Equivalence
	Comments	equivalence margin=0
Statistical Test of Hypothesis	p-Value	0.9684
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	64 CU-ATSM SUVmax @ Baseline
	Comments	Logistic Regression Evaluating Tissue to Muscle (T/M) uptake Ratio as a Predictor of Para Aortic Lymph Node Metastases at Baseline
	Type of Statistical Test	Equivalence
	Comments	equivalence margin=0
Statistical Test of Hypothesis	p-Value	0.7327
	Comments
	Method	Regression, Logistic
	Comments

6. Secondary Outcome

Title	Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and Carbonic Anhydrase IX (CA-IX) Percentage of Tumor Cells Staining Score as a Marker of Tumor Hypoxia
Description	The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with Carbonic anhydrase IX (CA-IX) markers using the Percentage of Tumor Cells Staining Score: 0=<1% tumor cells; 1=1 33% tumor cells; 2=34 66% tumor cells; and 3=>66% tumor cells.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0=<1% Tumor Cells	1-33% Tumor Cells	34-66% Tumor Cells	>66% Tumor Cells
Arm/Group Description	T/M ratio for subjects with Hypoxia categorized as 0=<1% tumor cells using the Percentage of Tumor Cells Staining Score.	T/M ratio for subjects with Hypoxia categorized as 1-33% tumor cells using the Percentage of Tumor Cells Staining Score.	T/M ratio for subjects with Hypoxia categorized as 34-66% tumor cells using the Percentage of Tumor Cells Staining Score.	T/M ratio for subjects with Hypoxia categorized as >66% tumor cells using the Percentage of Tumor Cells Staining Score.
Measure Participants	16	17	13	2
Mean (Standard Deviation) [ratio]	7.58 (2.87)	7.57 (3.17)	9.40 (5.26)	7.35 (1.20)

7. Secondary Outcome

Title	Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and CA-IX Staining Intensity Score: as a Marker of Tumor Hypoxia
Description	The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with CA-IX markers using the Staining Intensity Score: 0=No staining; 1=Weak staining; and 2=Moderate to strong staining.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	No Staining	Weak Staining	Moderate to Strong Staining
Arm/Group Description	T/M ratio for subjects with Hypoxia categorized as "No staining" using the Staining Intensity Score	T/M ratio for subjects with Hypoxia categorized as "Weak staining" using the Staining Intensity Score	T/M ratio for subjects with Hypoxia categorized as "Moderate to strong staining" using the Staining Intensity Score
Measure Participants	16	11	21
Mean (Standard Deviation) [ratio]	7.58 (2.87)	6.20 (2.56)	9.40 (4.37)

8. Secondary Outcome

Title	Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and CA-IX Composite Score as a Marker of Tumor Hypoxia
Description	The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with CA-IX markers using the Composite Score (range 0-6): Computed by using the coded values of Percentage of Tumor Cells Staining Score (0-3) multiplied by the coded value of Staining Intensity Score (0-2).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

No cases had a composite score of 5

Arm/Group Title	Composite Score: 0	Composite Score: 1	Composite Score: 2	Composite Score: 3	Composite Score: 4	Composite Score: 6
Arm/Group Description	T/M ratio for subjects with Hypoxia composite score of 0	T/M ratio for subjects with Hypoxia composite score of 1	T/M ratio for subjects with Hypoxia composite score of 2	T/M ratio for subjects with Hypoxia composite score of 3	T/M ratio for subjects with Hypoxia composite score of 4	T/M ratio for subjects with Hypoxia composite score of 6
Measure Participants	16	6	15	1	9	1
Mean (Standard Deviation) [ratio]	7.58 (2.87)	5.82 (1.99)	8.04 (3.44)	6.50 (NA)	10.60 (5.54)	8.20 (NA)

