REGORAFENIB for Advanced/metastatic colorectal cancer | Metastatic colorectal cancer

Inclusion criteria

• {"criterion_text":"- Capable of giving signed informed consent as described in Section 12.2 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Signed informed consent must be obtained prior to conducting any study specific procedures.\n- Women of childbearing potential (WOCBP) and men with sexual partners who are WOCBP must be willing to adhere to contraceptive requirements.\n- Suitable venous access for safe drug administration and the study-required drug concentration and pharmacodynamics sampling.\n- A valid archival tumor sample as defined in Section 7.20.1.\n- Pretreatment fresh biopsy is optional in Part 1. In Part 2, participants should provide a fresh pretreatment biopsy and commit to a fresh on-treatment biopsy. Notes: (i) In some circumstances, the Medical Monitor can waive the obtention of paired treatment biopsies upon request from the Investigator. The rationale for the decision needs to be documented in writing. (ii) A patient receiving treatment can decline the on-treatment biopsy without providing any explanation and continue on study. If it is the Investigator who decides to skip the on-treatment biopsy, the rationale needs to be discussed with the Medical Monitor and documented in writing. (Section 7.20.2).\n- Male and female patients aged 18 years and older.\n- Patients should have documented progression to the last line of therapy or, in the opinion of the Investigator, require a change in the therapy. This latter situation must be discussed and approved explicitly by the Sponsor’s Medical Monitor.\n- Patients must have histologically or cytologically confirmed adenocarcinoma of the colon or rectum, who had disease progression on or after receiving all the following SoC systemic therapies for advanced or metastatic disease* (if approved and locally available/reimbursed in the respective country/region/hospital) or were intolerant to those therapies: 1.\tFluoropyrimidine, oxaliplatin, and irinotecan 2.\tAnti-VEGF therapy (e.g., bevacizumab) 3.\tAnti-EGFR therapy (e.g., cetuximab, panitumumab) if RAS (KRAS/NRAS) wild type 4.\tBRAF inhibitor (e.g., dabrafenib, encorafenib) if BRAF V600E mutation In addition, patients may have received up to 2 additional lines of therapy for advanced or metastatic disease with any of the following drugs: trifluridine/tipiracil (TAS-102) with or without anti-VEGF therapy, fruquintinib, or other drugs approved in the country (except regorafenib), or investigational drugs that do not share mechanism of action with regorafenib (i.e., tyrosine kinase receptor inhibitors). *Neoadjuvant/adjuvant chemotherapy is included if disease had recurred during treatment or within six months after the last administration of neoadjuvant/adjuvant therapy\n- Microsatellite stable or pMMR CRC per previous local assessment.\n- Known extended RAS and BRAF status as per local SoC.\n- Measurable disease by RECIST 1.1 criteria on computerized tomography (CT), FAPI PET/CT (if available), fluorodeoxyglucose positron emission tomography (FDG-PET)/CT or magnetic resonance imaging (MRI) scan. Imaging tests outside the screening period are valid if performed no more than 2 weeks before consent signature and otherwise fulfill protocol criteria.\n- Easter Cooperative Oncology Group Performance (ECOG) performance status 0-1.\n- Adequate bone marrow, hepatic and renal function: \n1.\tTotal bilirubin ≤1.5 times the upper limit of normal (ULN) or total bilirubin <3.0×ULN with direct bilirubin within the normal range in patients with documented Gilbert’s syndrome*. *Regorafenib is a uridine diphosphate glucuronosyl transferase 1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome. 2.\tAspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3×ULN, (if liver metastases are present, then ≤5×ULN is allowed). 3. Serum creatinine ≤1.5×ULN or creatinine clearance ≥40 mL/min (measured or calculated using the Cockroft-Gault formula) 4. Hemoglobin ≥9.0 g/dL (whole or partial blood transfusions not allowed in the 2 previous weeks). 5. Absolute neutrophil count (ANC) ≥1.0×109/L (growth factors like G-CSF are not allowed in the 2 previous weeks). 6. Platelet count ≥75×109/L (platelet transfusions within the previous 2 weeks are not allowed). 7. INR/partial thromboplastin time (PTT) ≤1.5×ULN. Note: Patients who being treated chronically with warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists; close monitoring of at least weekly evaluations will be performed until INR/PTT ratio is stable based on a measurement that is pre-dose as defined by the local SoC."}

