VOLRUSTOMIG for Colorectal cancer

Inclusion criteria

• {"criterion_text":"- ​​Master: 1 Participant must be ≥ 18 years at the time of signing the ICF​\n- ​​Master: 10 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative ​\n- ​​Sub 1: 1 Histopathologically confirmed metastatic/recurrent colorectal adenocarcinoma who have no radiological evidence of liver metastases\n- ​​Sub 1: ​2 No prior systemic therapy for mCRC, except for neoadjuvant/adjuvant chemotherapy where, > 6 months have elapsed between completion of therapy and documented date of diagnosis of recurrent or metastatic disease\n- ​​Sub 1: 3 Known pMMR/MSS status (only pMMR/MSS mCRC allowed)​\n- ​​Sub 1: 4 Adequate organ and bone marrow function (in the absence of transfusions or growth factor support within 14 days prior to enrollment)​\n- ​​Sub 1: 5 Body weight > 35 kg at screening and at randomization ​\n- ​​Sub 1: 6 Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. ​For full list please refer to master and sub-study protocols\n- ​​Master: ​2 Histopathologically confirmed colorectal adenocarcinoma\n- ​​Master: 3 Provision of FFPE tumor sample collected as per SoC\n- ​​Master: 4 All races, gender and ethnic groups are eligible for this study​\n- ​​Master: ​5 Presence of measurable disease by RECIST 1.1 criteria\n- ​​Master: 6 ECOG performance status of 0 or 1, with no deterioration (that is, ECOG PS > 1) over the previous 4 weeks prior to baseline at screening and prior to randomization\n- ​​Master: 7 Life expectancy ≥ 12 weeks at the time of screening​\n- ​​Master:​ 8 Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol\n- ​​Master: 9 Provision of a signed and dated written ICF prior to any mandatory study-specific procedures, sampling, and analyses"}

