Gastrointestinal (GI) cancers represent a major global health burden and remain a leading cause of cancer-related morbidity and mortality worldwide.
Among gastrointestinal malignancies, colorectal cancer (CRC) remains one of the most significant oncologic challenges worldwide. March is recognized globally as Colorectal Cancer Awareness Month, highlighting the importance of prevention, early detection, and continued clinical research aimed at improving outcomes for patients with CRC.
The Alliance for Clinical Trials in Oncology is actively conducting a wide portfolio of clinical trials designed to address these challenges. The Alliance unites more than 25,000 cancer specialists across 115 main institutions and 1,400 affiliated sites in the United States and Canada.
These studies explore innovative approaches across GI cancers, including genetics, systemic therapy optimization, ablative strategies for metastatic disease, supportive care, survivorship interventions, financial toxicity, and early cancer detection.
Colorectal Cancer Burden and Epidemiology
According to the American Cancer Society Colorectal Cancer Statistics 2026 report, an estimated 158,850 new cases of colorectal cancer will be diagnosed in the United States in 2026, and 55,230 people will die from the disease.
Significant disparities also exist. The Alaska Native population has the highest CRC incidence (81 cases per 100,000 people) and death rates (32 deaths per 100,000) in the world—more than twice the rates observed among White Americans. The American Indian population has the second-highest colorectal cancer burden in the United States.
Recent data show that colorectal cancer trends are shifting across age groups. While incidence and mortality continue to decline among adults aged 65 years and older, rates are increasing among individuals younger than 65, particularly in cancers arising in the distal colon and rectum.
Incidence is rising by 3% per year among adults aged 20–49 and by 0.4% per year among those aged 50–64, while decreasing by 2.5% per year among people aged 65 and older. Early-onset colorectal cancer is increasing across all racial and ethnic groups, and many younger patients are diagnosed at advanced stages of disease, underscoring the growing need for continued research and improved screening strategies.
New Trials Opened in 2026
Among the Alliance studies highlighted this March, two newly opened trials focus on distinct but important challenges in colorectal cancer care: improving family communication after genetic testing and reducing unplanned chemotherapy delays through a proactive dosing strategy. Together, these studies reflect how research continues to expand beyond treatment efficacy alone to also address prevention, care delivery, and clinical decision-making.
Alliance A212101
ClinicalTrials.gov ID: NCT07143487
Study type: Interventional
Estimated start: November 5, 2025
Study completion: November 5, 2032
Estimated enrollment: 4,186 participants
The Alliance A212101 trial, co-chaired by Heather Hampel (City of Hope) and Frank Sinicrope (Mayo Clinic), investigates how genetic risk information should be communicated within families after a new diagnosis of colorectal cancer. Identifying hereditary cancer risk is important because some colorectal cancers are associated with inherited genetic variants that may also place relatives at increased risk.
The study compares two approaches for informing first-degree relatives about genetic testing results: proband-mediated communication, in which patients themselves share their genetic results with relatives, and provider-mediated communication, where healthcare professionals directly contact relatives to explain the genetic findings and encourage testing.
Key aspects of the trial
- Up to 30% of colorectal cancer cases may have a genetic basis, and about 15% of these patients carry a pathogenic germline variant in a cancer susceptibility gene
- Primary endpoint: proportion of first-degree relatives undergoing germline testing within 6 months
- Secondary endpoint: proportion of relatives with a pathogenic germline variant who initiate disease prevention efforts within 12 months
By comparing these communication strategies, the trial aims to determine whether provider-mediated outreach can improve cascade genetic testing and support earlier cancer prevention among at-risk family members.
PAGODA Trial
Alliance A232402 CD
ClinicalTrials.gov ID: NCT07283939
Study type: Interventional
Estimated start: December 15, 2025
Study completion: May 2, 2030
Estimated enrollment: 420 participants
Led by Gabriel Brooks, MD, MPH (Dartmouth Geisel School of Medicine), the PAGODA trial evaluates a structured strategy for guiding chemotherapy dose adjustments during FOLFOX treatment for gastrointestinal cancers. PAGODA (Proactive Graduated Dose Modification Algorithm) is designed to help clinicians proactively adjust chemotherapy dosing in order to reduce treatment interruptions during therapy.