Exclusion criteria

• {"criterion_text":"- Prior treatment with OMTX705, regorafenib, or RTK inhibitors for CRC. Combination with tislelizumab only. Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies including anti-CTLA-4, anti-PD-1, and anti PD L1 antibodies.\n- Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months before the start of study medication. Active pulmonary emboli or deep vein thrombosis that are significant or not adequately controlled on anticoagulation regimen\n- Active infection that requires parenteral or oral antibiotics. Antibiotics given for prophylaxis are allowed. They are also allowed for minor localized infections like cystitis, amygdalates or localized skin infections.\n- History of organ allograft (including corneal transplant).\n- Non-healing wound, ulcer, or bone fracture including fistulae (e.g., Chron’s disease)\n- Renal failure that requires hematological (hemo-) or peritoneal dialysis\n- Significant acute gastrointestinal disorders with diarrhea as a major symptom, e.g., Chron’s disease, malabsorption, or ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 2 diarrhea of any etiology.\n- Evidence of serious uncontrolled medical disorder that, in the opinion of the Investigator or Medical Monitor, makes it unwise for the patient to participate in the study or that might jeopardize compliance with the protocol.\n- Drainage of ascitic or pleural fluid two or more times in the four weeks prior to the first dose of study drug or permanent drain in place (e.g., PleurX®) for ascites or pleural effusion symptom management\n- Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or compromised ability to provide written informed consent\n- Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 3 years prior to the study entry and no additional therapy is required or anticipated to be required during the study period.\n- Treatment with systemic anticancer treatments, investigational products, or major surgery within four weeks before the first dose of study drug or 5 half-lives, whichever is shorter. Patients should have recovered from previous treatment toxicity to Grade 1, baseline (excluding anemia, lymphopenia, alopecia, skin pigmentation, and neurotoxicity).\n- Known hepatitis B virus surface antigen seropositive or detectable hepatitis C infection viral load. Note: Patients who have positive hepatitis B surface antigen antibody can be included but must have an undetectable hepatitis B viral load. Patients receiving antiviral therapy for hepatitis B for any reason are excluded.\n- Patients with previous history or evidence of liver cirrhosis.\n- Patients positive for human immunodeficiency virus (HIV) are not excluded from this study, but HIV-positive patients must meet the following criteria: 1. Have CD4+ T-cell (CD4+) counts ≥350 cells/µL. 2. Have not had an opportunistic infection within the past 12 months. Patients on prophylactic antimicrobials can be included in the trial. 3. Should be on established antiretroviral therapy for at least four weeks. 4. Have an HIV viral load of less than 400 copies/mL prior to enrollment. 5. Known history of any other relevant congenital or acquired immunodeficiency other than HIV infection.\n- Known or suspected allergies to study treatment or related products, and specifically patients with a prior history of life-threatening reaction to polysorbate 20 or for regorafenib, if they have allergy to soya-derived lecithin.\n- Women who are pregnant, breastfeeding, or trying to become pregnant.\n- Male patients wishing to father children, planning for future sperm banking, or expressing concerns about sterility.\n- Combination with tislelizumab only. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.\n- Combination with tislelizumab only. Patient who discontinued prior treatment with any immune checkpoint due to irAEs, irrespective of grade, recovery, or need for continued steroid therapy. Also, patients without formal contraindication due to previous irAE are not eligible if the AE has not resolved to Grade 1 or better and/or still requires steroids (>10 mg of prednisone equivalent per day) for ongoing management.\n- Combination with tislelizumab only. Patients with a history of pneumonitis/ILD, patients who received live vaccines within 30 days of enrollment, and patients who discontinued prior immune checkpoint inhibitors due to Grade 2 myocarditis.\n- Exclusions related to regorafenib: 1. Patients requiring strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort). 2. Patients that require strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole). 3. Not being able to swallow and absorb oral tablets.\n- History of uncontrolled brain metastasis. Patients with brain metastases are allowed if they are previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery and have new brain imaging confirming that brain metastasis are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either MRI or CT and considered controlled with ≤10 mg/day prednisone equivalent at the time of receiving the first dose of OMTX705). For asymptomatic participants, brain image screening is not required.\n- Exclusion related to OMTX705: The use of strong inhibitors or inducers of CYP3A4, 2D6, 1A2, 2C9, 2B6, and 2C19 is restricted from 14 days before the first dose of OMTX705 until 2 weeks after the last dose of OMTX705 (Appendix 15.4).\n- Patient has received extended field radiotherapy ≤4 weeks before the start of treatment (≤1 week for limited field radiation for palliation), and who has not recovered to Grade 1 or better from related side effects of such therapy (except for alopecia).\n- Major surgical procedure or significant traumatic injury ≤28 days prior to the planned first dose of OMTX705\n- Cardiac arrhythmias that require anti-arrhythmic therapy (excluding controlled atrial fibrillation). Note: pacemakers, beta-blockers, or digoxin are permitted.\n- Uncontrolled hypertension: systolic BP >140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management.\n- Patients with a history of arterial aneurysms or artery dissection.\n- Patients with unstable angina or new onset angina (within 3 months of enrollment), recent myocardial infarction (within 6 months of enrollment) and those with cardiac failure New York Heart Association (NYHA) classification II or higher"}

