Trial Title:
The Sagittarius Trial
NCT ID:
NCT06490536
Condition:
Colon Cancer Stage II
Colon Cancer Stage III
Conditions: Official terms:
Colonic Neoplasms
Leucovorin
Folic Acid
Capecitabine
Fluorouracil
Nivolumab
Oxaliplatin
Trastuzumab
Irinotecan
Temozolomide
Ipilimumab
Pertuzumab
Panitumumab
Levoleucovorin
Study type:
Interventional
Study phase:
Phase 3
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Oxaliplatin
Description:
Oxaliplatin is used as part of the chemotherapy regimens for patients with ctDNA+ results
in the SAGITTARIUS trial. It is administered in the following ways:
CAPOX Regimen: Oxaliplatin 130 mg/m² is given intravenously on day 1, in combination with
capecitabine 1000 mg/m² taken orally twice daily on days 1-14 of each 21-day cycle.
FOLFOX Regimen: Oxaliplatin 85 mg/m² is administered intravenously on day 1, alongside
folinic acid 400 mg/m² and fluorouracil 400 mg/m² IV bolus, followed by 2400 mg/m² IV
infusion over 46 hours, in each 14-day cycle.
Dosages are standardized, while the duration of treatment can be adjusted based on
patient response and liquid biopsy results, typically up to 6 months.
Arm group label:
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy
Arm group label:
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy
Arm group label:
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy
Arm group label:
Trial-2 (ctDNA-) Standard Therapy
Intervention type:
Drug
Intervention name:
Capecitabine
Description:
Capecitabine is used as part of the chemotherapy regimens for patients with ctDNA+ and
ctDNA- results in the SAGITTARIUS trial. It is administered in the following ways:
CAPOX Regimen: Capecitabine 1000 mg/m² is taken orally twice daily on days 1-14 of each
21-day cycle, in combination with oxaliplatin 130 mg/m² given intravenously on day 1.
Capecitabine Monotherapy for High-Risk ctDNA- Patients: Capecitabine 1250 mg/m² is taken
orally twice daily on days 1-14 of each 21-day cycle for patients identified as high-risk
but with negative ctDNA results.
The dosage of capecitabine is standardized, while the duration of treatment varies based
on patient response and monitoring results, typically up to 6 months.
Arm group label:
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy
Arm group label:
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy
Arm group label:
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy
Arm group label:
Trial-2 (ctDNA-) Standard Therapy
Intervention type:
Drug
Intervention name:
Folinic acid
Description:
Folinic acid is used as part of the FOLFOX chemotherapy regimen for patients with ctDNA+
results in the SAGITTARIUS trial. It is administered in the following way:
FOLFOX Regimen: Folinic acid (leucovorin) 400 mg/m² is given intravenously on day 1, in
combination with oxaliplatin 85 mg/m² IV on day 1 and fluorouracil 400 mg/m² IV bolus
followed by 2400 mg/m² IV infusion over 46 hours, in each 14-day cycle.
The dosage of folinic acid is standardized, while the duration of treatment can be
adjusted based on patient response and liquid biopsy results, typically up to 6 months.
Arm group label:
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy
Arm group label:
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy
Arm group label:
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy
Arm group label:
Trial-2 (ctDNA-) Standard Therapy
Intervention type:
Drug
Intervention name:
Fluorouracil
Description:
Fluorouracil is used as part of the FOLFOX chemotherapy regimen for patients with ctDNA+
results in the SAGITTARIUS trial. It is administered in the following way:
FOLFOX Regimen: Fluorouracil 400 mg/m² is given as an intravenous (IV) bolus on day 1,
followed by 2400 mg/m² as a continuous IV infusion over 46 hours, in combination with
folinic acid (leucovorin) 400 mg/m² IV on day 1 and oxaliplatin 85 mg/m² IV on day 1.
This regimen is repeated every 14 days.
The dosage of fluorouracil is standardized, while the duration of treatment is typically
up to 6 months, adjusted based on patient response and liquid biopsy results.
