BEVACIZUMAB for HER2-positive metastatic colorectal cancer

Inclusion criteria

• {"criterion_text":"- Written informed consent and any locally required authorization (such as the Euroean Union [EU] Data Privacy Directive) obtained from the patient/legal 8/20 CHIMERA trial Synopsis v1.0 dated 24 Oct 2024 representative before performing any protocol-related procedures, including screening evaluations."}
• {"criterion_text":"- Presence of locally determined HER2 overexpression/amplification defined as IHC 3+ or 2+/ISH amplified on archival /newly obtained tumor tissue, according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for gastric/gastroesophageal cancer."}
• {"criterion_text":"- Have RAS known status and pMMR/MSS status by standard local testing."}
• {"criterion_text":"- Have had an adequate washout period from previous treatment prior to screening, defined as: - ≥ 4 weeks from major surgery. - ≥ 4 weeks from radiotherapy, including palliative stereotactic chest radiotherapy. - ≥ 3 weeks from anticancer chemotherapy [immunotherapy (non-antibody therapy)], retinoid therapy, hormone therapy. - ≥ 4 weeks from antibody-based cancer therapy. - ≥ 2 weeks or 5 half-lives (whichever is longer) from therapy with targeted agents and small molecules - ≥ 6 weeks from nitrosuree or mitomycin C - ≥ 1 week from TKIs approved for the treatment of patients with non-small cell lung cancer (CT scan at baseline must be completed after discontinuation of TKIs) - > 2 weeks from chloroquine/hydroxychloroquine - ≥ 2 weeks from cell-free, concentrated ascites reinfusion therapy (CART), peritoneal shunt or drainage of ascites, pleural effusion or pericardial effusion"}
• {"criterion_text":"- Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta- human chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of IP. Women of childbearing potential are defined as those who are not surgically sterile (i.e. underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause."}
• {"criterion_text":"- Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, presented in Table 1. From the time of screening and must agree to continue using such precautions for 7 months after the last dose of investigational product (IP). Not all methods of contraception are highly effective. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of IP. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is line with the patient’s usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic, or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable."}
• {"criterion_text":"- Female participants must not donate, or retrieve for their own use, ova from the time of enrolment and throughout the study treatment period, and for at least 7 months after the final study drug administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study."}
• {"criterion_text":"- Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of IP for T-DXd while 6 months for capecitabine and bevacizumab. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the patient’s usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception throughout this period, by employing protocol-recommended methods. In addition, male patients should refrain from fathering a child, or freezing or donating sperm from the time of randomization/enrollment, throughout the study and for 4 months after the last dose of IP for T-DXd while 6 months for capecitabine and bevacizumab. Preservation of sperm should be considered prior to enrollment in this study."}
• {"criterion_text":"- Have radiographically measurable disease per RECIST v1.1"}
• {"criterion_text":"- Have adequate hematological, hepatic, renal, cardiac and coagulation function, as defined below, obtained within 7 days prior to enrollment (Cycle 1 Day 1): Absolute neutrophil count (ANC) ≥ 1500/mm3. (Granulocyte-colony stimulating factor administration is not allowed within 1 week prior to C1D1). - Platelet count ≥ 100000/mm3. (Platelet transfusion is not allowed within 1 week prior to C1D1) - Hemoglobin ≥ 9.0 g/dL -Total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3 x ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline. - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN (≤ 5 x ULN if liver metastases are present). - Serum albumin ≥ 2.5 g/dL. - Creatinine clearance ≥ 60 mL/min as determined by Cockcroft-Gault (using actual body weight). -\tLeft ventricular ejection fraction (LVEF) ≥ 50% within 28 days before enrollment. - International normalized ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 x ULN."}
• {"criterion_text":"- Patient state to comply with all the study procedures and treatments. Patients must be accessible for treatment and follow-up. Patients registered for this trial must be treated and followed at the participating Centre."}
• {"criterion_text":"- Age ≥ 18 years at the time of informed consent."}
• {"criterion_text":"- ECOG Performance Status ≤ 1."}
• {"criterion_text":"- Life expectancy ≥ 3 mesi."}
• {"criterion_text":"- Have histologically documented adenocarcinoma of the colon or rectum, which is initially metastatic or unresectable locally advanced"}
• {"criterion_text":"- Subjects must be willing to provide the most recently available formalin-fixed paraffin-embedded tumor tissue blocks (or at least 25 freshly sectioned slides) for translational analyses (sampled before 1st treatment course). If archival tissue is not available for HER2 testing or for exploratory aims, then a newly obtained baseline biopsy of an accessible tumor lesion is required before Cycle 1 Day 1 timeframe. Biopsy must contain adequate tissue for analysis; the following biopsy types are acceptable: resection, excision, punch (skin lesions only) and core needle biopsies."}

