A Study to Evaluate Multicancer Detection (MCD) Tests and Their Impact on Participant Health and Cancer Screening, The Vanguard Study

Not Applicable

Not yet recruiting

• Conditions: Bladder Carcinoma; Breast Carcinoma; Colorectal Carcinoma; Esophageal Carcinoma; Gastric Carcinoma; Liver Carcinoma; Lung Carcinoma; Malignant Solid Neoplasm; Ovarian Carcinoma; Pancreatic Carcinoma

• Registration Number: NCT06995898
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This clinical trial studies the impact of two multicancer detection (MCD) tests, Shield and Avantect, as cancer screening tests in a population of adults aged 45-75 without cancer in underrepresented communities. This study provides early information on how well MCD tests perform as cancer screening tools and help researchers understand how patients and their doctors make decisions about their care when the MCD test comes back with a normal (negative) or an abnormal (positive) result. The goal of cancer screening is to reduce the burden of cancer by identifying cancers before they show symptoms or signs, ideally at an early stage where the chance of cure is highest, and treatment may be less aggressive. MCD is a test that measures tumor cell biomarkers in blood in order to screen for multiple cancers simultaneously. MCDs are simple to implement for both health care providers and their patients, making them accessible even in under-resourced settings. The Avantect MCD test is a next-generation sequencing (NGS)- based screening test intended for the qualitative detection of the presence or absence of cancer-related abnormal signals in plasma cell free deoxyribonucleic acid (cfDNA) derived from whole blood. The Avantect MCD test reports on the possible presence of 8 cancers: breast, colorectal, esophagus, stomach, liver, lung, ovarian and pancreas and may indicate the presence of up to two predicted tissue of origins. The Shield MCD blood test reports cancer derived alterations associated from whole blood samples collected from individuals at average risk. The Shield MCD test is developed for the detection of cancers and the prediction of the tissue of origin of 10 cancer types: bladder, breast, colorectal, esophageal, stomach, liver, lung, ovarian, pancreatic, and prostate. Undergoing Avantect and Shield MCD testing may work better at screening participants aged 45-75 for cancer in underrepresented communities.

Detailed Description

PRIMARY OBJECTIVES:

I. Assess the feasibility of recruitment and adherence to protocol-required baseline and follow-up data and blood collection. (Feasibility) II. Assess the feasibility of achieving representative enrollment across participating recruitment sites. (Feasibility)

SECONDARY OBJECTIVES:

I. To assess the impact of participant blinding on willingness to participate, adherence to protocol required baseline and follow-up data, blood collection, and on rates of standard of care screening. (Feasibility) II. To determine the timeliness of returning test results to participants. (Feasibility) III. To understand the factors contributing to lack of diagnostic resolution of an abnormal MCD test. (Feasibility) IV. To examine the effects of participant characteristics, including cancer risk factors and social determinants of health, on all aspects of feasibility. (Feasibility) V. To estimate the proportion of participants receiving an MCD test outside of the trial. (Feasibility) VI. To assess the feasibility of a staggered introduction of the second MCD assay intervention arm. (Feasibility) VII. To estimate the proportion of abnormal MCD tests that are diagnostically resolved, and the time to resolution. (Clinical Impact and Outcomes) VIII. To compare the proportion of participants who receive standard of care screening during follow-up between the intervention and control arms. (Clinical Impact and Outcomes) IX. To assess the accuracy of tissue of origin prediction for each MCD assay. (Clinical Impact and Outcomes) X. To estimate the incidence of complications related to diagnostic evaluation of an abnormal MCD test result. (Clinical Impact and Outcomes) XI. To assess the effect of an abnormal MCD test and diagnostic workup on anxiety and cancer worry. (Clinical Impact and Outcomes) XII. To evaluate the clinical diagnostic performance of the MCD assays. (Clinical Impact and Outcomes)

EXPLORATORY OBJECTIVES:

I. To estimate rates of late-stage cancer, and the distribution of cancer stage.

II. To estimate assay-targeted cancer-specific mortality of each MCD assay, all cancer-specific mortality, and all-cause mortality.