Patients are randomized to one of two approaches while receiving standard-of-care FOLFOX chemotherapy(oxaliplatin, folinic acid/leucovorin, and fluorouracil). In the control arm, dose delays and modifications are made according to usual clinician-directed practice. In the intervention arm, dose adjustments follow the PAGODA algorithm, which provides structured guidance for dose modification during treatment cycles.
Key aspects of the trial
- Randomized comparison of clinician-directed dose modification vs PAGODA-guided dose adjustment
- Includes patients receiving FOLFOX chemotherapy for gastrointestinal cancers, including colon and rectal cancer
- Primary endpoint: proportion of chemotherapy cycles with unplanned treatment delays during cycles 2–7
- Secondary endpoints: time toxicity (healthcare contact days), incidence of moderate-to-severe neutropenia, and relative dose intensity of chemotherapy agents
If effective, the PAGODA approach could provide a standardized framework to help clinicians manage chemotherapy dosing, potentially reducing unplanned treatment delays while maintaining treatment intensity.
Ongoing Trials
Several Alliance studies are currently enrolling patients and investigating new approaches across multiple areas of cancer care, including metastatic disease management, treatment optimization, supportive care, and survivorship.
ERASur Trial
ClinicalTrials.gov ID: NCT05673148
Study type: Interventional (Phase 3)
Study start: October 9, 2023
Study completion: August 12, 2032
Estimated enrollment: 364 participants
Led by Eric Miller, MD, PhD (The Ohio State University Medical Center), the ERASur study is evaluating whether adding total ablative therapy (TAT) to standard-of-care systemic therapy can improve outcomes in patients with limited metastatic colorectal cancer. The trial enrolls patients with newly diagnosed oligometastatic colorectal cancer with up to four sites of metastatic disease, excluding liver-only metastases.
Patients are randomized to receive either standard-of-care chemotherapy alone or standard-of-care chemotherapy plus TAT. Total ablative therapy consists of stereotactic ablative radiotherapy (SABR) with or without surgical resection and/or microwave ablation, with SABR required for at least one lesion.
Key aspects of the trial
- Randomized comparison of TAT plus standard-of-care systemic therapy vs standard-of-care systemic therapy alone
- Includes patients with newly diagnosed oligometastatic colorectal cancer with ≤ 4 metastatic sites
- Primary endpoint: overall survival (OS)
- Secondary endpoints: event-free survival (EFS), adverse events, and time to local recurrence (TLR)
This study aims to determine whether ablative treatment of all known metastatic sites, when added to systemic therapy, can improve outcomes in carefully selected patients with limited metastatic colorectal cancer.
Alliance A022102
Study type: Interventional (Phase 3)
ClinicalTrials.gov ID: NCT05677490
Study start: January 31, 2023
Estimated enrollment: 382 participants
The Alliance A022102 trial is a randomized phase III study evaluating whether modified FOLFIRINOX (mFOLFIRINOX) can improve outcomes compared with modified FOLFOX (mFOLFOX) as first-line treatment for patients with advanced, unresectable, or metastatic HER2-negative esophageal, gastroesophageal junction, or gastric adenocarcinoma.
FOLFOX-based chemotherapy is commonly used as first-line treatment for metastatic gastroesophageal adenocarcinoma. This study investigates whether intensifying chemotherapy by adding irinotecan (mFOLFIRINOX) may improve survival outcomes. In both arms, nivolumab may be administered according to protocol-specified indications.
Key aspects of the trial
- Randomized comparison of mFOLFIRINOX ± nivolumab vs mFOLFOX ± nivolumab
- Enrolls patients with advanced, unresectable, or metastatic HER2-negative gastroesophageal adenocarcinoma
- Primary endpoint: overall survival (OS)
- Secondary endpoints: progression-free survival (PFS), objective response rate (ORR), duration of response, safety, and patient-reported tolerability (PRO-CTCAE)
- Exploratory analyses: evaluation of PD-L1 combined positive score (CPS) and circulating cell-free DNA (cfDNA)as potential biomarkers
This study aims to determine whether a more intensive chemotherapy backbone combined with immunotherapy can improve survival outcomes for patients with advanced gastroesophageal adenocarcinoma in the first-line setting.
Alliance A222004
Study type: Interventional (Phase III)
ClinicalTrials.gov ID: NCT04939090
Study start: January 3, 2022
Primary completion: April 1, 2027
Estimated enrollment: 360 participants
Led by Aminah Jatoi, MD (Mayo Clinic), this phase III trial evaluates treatment strategies for cancer-associated anorexia, a common and challenging complication among patients with advanced malignancies.