Primary endpoints

• {"endpoint_text":"- Safety and tolerability (for Part 1 and Part 2) will be assessed by: The nature and frequency of DLTs (Part 1 only). Frequency, duration, seriousness, relatedness, and severity of treatment emerging adverse events (TEAEs), per Common Terminology Criteria for Adverse Events, version 5.0.","definition_or_measurement_approach":"Assess DLTs (Part 1 only); frequency, duration, seriousness, relatedness and severity of TEAEs graded per CTCAE v5.0."}
• {"endpoint_text":"- Changes in vital signs, serum chemistry, and hematology. Frequency of treatment modifications, measured as dose modifications, interruptions, or percentage of relative dose intensity. MTD dose or recommended Part 2 dose.","definition_or_measurement_approach":"Laboratory and vital sign monitoring; record dose modifications, interruptions, relative dose intensity; determination of MTD or recommended Part 2 dose based on observed toxicities and DLTs."}
• {"endpoint_text":"- Part 2 efficacy will be assessed by: The overall response rate (ORR), determined by the Investigator, according to Response Evaluation Criteria in Solid Tumors, version1.1 (RECIST 1.1).","definition_or_measurement_approach":"ORR per investigator assessment using RECIST 1.1."}

Secondary endpoints

• {"endpoint_text":"- Part 1 and 2: Additional efficacy endpoints will be evaluated by using RECIST 1.1: Response-associated endpoints: disease control rate (DCR= complete response [CR]+partial response [PR]+stable disease [SD]≥ 6, 12 and 21 weeks), duration of response, and time to response. Time-to-event efficacy endpoints: progression-free survival (PFS), proportion of participants without progression/death at 3, 6, and 12 months.","definition_or_measurement_approach":"Response-associated endpoints per RECIST 1.1 (DCR at specified timepoints, duration/time to response); PFS and proportions without progression/death at 3, 6, 12 months."}
• {"endpoint_text":"- Overall survival (OS) and proportion of participants alive at 3, 6, 12, and 18 months. Changes in carcino‐embryonic antigen (CEA) tumor biomarker from baseline upon treatment. For patients with other abnormal standard serum biomarkers, they will be followed.","definition_or_measurement_approach":"OS measured from enrollment to death; survival proportions at specified timepoints; serial CEA measurements from baseline."}
• {"endpoint_text":"- Part 1 and Part 2 immunogenicity of OMTX705 will be assessed by: Quantification (titer) of anti-drug antibodies (ADAs) against OMTX705 and percentage of ADA positive participants.","definition_or_measurement_approach":"ADA titers measured; report percentage ADA-positive participants."}
• {"endpoint_text":"- Part 1 and Part 2 PK profile of OMTX705 with regorafenib/tislelizumab: Blood drug concentrations of total OMTX705, conjugated antibody, and unconjugated payload (TAM470), determined by non-compartmental analysis to derive main PK parameters (such as, maximum observed concentration [Cmax], time of first occurrence of Cmax [Tmax], area under the analytes concentration versus time curve from time 0 to time t [AUC0-t]).","definition_or_measurement_approach":"PK sampling with measurement of total OMTX705, conjugated antibody and unconjugated payload; non-compartmental analysis to derive Cmax, Tmax, AUC0-t and other PK parameters."}