OUTLINE: Participants are randomized to 1 of 3 arms.

ARM I: Participants undergo blood collection for Shield MCD testing at enrollment and after one year on study. Participants are provided results of tests and those with abnormal results follow up with their clinician for additional testing.

ARM II: Participants undergo blood collection for Avantect MCD testing at enrollment and after one year on study. Participants are provided results of tests and those with abnormal results follow up with their clinician for additional testing.

ARM III (Control): Participants undergo blood collection at enrollment and after one year on study.

After completion of study intervention, participants are followed up at 1 year and then up to 10 years.

Study Timeline

• Study First Submitted: 2025-05-29
• Study First Submitted QC: 2025-05-29
• Study First Posted: 2025-05-30
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-07
• Last Update Posted: 2025-06-10
• Study Start: 2025-11-19
• Primary Completion: 2027-12-31
• Study Completion: 2029-06-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 24000

Inclusion Criteria

• Ages 45-75 years old

• Agree to provide blood samples for possible MCD testing at enrollment and at 1 year following enrollment

• Agree to allow collection of information from their medical records for study-related purposes

• Understand and be able to complete informed consent and participant questionnaires in English, Spanish, or Arabic

  • Note: Eligibility for Spanish and Arabic languages are at the Hub's discretion

Exclusion Criteria

• Solid malignant tumor or blood cancer diagnosis, with or without treatment, within the last 5 years

  • Note: Persons with a history of in situ cancers (e.g., ductal carcinoma in situ of the breast, cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ) or nonmelanoma skin cancer are eligible

• Ongoing cancer diagnostic work-up as determined by site investigator

• Ongoing participation in another study of an investigational cancer screening test or technology

• Currently breastfeeding or pregnant, or planning to become pregnant in the next year

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Feasibility of initial enrollment onto study	At time of enrollment	Will be defined by recruitment method. ACCESS Hubs will be asked to provide details of their recruitment process including modality (community events, provider, email/mail, etc.) and an estimate of the number of potential participants approached. Where relevant, data from multiple ACCESS Hubs with similar strategies will be combined. Summaries will be for blinded ACCESS Hubs, unblinded ACCESS Hubs, and overall (no confidence intervals).
Feasibility of randomization	At time of randomization	Results will be computed per ACCESS Hub and for all Hubs combined. Success will also be ascertained separately for the ACCESS Hubs that are blinded and those that are unblinded.
Proportion of participants who complete baseline and follow-up questionnaires within 60 days of receipt (Feasibility)	Up to 1 year	For each questionnaire compute the fraction of participants who complete the questionnaire within 90 days the expected date. Also compute the fraction of participants who ever complete the questionnaire. The data will be analyzed via a logistic regression model with arm and blinding as two main effects and an arm blinding interaction term. Exploratory analyses for each ACCESS Hub will also be carried out.
Proportion of participants who provide the required blood sample for year 1 for Multi-Cancer Detection (MCD) testing within 90 days of recommended time point (Feasibility)	Up to 1 year	Compute the fraction of participants who have a second blood draw within 90 days of their one-year anniversary of the first blood draw. Also compute the fraction of participants who ever complete the second blood draw. The data will be analyzed via a logistic regression model with arm and blinding as two main effects and an arm blinding interaction term. Exploratory analyses for each ACCESS Hub will also be carried out.
Proportion of participants considered lost to follow-up within 2 years of randomization (Feasibility)	Up to 2 years	The data will be analyzed via a logistic regression model with arm and blinding as two main effects and an arm blinding interaction term. Exploratory analyses for each ACCESS Hub will also be carried out.
Representative enrollment (Feasibility)	At enrollment	Defined as meeting or exceeding the trial enrollment goals (according to race (5 National Institutes of Health categories), ethnicity (Hispanic and non-Hispanic), and sex. The fraction of trial participants in each race, ethnicity, and sex category (marginally, i.e., combined over the other factors) will be computed and compared to the planned enrollment overall. Exploratory analyses for each ACCESS Hub will also be carried out.
Staggered start of intervention arm 2 (Feasibility)	Up to 2 years	Sites will be surveyed about advantages and challenges arising from trial activation with one intervention arm and later addition of a second intervention arm, and the responses qualitatively summarized.