9. Secondary Outcome

Title	Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and VEGF Percentage of Tumor Cells Staining Score as a Marker of Tumor Hypoxia
Description	The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with VEGF markers using the Percentage of Tumor Cells Staining Score: 0=<1% tumor cells; 1=1 33% tumor cells; 2=34 66% tumor cells; and 3=>66% tumor cells.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0=<1% Tumor Cells	1-33% Tumor Cells	34-66% Tumor Cells	>66% Tumor Cells
Arm/Group Description	T/M ratio for subjects with Hypoxia categorized as 0=<1% tumor cells using the Percentage of Tumor Cells Staining Score.	T/M ratio for subjects with Hypoxia categorized as 1-33% tumor cells using the Percentage of Tumor Cells Staining Score.	T/M ratio for subjects with Hypoxia categorized as 34-66% tumor cells using the Percentage of Tumor Cells Staining Score.	T/M ratio for subjects with Hypoxia categorized as >66% tumor cells using the Percentage of Tumor Cells Staining Score.
Measure Participants	11	4	19	14
Mean (Standard Deviation) [ratio]	6.98 (2.54)	7.57 (4.57)	8.51 (3.65)	8.44 (4.50)

10. Secondary Outcome

Title	Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and Vascular Endothelial Growth Factor (VEGF) Staining Intensity Score: as a Marker of Tumor Hypoxia
Description	The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with Vascular endothelial growth factor (VEGF) markers using the Staining Intensity Score: 0=No staining; 1=Weak staining; and 2=Moderate to strong staining.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	No Staining	Weak Staining	Moderate to Strong Staining
Arm/Group Description	T/M ratio for subjects with Hypoxia categorized as "No staining" using the Staining Intensity Score	T/M ratio for subjects with Hypoxia categorized as "Weak staining" using the Staining Intensity Score	T/M ratio for subjects with Hypoxia categorized as "Moderate to strong staining" using the Staining Intensity Score
Measure Participants	11	25	12
Mean (Standard Deviation) [ratio]	6.98 (2.54)	7.50 (3.17)	10.22 (4.93)

11. Secondary Outcome

Title	Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and Vascular Endothelial Growth Factor (VEGF) Composite Score as a Marker of Tumor Hypoxia
Description	The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with Vascular endothelial growth factor (VEGF) markers using the Composite Score (range 0-6): Computed by using the coded values of Percentage of Tumor Cells Staining Score (0-3) multiplied by the coded value of Staining Intensity Score (0-2).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

No cases had a composite score of 5

Arm/Group Title	Composite Score: 0	Composite Score: 1	Composite Score: 2	Composite Score: 3	Composite Score: 4	Composite Score: 6
Arm/Group Description	T/M ratio for subjects with Hypoxia composite score of 0	T/M ratio for subjects with Hypoxia composite score of 1	T/M ratio for subjects with Hypoxia composite score of 2	T/M ratio for subjects with Hypoxia composite score of 3	T/M ratio for subjects with Hypoxia composite score of 4	T/M ratio for subjects with Hypoxia composite score of 6
Measure Participants	11	2	16	9	5	5
Mean (Standard Deviation) [ratio]	6.98 (2.54)	4.44 (1.22)	8.79 (3.67)	6.59 (1.83)	8.48 (4.11)	11.76 (6.13)

12. Secondary Outcome

Title	Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and Glucose Transporter 1 (GLUT1) Percentage of Tumor Cells Staining Score as a Marker of Tumor Hypoxia
Description	The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with Glucose transporter 1 (GLUT1) markers using the Percentage of Tumor Cells Staining Score: 0=<1% tumor cells; 1=1 33% tumor cells; 2=34 66% tumor cells; and 3=>66% tumor cells.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0=<1% Tumor Cells	1-33% Tumor Cells	34-66% Tumor Cells	>66% Tumor Cells
Arm/Group Description	T/M ratio for subjects with Hypoxia categorized as 0=<1% tumor cells using the Percentage of Tumor Cells Staining Score.	T/M ratio for subjects with Hypoxia categorized as 1-33% tumor cells using the Percentage of Tumor Cells Staining Score.	T/M ratio for subjects with Hypoxia categorized as 34-66% tumor cells using the Percentage of Tumor Cells Staining Score.	T/M ratio for subjects with Hypoxia categorized as >66% tumor cells using the Percentage of Tumor Cells Staining Score.
Measure Participants	2	5	23	18
Mean (Standard Deviation) [ratio]	9.70 (0.42)	6.01 (1.08)	8.83 (4.22)	7.46 (3.49)