Spain

Earliest CTIS Part Ii Submission Date

09-06-2025

Latest Decision Or Authorization Date

21-07-2025

Processing Time Days

42

Number Of Sites

5

Number Of Participants

69

Primary sponsor

Full Name

Oncomatryx Biopharma S.L.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Spain

Contract research organisations

Name

Optimapharm d.o.o.

Responsibilities

sponsorDuties codes: 1, 10, 11, 12, 5, 6, 7, 8 (as listed in CTIS record); contact email: ctis@optimapharm.eu

Third parties

• {"country":"Spain","full_name":"Institut Català d'Oncologia. Programa ProCURE","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Health care"}
• {"country":"Spain","full_name":"Laboratorio de Tumores gastrointestinales y Neuroendocrinos","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Health care"}
• {"country":"Spain","full_name":"Anapharm Europe S.L.","duties_or_roles":"sponsorDuties: code 15; value: immunogenicity analysis (antibody anti-drug or ADA detection)","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Alcura Health Espana S.A.","duties_or_roles":"sponsorDuties codes: 14; 15 (value: OMTX705 import, IMPs labelling, packaging, IMPs supply/re-supply to the sites, IMPs storage, IMPs destruction; IMPs release)","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"BeiGene Switzerland GmbH","duties_or_roles":"sponsorDuties: code 15; value: tislelizumab provider and release","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"World Courier","duties_or_roles":"sponsorDuties: code 15; value: OMTX705 logistics","organisation_type":"Industry"}
• {"country":"Spain","full_name":"Polar Expres","duties_or_roles":"sponsorDuties: code 15; value: biological sample logistics, laboratory material provider, lab kits building and supply to the sites","organisation_type":"Industry"}
• {"country":"Taiwan","full_name":"Eirgenix Inc. Zhubei Branch","duties_or_roles":"sponsorDuties: code 15; value: Drug substance (OMTX705) manufacturer","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Centro de Investigación del Cáncer-Universidad de Salamanca","duties_or_roles":"sponsorDuties: code 15; value: biomarkers detection (OMTX705 pharmacodynamics profiling)","organisation_type":"Health care"}
• {"country":"Denmark","full_name":"Nordics Bioscience","duties_or_roles":"sponsorDuties: code 15; value: biomarkers detection (OMTX705 pharmacodynamics profiling)","organisation_type":"Industry"}
• {"country":"France","full_name":"CERTARA","duties_or_roles":"sponsorDuties: code 15; value: OMTX705 pharmacokinetic non-compartimental analysis","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Croatia","full_name":"Optimapharm d.o.o.","duties_or_roles":"sponsorDuties codes: 1, 10, 11, 12, 5, 6, 7, 8","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"CTI Laboratory Services Spain S.L.","duties_or_roles":"sponsorDuties: code 15; value: OMTX705 pharmacokinetic bioanalysis","organisation_type":"Pharmaceutical company"}
• {"country":"Taiwan","full_name":"Formosa Laboratories Inc.","duties_or_roles":"sponsorDuties: code 15; value: Drug product (OMTX705) manufacturer","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Cerba","duties_or_roles":"sponsorDuties: code 15; value: biomarkers detection (OMTX705 pharmacodynamics profiling)","organisation_type":"Laboratory/Research/Testing facility"}