Secondary Outcome Measures

Name	Time	Method
Impact of participant blinding (Feasibility)	Up to 2 years	Comparisons between blinded and unblinded sites on participation rates, adherence to protocol-required baseline and follow-up questionnaires and blood collection, and participation in standard of care (Soc) screening. The fraction of participants receiving any SoC screening test or procedure, within the year prior to questionnaire, will be summarized separately for the year 1 and year 2 questionnaire. The data will be analyzed via a logistic regression model with arm and blinding as two main effects and an arm blinding interaction term. These proportions will also be summarized for each SoC modality. The rates will be compared to the recommended rates, combining multiple screening modalities for cancers where multiple modalities are used (e.g., colorectal cancer). Exploratory analysis for each ACCESS Hub will also be carried out.
Timely return of MCD test result (Feasibility)	Up to 2 years	Defined as the time from the Statistics and Data Management Center (SDMC) to the ACCESS Hub, and from the ACCESS Hub to the participant, each measured separately. The average (range) time from an MCD company receiving a participant sample until the test result is reported to the SDMC will be computed separately for each company. The average (range) times for receipt of the test result from the SDMC to the ACCESS Hub, and from the ACCESS Hub to the participant, will be computed overall, separately by blinded versus (vs) unblinded Hubs. Exploratory analyses for each ACCESS Hub will also be carried out.
Factors contributing to lack of diagnostic resolution of an abnormal MCD test (Feasibility)	Up to 2 years	Factors contributing to lack of diagnostic resolution include refusing diagnostic workup, health system or provider/test availability, other costs (e.g., childcare, transportation, inability to take off work without penalty), inability to tolerate diagnostic procedure due to co-morbidities, and complications from prior diagnostic procedures. The fractions of tests that are non-reportable due to the sample and due to the assay will be computed for each intervention arm. The fractions of non-reportable MCD tests that can be recovered after an additional blood draw and/or assay, and the fractions of non-reportable MCD tests due to the assay in year 1 that are resolved in year 2, will also be reported.
Contamination (Feasibility)	Up to 2 years	Will be estimated as the number of participants receiving MCD testing outside the trial. The proportions will be estimated for the overall trial and described according to calendar time to capture possible secular trends in MCD use. The data will be analyzed via a logistic regression model with arm and blinding as two main effects and an arm blinding interaction term.; Exploratory analyses for each ACCESS Hub will also be carried out.
Effects of participant characteristics (Feasibility)	At time of enrollment	Demographics, social determinants of health, and cancer risk factors will be examined as potential correlates of primary feasibility outcomes.
Diagnostic resolution following an abnormal MCD test result (Clinical Impact and Outcomes)	Within 12 months following an abnormal MCD test result	The proportion of participants with a "cancer diagnosis" or "no cancer diagnosis" among all participants with an abnormal MCD test result will be reported for each MCD test. The fraction of "unresolved" will also be reported.
Time to diagnostic resolution (Clinical Impact and Outcomes)	From date of ACCESS Hub receipt of abnormal MCD test result to date of provider-reported diagnostic resolution	Defined as the number of days from date of ACCESS Hub receipt of abnormal MCD test result to date of provider-reported diagnostic resolution. Participants last known to be alive and without diagnostic resolution are censored at the date of last contact. Will construct tables with the median (25th, 75th percentile) of times to diagnostic resolution for all abnormal MCD tests that result in "Cancer Diagnosis", and for those that result in "No Cancer Diagnosis". These tables will be supplemented by cumulative incidence curves to summarize the number of days from date of Hub receipt of abnormal MCD test result to date of provider-reported diagnostic resolution (cancer diagnosis or no cancer diagnosis), among participants who received an abnormal test. Exploratory analyses for each ACCESS Hub will also be carried out, including cumulative incidence curves for the time to diagnostic resolution by ACCESS Hub to monitor progress.