Arm group label:
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy
Arm group label:
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy
Arm group label:
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy
Arm group label:
Trial-2 (ctDNA-) Standard Therapy
Intervention type:
Drug
Intervention name:
Temozolomide
Description:
Temozolomide is used as part of the tailored chemotherapy regimen for patients with
ctDNA+ results in the SAGITTARIUS trial, specifically for those with MGMT-negative
tumors. It is administered in the following way:
TEMIRI Regimen: Temozolomide 150-200 mg/m² is taken orally once daily on days 1-5 of each
28-day cycle, in combination with irinotecan 250 mg/m² administered intravenously on day
1 of each cycle.
The dosage of temozolomide is standardized, while the duration of treatment can be
adjusted based on patient response and liquid biopsy results.
Arm group label:
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy
Intervention type:
Drug
Intervention name:
Irinotecan
Description:
Irinotecan is used as part of the tailored chemotherapy regimen for patients with ctDNA+
results in the SAGITTARIUS trial. It is administered in the following ways:
TEMIRI Regimen: Irinotecan 250 mg/m² is administered intravenously on day 1 of each
28-day cycle, in combination with temozolomide 150-200 mg/m² taken orally once daily on
days 1-5.
FOLFIRI Regimen: Irinotecan 180 mg/m² is given intravenously on day 1, in combination
with folinic acid (leucovorin) 400 mg/m² IV, fluorouracil 400 mg/m² IV bolus, followed by
2400 mg/m² IV infusion over 46 hours, in each 14-day cycle.
The dosage of irinotecan is standardized, while the duration of treatment can be adjusted
based on patient response and liquid biopsy results.
Arm group label:
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy
Intervention type:
Drug
Intervention name:
Nivolumab
Description:
Nivolumab is used as part of the tailored immunotherapy regimen for patients with ctDNA+
results, specifically for those with MSI-H/MMRd tumors in the SAGITTARIUS trial. It is
administered in the following way:
Nivolumab: 3 mg/kg is given intravenously every 2 weeks. This dosage is standardized,
while the duration of treatment can be adjusted based on patient response and liquid
biopsy results.
Arm group label:
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy
Intervention type:
Drug
Intervention name:
Ipilimumab
Description:
Ipilimumab is used as part of the tailored immunotherapy regimen for patients with ctDNA+
results, specifically for those with MSI-H/MMRd tumors in the SAGITTARIUS trial. It is
administered in the following way:
Ipilimumab: 1 mg/kg is given intravenously every 6 weeks. This dosage is standardized,
while the duration of treatment can be adjusted based on patient response and liquid
biopsy results.
Arm group label:
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy
Intervention type:
Drug
Intervention name:
Trastuzumab
Description:
Trastuzumab is used as part of the tailored targeted therapy regimen for patients with
ctDNA+ results, specifically for those with HER2-amplified tumors in the SAGITTARIUS
trial. It is administered in the following way:
Trastuzumab: 8 mg/kg as an initial intravenous (IV) loading dose, followed by 6 mg/kg IV
every 3 weeks.
The dosage is standardized, while the duration of treatment can be adjusted based on
patient response and liquid biopsy results.
Arm group label:
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy
Intervention type:
Drug
Intervention name:
Pertuzumab
Description:
Pertuzumab is used as part of the tailored targeted therapy regimen for patients with
ctDNA+ results, specifically for those with HER2-amplified tumors in the SAGITTARIUS
trial. It is administered in the following way:
Pertuzumab: 840 mg as an initial intravenous (IV) loading dose, followed by 420 mg IV
every 3 weeks.
The dosage is standardized, while the duration of treatment can be adjusted based on
patient response and liquid biopsy results.