Exclusion criteria

• {"criterion_text":"- ​​Master: 1 Central nervous system metastases or spinal cord compression (including asymptomatic and adequately treated disease, unless specified in the respective substudy protocol). Participants with suspected brain metastases at screening should have an MRI (preferred) or CT scan, each preferably with IV contrast of the brain prior to randomization​\n- ​​Sub 1: 2 As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including, but not limited to, ongoing or active infection, ILD, serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations, and active bleeding diseases) and/or history of organ transplant or allogenic stem cell transplant, which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol\n- ​​Sub 1: 3 Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel disease (eg, colitis or Crohn's disease), diverticulitis (with the exception of diverticulosis), systemic lupus erythematosus, sarcoidosis syndrome, Wegener syndrome (granulomatosis with polyangiitis), Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, pneumonitis (past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD) etc​.\n- ​​Sub 1: 4 Any of the following cardiac conditions : ​− Cardiomyopathy of any etiology or history of myocarditis ​− Heart failure (as defined by New York Heart Association class III-IV) ​− Uncontrolled hypertension defined as diastolic blood pressure ≥ 90 mmHg or systolic blood pressure ≥ 140 mmHg ​− Unstable angina pectoris ​− Clinically significant coronary, carotid, or peripheral artery stenosis ​− Acute coronary syndrome/acute myocardial infarction and/or coronary intervention with percutaneous coronary intervention/coronary artery bypass grafting within 12 months prior to randomization ​− Prior arterial or peripheral vascular intervention within 12 months prior to ​randomization ​− Ventricular arrhythmias requiring treatment, high degree AV block (II-III), or sinus node dysfunction with significant sinus pause, untreated with pacemaker. Note: Patients with atrial fibrillation or flutter who are clinically stable and have an optimally controlled ventricular rate (eg, mean of < 100 bpm on resting ECG or 24-hour Holter-ECG) may be eligible if all other cardiac eligibility criteria are met, and a cardiology assessment confirms suitability for study treatment. ​− History of QT prolongation associated with other medications that required discontinuation of that medication. ​− Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives. ​− Planned or scheduled cardiac surgery or percutaneous coronary intervention ​procedure. ​− Planned revascularization procedure within 6 months of randomization\n- ​​Sub 1: 5 Participants with a prior history of hypertensive crisis or hypertensive encephalopathy​\n- ​​Sub 1: 6 Any of the following bleeding risks: ​− CT/MRI images showing tumor encircling or invading a large vascular lumen (eg, pulmonary artery or superior vena cava). ​− History of hemoptysis (≥ 2.5 mL of bright red blood per episode) within 6 months prior to randomization. ​− Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). ​− History of significant bleeding disorders or vasculitis within 6 months prior to randomization. Well-controlled hemorrhoidal bleeding is not considered significant bleeding if the condition does not pose a significant risk for use of bevacizumab as determined by investigator. ​− Major vascular disease (eg, aortic aneurysm requiring surgical repair or associated with recent peripheral artery thrombosis) within 6 months prior to randomization\n- ​​Sub 1: 7 Serious or non-healing wound, active ulcer, or bone fracture (except vertebral compression fracture which do not need any treatment) within 28 days prior to randomization​\n- ​​Sub 1: 8 Deep venous thrombosis, pulmonary embolism, arterial thrombosis, transient ischemic attack or cerebrovascular accident within 12 months prior to randomization ​\n- ​​Sub 1: 9 Intestinal obstruction and/or previous clinical signs or symptoms of GI obstruction, including incomplete obstruction associated with a pre-existing disease or requiring routine parenteral hydration, parenteral nutrition, or tube feeding within 6 months prior to initiation of study treatment unless the obstruction is totally resolved after surgery treatment\n- ​​Sub 1: 10 History of abdominal or tracheoesophageal fistula, GI perforation and/or fistulae, or intraabdominal abscess within 6 months prior to randomization​\n- ​​Sub 1: 11 Participant with known Gilbert’s syndrome\n- ​​Master: 2 Known history of severe allergy to any monoclonal antibody or study intervention excipients or any of the study interventions of the chemotherapy regimen​\n- ​​Sub 1: 12 Any history of nephrotic or nephritic syndrome\n- ​​Sub 1: 13 Known dihydropyrimidine dehydrogenase enzyme deficiency or/and to be homozygous for the UGT1A1*28 as per standard of care local laboratory testing. Routine screening is not mandatory but encouraged for enrollment - only mandatory in countries where testing is SoC ​For full list please refer to master and sub-study protocols​\n- ​​Master: 3 Clinically meaningful ascites, pleural effusion, pericardial effusion defined as any ascites/effusion requiring non-pharmacologic intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose. Participants on stable doses of diuretics for ascites for ≥ 2 months are eligible ​\n- ​​Master: 4 Evidence of the following infections: ​• Active infection including tuberculosis ​• Uncontrolled HIV infection ​• Co-infection of HBV and HDV ​• Active or uncontrolled hepatitis B or hepatitis C ​• Known active hepatitis A\n- ​​Master: 5 Any unresolved toxicity CTCAE Grade ≥ 2 from a previous anticancer therapy, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria of the respective substudy​\n- ​​Master: 6 History of another primary malignancy except for: ​a) Malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence. ​b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. ​c) Adequately treated carcinoma in situ without evidence of disease\n- ​​Master: ​​7 As judged by the investigator, any condition that would interfere with evaluation of the IP or interpretation of participant safety or study results\n- ​​Master: 8 Known history of immunodeficiency, other acquired or congenital immunodeficiency disorders, or history of organ transplantation and allogeneic bone marrow transplantation\n- ​​Sub 1: 1 Potentially resectable disease with multidisciplinary plan for radical surgery"}

Primary endpoints

• {"endpoint_text":"- ​​Master/Sub 1: ​• Incidence and severity of AEs/SAEs ​• Change from baseline in vital signs, clinical laboratory assessments, ECGs, ECOG performance status, and physical examination","definition_or_measurement_approach":"Safety endpoints assessed by incidence and severity (AEs/SAEs); clinical and laboratory measures recorded as change from baseline (vital signs, labs, ECGs, ECOG PS, physical exam)."}
• {"endpoint_text":"- ​​Sub 1: ​PFS is defined as the time from randomization until progression per RECIST 1.1, or death due to any cause. ​The measure of interest is the difference in the PFS ​","definition_or_measurement_approach":"PFS measured from randomization to progression per RECIST 1.1 or death; primary comparison is difference in PFS between treatment arms."}