The study compares olanzapine, an antipsychotic medication that has been shown to stimulate appetite, with megestrol acetate, a commonly used appetite stimulant. The goal is to determine whether olanzapine can produce greater improvements in appetite and potentially help prevent weight loss in patients experiencing cancer-related anorexia.
Key aspects of the trial
- Randomized phase III comparison of olanzapine vs megestrol acetate
- Enrolls patients with advanced cancer experiencing loss of appetite
- Primary endpoint: change in appetite score from baseline to 4 weeks, measured using a 0–10 numerical rating scale
- Secondary endpoints: proportion of patients achieving ≥5% weight gain and changes in anorexia/cachexia symptoms measured using the FAACT Anorexia/Cachexia Subscale
This study aims to determine whether olanzapine may offer a more effective strategy than current standard therapy for managing cancer-associated anorexia and improving nutritional outcomes in patients with advanced cancer.
DEFEND Trial
Alliance A222302
Study type: Interventional (Phase: Not applicable)
ClinicalTrials.gov ID: NCT07059884
Study start: February 11, 2026
Primary completion: January 1, 2027
Estimated enrollment: 104 participants
Led by Jennifer Ligibel, MD (Dana-Farber Cancer Institute) and Kathryn Schmitz, PhD, MPH (UPMC Hillman Cancer Center), the DEFEND (Distance-Based Exercise to Preserve Function and Prevent Disability) study evaluates whether a structured exercise program can be delivered successfully through telehealth to patients receiving curative-intent outpatient cytotoxic chemotherapy.
In this single-arm interventional study, participants complete supervised telehealth resistance exercise sessions twice weekly and unsupervised aerobic exercise sessions lasting at least 30 minutes three times per week. The program continues until completion of standard-of-care chemotherapy or for up to 6 months. Participants also receive adjustable-weight dumbbells and wear an accelerometer throughout the study to monitor physical activity.
Key aspects of the trial
- Single-arm feasibility study evaluating a telehealth-delivered exercise intervention during chemotherapy
- Includes patients receiving curative-intent cytotoxic chemotherapy for cancer
- Primary endpoints: feasibility metrics including exercise session completion and intervention attrition rate
- Secondary endpoint: recruitment feasibility in a diverse patient population
- Exploratory outcomes: changes in 6-minute walk test distance, grip strength, physical activity levels, and patient-reported outcomes
The study aims to determine whether remotely delivered exercise programs can be successfully integrated into cancer care to help preserve physical function and prevent disability during chemotherapy.
PROOF Trial
Alliance A232403
ClinicalTrials.gov ID: NCT06963723
Study type: Interventional (Phase: Not applicable)
Study start: July 1, 2025
Estimated primary completion: October 1, 2028
Estimated enrollment: 1,000 participants
Led by Victoria Blinder, MD, MSc (Memorial Sloan Kettering Cancer Center), the PROOF (Longitudinal Screening for Financial Hardship to Improve Outcomes in Patients With Advanced Cancer) trial evaluates whether regular digital screening for financial hardship can improve outcomes among adults with advanced or metastatic cancer receiving systemic therapy with non-curative intent.
Participants are randomized to either monthly remote financial hardship screening or enhanced usual care. In the intervention arm, patients complete a single-item financial hardship screening question every four weeks for 12 months, allowing clinicians to identify financial distress and connect patients with financial navigation resources.
Key aspects of the trial
- Randomized study evaluating monthly digital screening for financial hardship
- Enrolls adults receiving systemic therapy for advanced or metastatic cancer
- Primary endpoint: patient-reported financial worry, measured using the FACIT-COST scale
- Secondary endpoints: health-related quality of life, symptom burden, and treatment adherence
By systematically identifying financial toxicity and connecting patients with supportive resources, the trial aims to determine whether proactive financial screening can improve patient-centered outcomes in advanced cancer care.
Prevention and Early Detection Studies
Beyond treatment, Alliance research is also exploring strategies aimed at reducing cancer risk, improving early detection, and expanding access to preventive interventions for high-risk populations.
Project REACH
Alliance A211901
Study type: Interventional (Phase III)
ClinicalTrials.gov ID: NCT05008848
Study start: April 1, 2022
Estimated primary completion: March 26, 2028
Estimated enrollment: 600 participants
Also known as Project REACH (Reaching Rural Cancer Survivors Who Smoke Using Text-Based Cessation Interventions), this phase III randomized trial, led by Devon Noonan, PhD, MPH, FNP-BC (Duke University School of Nursing), evaluates whether a text-based smoking cessation strategy can improve quit rates among rural cancer survivors who currently smoke, including individuals with a prior diagnosis of colorectal cancer.