Participation in Soc screening (Clinical Impact and Outcomes)	From baseline up to 2 years	Will compare the proportion of participants who report having been screened during follow-up between the intervention and control arms. The fraction of participants receiving any SoC screening test or procedure, within the year prior to questionnaire, will be summarized separately for the year 1 and year 2 questionnaire. The data will be analyzed via a logistic regression model with arm and blinding as two main effects and an arm blinding interaction term. These proportions will also be summarized for each ACCESS Hub and for each SoC modality. The rates will be compared to the recommended rates, combining multiple screening modalities for cancers where multiple modalities are used (e.g., colorectal cancer).
Accuracy of tissue of origin prediction (Clinical Impact and Outcomes)	Up to 2 years	Defined as the proportion of diagnosed cancers that match the tissue of origin predicted by an MCD test, for each screening episode.
Complications related to diagnostic evaluation of an abnormal MCD test result (Clinical Impact and Outcomes)	From the time of the first diagnostic procedure until either diagnostic resolution or discontinuation of the workup	Defined as adverse events (AEs) occurring in participants undergoing a diagnostic workup following receipt of an abnormal MCD test result, from the time of the first diagnostic procedure until either diagnostic resolution or discontinuation of the workup. AEs ad serous AEs will be tabulated.
Anxiety and Cancer Worry Questionnaire (Clinical Impact and Outcomes)	At year 1 and year 2 follow-up	Participant anxiety will be assessed with the Patient Reported Outcomes Measurement Information System instrument. Cancer-related worry will be assessed using the Lehrman Cancer Worry Scale. Both instruments will be analyzed using linear regression by arm, in combination with blinding status, race, ethnicity, age, sex, and categories of reported household income with adjustment for baseline levels of the outcome. Will summarize these outcomes as measured at year 1 and year 2 follow-up. In addition, the outcomes will be compared between participants who received an abnormal MCD test result (cases) and randomly selected participants without abnormal MCD test results (cohort), for each screening event.
(Empirical) Sensitivity of clinical diagnostic performance of each MCD assay (Clinical Impact and Outcomes)	Up to 2 years	The various types of sensitivity will be estimated for each MCD assay. These sensitivities will also be calculated by early- vs late-stage, and for MCD test-targeted cancers and all cancers.
Specificity of each MCD assay (Clinical Impact and Outcomes)	After 12 month follow up period	The various types of specificity will be estimated for each MCD assay.
Test positive rates (Clinical Impact and Outcomes)	Up to 2 years	Defined as the proportion of abnormal MCD tests at each screening episode, and proportion of participants with at least one abnormal test. Measures will be estimated for each MCD assay.
False positives (Clinical Impact and Outcomes)	Up to 2 years	Measures will be estimated for each MCD assay.
(Targeted cancer) Positive predictive value (PPV) (Clinical Impact and Outcomes)	Up to 2 years	Defined as the proportion of abnormal MCD tests that result in diagnosis of one of the MCD test-targeted cancers among participants with at least one abnormal test, for each screening episode. Measures will be estimated for each MCD assay.
(All cancer) PPV (Clinical Impact and Outcomes)	Up to 2 years	Defined as the proportion of abnormal MCD tests that result in diagnosis of any cancer among participants with at least one abnormal test, for each screening episode. Measures will be estimated for each MCD assay.
Interval cancers (Clinical Impact and Outcomes)	Up to 2 years	Defined as the number of MCD test-targeted cancer cases diagnosed within 12 months of a normal MCD test result among participants who received an MCD test, for each screening episode. Measures will be estimated for each MCD assay.
Detected cancers (Clinical Impact and Outcomes)	Up to 2 years	The number of cancer cases diagnosed within a 12-month follow-up period of an abnormal test result among participants who received an MCD test, for each screening episode. Measures will be estimated for each MCD assay.
(Targeted cancer) Negative predictive value (Clinical Impact and Outcomes)	Up to 2 years	Defined as the proportion of normal MCD tests that did not result in diagnosis of one of the MCD test-targeted cancers among participants with a normal test, for each screening episode. Measures will be estimated for each MCD assay.