Exclusion criteria

• {"criterion_text":"- Have previously received any systemic anticancer therapy for CRC in the metastatic setting or have participated in any interventional clinical trial for CRC in the metastatic setting. Subjects may have received prior fluoropyrimidine with or without oxaliplatin for CRC in the adjuvant or neoadjuvant setting if it was completed > 6 months before enrollment."}
• {"criterion_text":"- Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment."}
• {"criterion_text":"- Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g., severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.)."}
• {"criterion_text":"- Any autoimmune, connective tissue, or inflammatory disorders (e.g., Rheumatoid arthritis, Sjögren’s, sarcoidosis etc.) where there is documented, or a suspicion of, pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for patients who are included in the study"}
• {"criterion_text":"- Prior pneumonectomy (complete)."}
• {"criterion_text":"- A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART)."}
• {"criterion_text":"- Have unresolved toxicities from previous anticancer therapy, defined as toxicity (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade > 2 for at least 3 months before enrollment/cycle 1 day 1 and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy such as: chemotherapy-induced neuropathy and fatigue."}
• {"criterion_text":"- Patients with known hypersensitivity to the study drug or to its excipients."}
• {"criterion_text":"- Patients with known hypersensitivity to other monoclonal antibodies."}
• {"criterion_text":"- Pregnant or breastfeeding female patients, or patients who are planning to become pregnant. Sexually active men not willing to use adequate contraception during whole study period."}
• {"criterion_text":"- Previous or concurrent malignancy within 3 years of study entry. Exceptions are adequately resected non-melanoma skin cancer, curatively treated in-situ diseases, and other solid tumors that have been curatively treated."}
• {"criterion_text":"- Presence of any of the following dihydropyrimidine dehydrogenase (DPYD) polymorphism, based on local laboratory testing: DPYD 2a (c.1905+1G>A); DPYD13 (c.1679 T>G); DPYD D949V (c.2846 A>T)."}
• {"criterion_text":"- Have a history of transient ischemic attack, cerebrovascular accident, myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac surgery within 6 months prior to enrollment (Cycle 1 Day 1)."}
• {"criterion_text":"- Have a history of a significant bleeding event (e.g., bleeding needing medical intervention) within 6 months prior to enrollment (Cycle 1 Day 1) unless the source of bleeding has been definitively treated."}
• {"criterion_text":"- Have a history of GI perforation within 12 months prior to enrollment (Cycle 1 Day 1)."}
• {"criterion_text":"- Major surgical procedure or significant traumatic injury ≤ 28 days prior to enrollment (≤ 56 days for hepatectomy, open thoracotomy or major neurosurgery) or anticipation of need for major surgical procedure during the course of the study."}
• {"criterion_text":"- Serious, non-healing wound, ulcer, or bone fracture"}
• {"criterion_text":"- Prior organ transplantation, including allogenic stem-cell transplantation."}
• {"criterion_text":"- Known history of HIV infection."}
• {"criterion_text":"- Active infection including tuberculosis, hepatitis B, hepatitis C. Patients positive for hepatitis C (HCV) antibody are eligible only if HCV RNA polymerase chain reaction (PCR) is negative. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible only if meeting the following criteria: -HBsAg negativity (for more than 6 months off anti-viral treatment);\tAnti-HBc positivity (IgG or total Ig);\tAbsence of cirrhosis or fibrosis on prior imaging or biopsy; Absence of HCV co-infection and no history of HCV co-infection; Access to a local HBV expert during and after the study"}
• {"criterion_text":"- Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trastuzumab deruxtecan."}
• {"criterion_text":"- Any psychiatric condition that would prohibit the understanding or rendering of informed consent and that would limit compliance with trial requirements."}
• {"criterion_text":"- Have previously been treated with an anti-HER2 agent and/or a topoisomerase I inhibitor."}
• {"criterion_text":"- Use of any disallowed drugs"}
• {"criterion_text":"- Patient who is under judicial protection and patient who is legally institutionalized or under guardianship or not able to give consent. (only for French)"}
• {"criterion_text":"- Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medications"}
• {"criterion_text":"- Haves substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results."}
• {"criterion_text":"- Patients with a medical history of myocardial infarction (MI) within 6 months before enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Subjects with troponin levels above ULN at screening (as defined by the manufacturer) and without any myocardial-related symptoms should undergo a cardiologic consultation before enrollment to rule out MI."}
• {"criterion_text":"- Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening 12-lead ECG."}
• {"criterion_text":"- Symptomatic arterial hypertension or uncontrolled arterial hypertension, as determined by the investigator."}
• {"criterion_text":"- Have a history of (non-infectious) ILD/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening"}