13. Secondary Outcome

Title	Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and Glucose Transporter 1 (GLUT1) Staining Intensity Score: as a Marker of Tumor Hypoxia
Description	The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with GLUT-1 markers using the Staining Intensity Score: 0=No staining; 1=Weak staining; and 2=Moderate to strong staining.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	No Staining	Weak Staining	Moderate to Strong Staining
Arm/Group Description	T/M ratio for subjects with Hypoxia categorized as "No staining" using the Staining Intensity Score	T/M ratio for subjects with Hypoxia categorized as "Weak staining" using the Staining Intensity Score	T/M ratio for subjects with Hypoxia categorized as "Moderate to strong staining" using the Staining Intensity Score
Measure Participants	2	6	40
Mean (Standard Deviation) [ratio]	9.70 (0.42)	7.15 (1.47)	8.11 (4.01)

14. Secondary Outcome

Title	Relationship of Copper Cu 64-ATSM Uptake T/M Ratio and Glucose Transporter 1 (GLUT1) Composite Score as a Marker of Tumor Hypoxia
Description	The Ratio of Tissue to Muscle (T/M) agent uptake measured at baseline was used as a predictor of Hypoxia Tumor Hypoxia was assessed with Glucose transporter 1 (GLUT1) markers using the Composite Score (range 0-6): Computed by using the coded values of Percentage of Tumor Cells Staining Score (0-3) multiplied by the coded value of Staining Intensity Score (0-2).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

No cases had a composite score of 5

Arm/Group Title	Composite Score: 0	Composite Score: 1	Composite Score: 2	Composite Score: 3	Composite Score: 4	Composite Score: 6
Arm/Group Description	T/M ratio for subjects with Hypoxia composite score of 0	T/M ratio for subjects with Hypoxia composite score of 1	T/M ratio for subjects with Hypoxia composite score of 2	T/M ratio for subjects with Hypoxia composite score of 3	T/M ratio for subjects with Hypoxia composite score of 4	T/M ratio for subjects with Hypoxia composite score of 6
Measure Participants	2	2	6	1	20	17
Mean (Standard Deviation) [ratio]	9.70 (0.42)	6.55 (0.07)	6.89 (1.84)	5.40 (NA)	8.93 (4.50)	7.58 (3.56)

15. Secondary Outcome

Title	Relationship Between Copper Cu 64-ATSM Uptake and Development of Distant Metastasis
Description	Existence of distant metastasis was evaluated every 3 months for first 2 years and every 6 months during year 3 Copper Cu 64-ATSM Uptake (T/M) measured within 14 days of baseline;
Time Frame	every 3 months for first 2 years and every 6 months during year 3, up to 3 years

Outcome Measure Data

Analysis Population Description

Participants were divided into two groups by whether their T/M Ratio fell at or above vs. below the observed median of 7.3 and the median time (days) was calculated for the development of new distant metastases.

Arm/Group Title	T/M Below Median	T/M at or Above Median
Arm/Group Description	Tumor-to-muscle ratio (T/M) below the observed median value of 7.3	Tumor-to-muscle ratio (T/M) at or above the observed median value of 7.3
Measure Participants	28	31
Median (Full Range) [days]	725.5	786.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	64 CU-ATSM SUVmax @ Baseline, 64 CU-ATSM T/M Ratio @ Baseline
	Comments	Participants were divided into two groups by whether their T/M Ratio fell at or above vs. below the observed median of 7.3 and the time to observe new distant metastases was compared between the groups
	Type of Statistical Test	Equivalence
	Comments	equivalence margin=0
Statistical Test of Hypothesis	p-Value	.4981
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	within 24 hours of 64Cu-ATSM administration
Adverse Event Reporting Description	Any death or AE occurring at any time after a participant has discontinued or terminated study participation that might be reasonably related to the 64Cu-ATSM-PET/CT trial was to be reported.
Arm/Group Title	Copper ATSM
Arm/Group Description	pre-therapy pelvic 64Cu-ATSM-PET/CT with Pre- and post- therapy FDG PET/CT
All Cause Mortality
	Copper ATSM
	Affected / at Risk (%)	# Events
Total	0/59 (0%)
Serious Adverse Events
	Copper ATSM
	Affected / at Risk (%)	# Events
Total	0/59 (0%)
Other (Not Including Serious) Adverse Events
	Copper ATSM
	Affected / at Risk (%)	# Events
Total	0/59 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.