Arm group label:
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy
Intervention type:
Drug
Intervention name:
Panitumumab
Description:
Panitumumab is used as part of the tailored targeted therapy regimen for patients with
ctDNA+ results, specifically for those with multiple wild-type tumors (MSS/MMRp extended
RAS/RAF wild-type) in the SAGITTARIUS trial. It is administered in the following way:
Panitumumab: 6 mg/kg is given intravenously every 2 weeks. The dosage is standardized,
while the duration of treatment can be adjusted based on patient response and liquid
biopsy results.
Arm group label:
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy
Summary:
Background & Rationale:
Colon cancer is a leading cause of cancer deaths, with a high recurrence rate in stage II
high-risk and stage III patients due to undetectable micro-metastases. Liquid biopsy (LB)
detects residual cancer DNA post-surgery and monitors treatment response.
Primary Objective:
Show that therapy based on tumor genetics and LB improves outcomes and quality of life
for high-risk stage II and stage III colon cancer patients compared to conventional
therapy.
Secondary Objectives:
Compare recurrence times. Evaluate side effects and quality of life. Assess cost
differences. Validate LB accuracy.
Study Design: Patients are randomized into standard or personalized treatment groups
based on LB results.
For positive LB results:
Randomized to standard or customized therapy. Monitor treatment response with LB.
For negative LB results:
Randomized to standard chemotherapy or follow-ups, starting treatment if a positive
result appears.
Treatments:
Standard Chemotherapy:
CAPOX (capecitabine and oxaliplatin) FOLFOX (folinic acid, fluorouracil, and oxaliplatin)
Personalized Treatments:
Customized chemotherapy with CAPOX. Immunotherapy with nivolumab and ipilimumab. Targeted
therapy with trastuzumab and pertuzumab. FOLFOX with anti-EGFR (epidermal growth factor
receptor) therapy (panitumumab).
Population: 700 patients with operable stage III and high-risk stage II colon cancer.
Inclusion Criteria:
Aged 18 or older. Confirmed diagnosis. Tumor tissue sample available.
Exclusion Criteria:
History of other tumors within five years. Incomplete colonoscopy or recent polyp
removal. Metastatic disease or recent experimental study participation. Major
cardiovascular diseases, intestinal obstruction, autoimmune diseases, neuropathy, HIV
(Human Immunodeficiency Virus), active TB (Tuberculosis), or hepatitis B/C infection.
Medical conditions contraindicating treatment.
Endpoints:
Primary:
Evaluate disease recurrence after two years.
Secondary:
Assess disease recurrence and overall survival at 3 and 5 years. Measure treatment safety
and tolerability. Validate LB accuracy. Monitor quality of life using questionnaires.
The study will last 5 years and be conducted in 25-30 hospitals across Italy, Spain, and
Germany.
Detailed description:
Background & Rationale:
Colon cancer (CC) is the second most lethal malignancy, accounting for nearly 10% of all
cancer-related deaths. Despite over two-thirds of CC patients undergoing surgical
resection, 50% of stage III patients relapse within 5 years. Adjuvant chemotherapy (ACT),
typically involving oxaliplatin combined with a fluoropyrimidine, offers only a 10-15%
survival advantage over 5-fluorouracil alone. The benefit from ACT is predicted by
clinical and pathological parameters rather than metastatic propensity or biological
sensitivity, and its success is limited by high toxicity levels, particularly
oxaliplatin-induced peripheral sensory neuropathy.
Liquid biopsy (LB) profiling circulating tumor DNA (ctDNA) has emerged as an effective
diagnostic tool for early cancer detection, staging, prognosis, monitoring drug
resistance, and detecting minimal residual disease (MRD). Retrospective studies show that
ctDNA detection post-surgery and post-ACT is associated with high recurrence risk and
worse recurrence-free survival (RFS) in stage I-III colorectal cancer (CRC) patients.
Prospective studies confirm ctDNA's prognostic value post-surgery and ACT.
SAGITTARIUS Trial Objectives:
Diagnosing MRD After Surgery: Utilize post-surgical LB to identify high-risk tumors and
stratify stage II high-risk and stage III CC patients, enabling targeted treatments and
reducing unnecessary chemotoxicity.