Secondary endpoints

• {"endpoint_text":"- Sub 1: OS is defined as the time from randomization until the date of death due to any cause. The measure of interest is the HR of OS","definition_or_measurement_approach":"OS measured from randomization to death from any cause; measure of interest is hazard ratio (HR) of OS between arms."}
• {"endpoint_text":"- ​​Sub 1: ORR is defined as the proportion of participants who have a confirmed CR or confirmed PR, as determined per RECIST 1.1. ​The measure of interest is the difference in ORR​","definition_or_measurement_approach":"ORR per RECIST 1.1 (confirmed CR or PR); measure of interest is difference in proportions between arms."}
• {"endpoint_text":"- ​​Sub-1: DCR is defined as the percentage of participants who have a confirmed CR or PR or who have SD per RECIST 1.1. The measure of interest is the difference in DCR","definition_or_measurement_approach":"DCR per RECIST 1.1 (confirmed CR, PR or stable disease); measure of interest is difference between arms."}
• {"endpoint_text":"- ​​DoR is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1 or death due to any cause. ​The measure of interest is the difference in the median DoR","definition_or_measurement_approach":"DoR measured from first documented confirmed response to progression per RECIST 1.1 or death; measure is difference in median DoR."}
• {"endpoint_text":"- ​​Sub 1: PFS2 is defined as the time from randomization to the earliest of the progression event, after first subsequent therapy, or death. The date of second progression will be recorded by the investigator in the eCRF and defined according to local standard clinical practice. ​The measure of interest is the HR of PFS2","definition_or_measurement_approach":"PFS2 measured from randomization to second progression after subsequent therapy or death; investigator records date in eCRF; measure is HR of PFS2."}
• {"endpoint_text":"- ​​Sub 1: Concentration of volrustomig in serum and PK parameters as data allow (such as peak and trough concentrations)​","definition_or_measurement_approach":"PK sampling for serum concentrations and derived PK parameters (e.g., Cmax, trough) as data allow."}
• {"endpoint_text":"- ​​Sub 1: Presence of ADAs against volrustomig in serum (confirmatory results: positive or negative, titers)​","definition_or_measurement_approach":"Immunogenicity testing for anti-drug antibodies (ADAs) in serum with confirmatory positive/negative results and titers recorded."}

France

Earliest CTIS Part Ii Submission Date

05-03-2025

Latest Decision Or Authorization Date

25-02-2026

Processing Time Days

357

Number Of Sites

6

Number Of Participants

10

Germany

Earliest CTIS Part Ii Submission Date

15-04-2025

Latest Decision Or Authorization Date

25-02-2026

Processing Time Days

316

Number Of Sites

5

Number Of Participants

19

Netherlands

Earliest CTIS Part Ii Submission Date

14-05-2025

Latest Decision Or Authorization Date

25-02-2026

Processing Time Days

287

Number Of Sites

3

Number Of Participants

17

Italy

Earliest CTIS Part Ii Submission Date

17-04-2025

Latest Decision Or Authorization Date

24-02-2026

Processing Time Days

313

Number Of Sites

9

Number Of Participants

6

Spain

Earliest CTIS Part Ii Submission Date

05-05-2025

Latest Decision Or Authorization Date

23-02-2026

Processing Time Days

294

Number Of Sites

9

Number Of Participants

17

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

Multiple sponsor duties including logistic management and other operational roles (sponsorDuties codes listed in record); contact Clinicaltrial.Enquiries@parexel.com

Third parties

• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"sponsorDuties codes: 1,10,11,12,13,14,15 (Logistic management),2,3,4,5,6,7,8,9; contact email: Clinicaltrial.Enquiries@parexel.com","organisation_type":"Pharmaceutical company"}