Primary endpoints

• {"endpoint_text":"- to evaluate the activity of upfront T-DXd, capecitabine and bevacizumab in terms of confirmed ORR by BICR. Overall response rate will be defined as the proportion of patients who achieve either a partial or complete response as best responses to study treatment.","definition_or_measurement_approach":"Overall response rate (ORR) defined as the proportion of patients who achieve either a partial or complete response as best responses to study treatment; confirmed by Blinded Independent Central Review (BICR)."}

Secondary endpoints

• {"endpoint_text":"- Progression-free survival (PFS) by BICR and Investigator assessment, defined as the time from treatment start to radiological evidence of disease progression (as per RECIST v1.1 criteria) or death, whichever occurs first.","definition_or_measurement_approach":"Time from treatment start to radiological evidence of disease progression per RECIST v1.1 or death; assessed by BICR and investigator."}
• {"endpoint_text":"- Overall survival (OS), defined as the time from treatment start to death.","definition_or_measurement_approach":"Time from treatment start to death from any cause."}
• {"endpoint_text":"- Treatment safety, defined as the incidence of adverse events during treatment and follow-up, assessed according to CTCAE v5.0.","definition_or_measurement_approach":"Incidence and severity of adverse events graded by CTCAE v5.0 during treatment and follow-up."}
• {"endpoint_text":"- Disease control rate (DCR) by BICR and Investigator assessment, defined as the proportion of subjects achieving a complete response (CR), partial response (PR) or stable disease (SD) as best response during study treatment, as per RECIST v1.1.","definition_or_measurement_approach":"Proportion of subjects with CR, PR or SD as best response during study treatment per RECIST v1.1; assessed by BICR and investigator."}
• {"endpoint_text":"- Early tumor shrinkage (ETS), defined as the proportion of patients achieving a reduction in tumor size of at least 20% at first radiological reassessment.","definition_or_measurement_approach":"Proportion of patients with ≥20% reduction in tumor size at first radiological reassessment."}
• {"endpoint_text":"- Duration of response (DOR), defined as the time from first radiological evidence of complete or partial response to disease progression or death whichever occurs first","definition_or_measurement_approach":"Time from first radiological evidence of CR or PR to disease progression or death."}
• {"endpoint_text":"- Depth of response (DoR) defined as the maximum percentage of tumor shrinkage at best response relative to baseline.","definition_or_measurement_approach":"Maximum percent tumor shrinkage at best response relative to baseline."}
• {"endpoint_text":"- Patients reported outcomes (completion of quality-of-life questionnaires)","definition_or_measurement_approach":"Completion and scores of QoL questionnaires (EORTC QLQ-C30, QLQ-CR29, EQ-5D-5L) as patient-reported outcomes."}
• {"endpoint_text":"- CEA and CA19.9 dynamics and their correlation with activity and efficacy outcomes.","definition_or_measurement_approach":"Serial measurements of CEA and CA19.9 and correlation analyses with activity and efficacy endpoints."}
• {"endpoint_text":"- Central review of HER2 status (VENTANA anti-HER2/neu 4B5 Rabbit Monoclonal Primary Antibody and VENTANA HER2 Dual ISH Probe Cocktail)","definition_or_measurement_approach":"Central laboratory assessment of HER2 status using specified VENTANA assays."}

France

Earliest CTIS Part Ii Submission Date

24-09-2025

Latest Decision Or Authorization Date

02-10-2025

Processing Time Days

8

Number Of Sites

5

Number Of Participants

7

Germany

Earliest CTIS Part Ii Submission Date

09-09-2025

Latest Decision Or Authorization Date

07-10-2025

Processing Time Days

28

Number Of Sites

3

Number Of Participants

5

Italy

Earliest CTIS Part Ii Submission Date

27-08-2025

Latest Decision Or Authorization Date

06-10-2025

Processing Time Days

40

Number Of Sites

16

Number Of Participants

23

Spain

Earliest CTIS Part Ii Submission Date

28-08-2025

Latest Decision Or Authorization Date

06-10-2025

Processing Time Days

39

Number Of Sites

5

Number Of Participants

7

Primary sponsor

Full Name

Gruppo Oncologico Del Nord Ovest

Organisation Type

Patient organisation/association

Country Of Registered Address

Italy