Establishing the Efficacy of Adjuvant Chemotherapy and Targeted Therapies: Tailor
treatment based on the individual tumor genomic landscape to improve clinical outcomes
and quality of life compared to conventional chemotherapy.
Study Design:
The SAGITTARIUS trial is a randomized phase III study designed to demonstrate the
efficacy of ctDNA detection in guiding adjuvant clinical management of stage III and
high-risk stage II CC patients. The trial employs the CE-IVD marked tumor-informed MRD
assay Signatera (NATERA® Inc.) and comprehensive tumor genomic profiling (TruSight
Oncology Comprehensive (EU), TSOComp, Illumina, Inc.). These tools will provide a
detailed molecular genomic landscape of each patient's tumor, with results available
within 8 weeks post-surgery for timely adjuvant treatment initiation.
Patient Stratification and Randomization:
Patients are stratified based on ctDNA status into two main trials:
Trial-1 (ctDNA Positive Patients): Includes further stratification based on MSS/MMRp
extended RAS/RAF mutation status and MSI-H/MMRd status. Treatment arms include standard
chemotherapy (CAPOX/FOLFOX) or personalized treatments with reassessment of ctDNA status
guiding subsequent therapies.
Trial-2 (ctDNA Negative Patients): Patients are randomized to either a physician-choice
chemotherapy regimen or intensive follow-up, with interventional LBs at specified
intervals.
Therapeutic Approaches:
Standard Chemotherapy Regimens: CAPOX (capecitabine and oxaliplatin) and FOLFOX (folinic
acid, fluorouracil, and oxaliplatin).
Personalized Therapies: Include options such as FOLFIRI or TEMIRI for RAS/RAF-mutated
tumors, double immunotherapy (nivolumab and ipilimumab) for MSI-H/MMRd, anti-HER2 therapy
(trastuzumab and pertuzumab) for HER2-amplified tumors, and FOLFOX combined with
anti-EGFR (panitumumab) for multiple wild-type tumors.
Data Collection and Analysis:
Data will be collected through regular clinical evaluations, imaging studies, and
questionnaires to assess various endpoints, including RFS, overall survival, treatment
safety, tolerability, and quality of life. The primary endpoint is the 2-year RFS in
ctDNA positive patients, while secondary endpoints include 3 and 5-year RFS, overall
survival, and the accuracy of LB in detecting residual disease. Statistical analyses will
follow the intention-to-treat principle, utilizing the Kaplan-Meier method for
time-to-event data and stratified log-rank tests for comparison.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- SAGITTARIUS trial written informed consent.
- Age ≥ 18 years.
- Histologically confirmed diagnosis of operable stage III and High-Risk stage II CC
located at least 12 cm from the anal verge by endoscopy and above the peritoneal
reflection at surgery.
- Availability of the original FFPE tumor tissue.
- ECOG performance status 0-1.
- Normal organ functions (as defined in section 9.3).
- Women with childbearing potential (WOCBP) should complete a pregnancy test and be
willing to use highly effective contraceptive methods.
Exclusion Criteria:
- History of another neoplastic disease, unless in remission for ≥ 5 years.
Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that
have undergone potentially curative therapy are not excluded.
- Had an incomplete diagnostic colonoscopy.
- Recent polyps' removal (within one month).
- Macroscopic or microscopic evidence of residual tumor (R1 or R2 resections).
Patients should never have had any evidence of metastatic disease (including
presence of tumor cells in the peritoneal lavage).
- Current or recent treatment with another investigational drug or participation in
another investigational study.
- Patient unable to comply with the study protocol owing to psychological, social or
geographical reasons.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study.
- Inadequate contraception (male or female patients) if of childbearing or
procreational potential.
- Clinically relevant cardiovascular disease.
- Acute or subacute intestinal occlusion or history of inflammatory bowel disease or
any other autoimmune disease.