Participants are randomized to one of two interventions. In the experimental arm, patients follow an 8-week scheduled gradual reduction (SGR) program designed to progressively decrease cigarette consumption, combined with supportive cessation text messages for 12 weeks through the NCI Smokefree.TXT program. In the control arm, participants receive the NCI “Clearing the Air” smoking cessation booklet, which provides educational guidance to support gradual smoking cessation.
Key aspects of the trial
- Randomized phase III study evaluating a digital smoking cessation intervention in rural cancer survivors
- Compares an 8-week text-based gradual reduction program with supportive messaging to a booklet-based cessation intervention
- Primary endpoint: biochemically validated tobacco cessation at 6 months after the quit date
- Secondary endpoint: overall quality of life, assessed using the LASA scale at 30 days and 6 months
The trial aims to determine whether text-based behavioral interventions can improve smoking cessation rates and support survivorship outcomes among cancer patients living in rural communities, where access to traditional cessation programs may be limited.
Alliance A212102
Study type: Observational
ClinicalTrials.gov ID: NCT05334069
Study start: August 18, 2022
Primary completion: January 31, 2026
Estimated enrollment: 2,000 participants
This observational study, led by Marie Wood, MD (University of Colorado School of Medicine), aims to create a blinded reference set of blood samples from individuals with and without cancer to support the development of blood-based multicancer early detection (MCED) tests. Participants complete a baseline questionnaire and undergo blood sample collection at study registration and again after 12 months. Individuals diagnosed with cancer may also provide tissue samples at the same time points. Participants are followed for one year after enrollment.
Key aspects
- Observational biospecimen collection study designed to support development of multicancer early detection blood tests
- Includes participants with and without cancer to establish a blinded reference dataset
- Blood samples collected at baseline and 12 months, with optional tissue collection for patients with cancer
- Primary objective: create a blinded reference set to validate assays for future MCED clinical trials
- Secondary objectives: evaluate test performance according to tumor type and stage at diagnosis
The study aims to support the development of liquid biopsy–based screening technologies that could enable earlier detection across multiple cancer types.
AYA ACCESS Study
Study type: Interventional
ClinicalTrials.gov ID: NCT07091617
Study start: December 10, 2025
Primary completion: April 28, 2028
Estimated enrollment: 535 participants
Led by Angela Bradbury, MD (University of Pennsylvania Abramson Cancer Center), the AYA ACCESS study evaluates whether a digital chatbot-enabled genetic service model can improve access to genetic counseling and testing among adolescents and young adults (AYA) with cancer aged 18–39, including survivors of colorectal cancer. Many AYAs meet criteria for genetic testing but do not receive it due to barriers such as limited access to genetic specialists, geographic distance, or time constraints in community oncology settings.
Participants are randomized to standard remote genetic services via telehealth or an enhanced digital model using the “Genetic Journey” chatbot, which provides education, reminders, and navigation through the genetic testing process while allowing patients to request telehealth consultations when needed.
Key aspects
- Randomized trial comparing standard tele-genetic services vs chatbot-enabled digital delivery
- Focus on AYA cancer patients and survivors aged 18–39
- Primary endpoints: uptake of genetic counseling and genetic testing
- Secondary outcomes: patient knowledge, distress, satisfaction, health behaviors, and cost of genetic services
The study aims to determine whether a digital, chatbot-supported approach can expand access to genetic services and improve testing uptake in young cancer patients treated in community settings.
Conclusion
The diverse portfolio of Alliance trials highlighted this March illustrates how research in GI cancers extends far beyond the development of new drugs alone. Current studies are exploring advances in genetics, treatment optimization, metastatic disease management, supportive care, survivorship, prevention, financial toxicity, and early detection.
Together, these efforts reflect a broader shift toward more comprehensive and multidisciplinary cancer care, where improving outcomes depends not only on advancing therapies but also on strengthening prevention strategies, expanding access to care, and supporting patients throughout the cancer journey.
These trials highlight the critical role of clinical research in advancing prevention, improving treatments, and shaping the future of care for patients with GI cancers.
Full details are available on the official Alliance for Clinical Trials in Oncology website.