- Pre-existing neuropathy > grade 1. Known grade 3 or 4 allergic reaction to any of
the components of the treatment.
- Has a known DPD (DihydroPyrimidine Dehydrogenase) deficiency.
- Has a known Gilbert Syndrome or UGT1A1 homozygous *28/*28 germline variant.
- Has a known history of Human Immunodeficiency Virus (HIV).
- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) or known active Hepatitis C virus infection.
- Has a known history of active TB (Bacillus Tuberculosis).
- Has a medical condition that contraindicate the use of the investigational medicinal
product (IMP) according to product indications.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Istituto Clinico Humanitas
Address:
City:
Rozzano
Zip:
20089
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Armando Santoro, MD
Phone:
+390282244080
Email:
armando.santoro@hunimed.eu
Facility:
Name:
Istituto di Candiolo
Address:
City:
Candiolo
Zip:
10060
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Elisabetta Fenocchio, MD
Phone:
+390119933250
Email:
elisabetta.fenocchio@ircc.it
Facility:
Name:
Azienda Sanitaria Locale di Biella
Address:
City:
Biella
Zip:
13875
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Francesco Leone, MD
Phone:
+3901515157503
Email:
francesco.leone@aslbi.piemonte.it
Facility:
Name:
Fondazione Poliambulanza
Address:
City:
Brescia
Zip:
25124
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Michela Libertini, MD
Phone:
+390303515557
Email:
michela.libertini@poliambulanza.it
Facility:
Name:
Azienda Ospedaliera Universitaria San Martino
Address:
City:
Genova
Zip:
16132
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Maria Stefania Sciallero, MD
Phone:
+390105553302
Email:
stefania.sciallero@hsanmartino.it
Facility:
Name:
Istituto Europeo di Oncologia
Address:
City:
Milano
Zip:
20141
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Maria Giulia Zampino, MD
Phone:
+390257489406
Email:
maria.zampino@ieo.it
Facility:
Name:
Ospedale Niguarda
Address:
City:
Milan
Zip:
20162
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Salvatore Siena, MD
Phone:
+390264442291
Email:
salvatore.siena@ospedaleniguarda.it
Facility:
Name:
Ospedale Maggiore di Novara
Address:
City:
Novara
Zip:
28100
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Alessandra Gennari, MD
Phone:
+3903213733822
Email:
alessandra.gennari@maggioreosp.novara.it
Facility:
Name:
Azienda Ospedaliera Universitaria di Parma
Address:
City:
Parma
Zip:
43126
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Francesca Negri, MD
Phone:
+390521703749
Email:
fnegri@ao.pr.it
Facility:
Name:
Ospedale Santa Maria della Misericordia
Address:
City:
Perugia
Zip:
06129
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Mario Mandalà, MD
Phone:
+390755784205
Email:
mario.mandala@unipg.it
Facility:
Name:
Azienda Unità Sanitaria Locale della Romagna
Address:
City:
Ravenna
Zip:
48121
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Stefano Tamberi, MD
Phone:
+290544287175
Email:
stefano.tamberi@auslromagna.it
Facility:
Name:
Policlinico Universitario Gemelli
Address:
City:
Roma
Zip:
00168
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Lisa Salvatore, MD
Phone:
+390630156318
Email:
lisa.salvatore@policlinicogemelli.it
Facility:
Name:
Hospital del Mar
Address:
City:
Barcelona
Zip:
08003
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Clara Montagut, MD
Phone:
+34932483137
Email:
cmontagut@psmar.cat
Facility:
Name:
Hospital Universitari Vall d'Hebron
Address:
City:
Barcelona
Zip:
08035
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Elena Elez, MD
Phone:
+349327460000
Email:
meelez@vhio.net
Start date:
October 22, 2024
Completion date:
September 1, 2028
Lead sponsor:
Agency:
IFOM ETS - The AIRC Institute of Molecular Oncology
Agency class:
Other
Source:
IFOM ETS - The AIRC Institute of Molecular Oncology
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06490536
