Dose-Escalation Study of OMTX705 with Regorafenib and Tislelizumab in Advanced/Metastatic Colorectal Cancer
- Trial ID
- 2025-520743-33-00
- Protocol
- OMTX705-004
- Sponsor
- Oncomatryx Biopharma S.L.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **safety** and **tolerability** of OMTX705 in combination with regorafenib, and OMTX705 in combination with regorafenib and tislelizumab, in patients with advanced/metastatic microsatellite stable colorectal cancer (MSS CRC) who have progressed to at least the second line of standard systemic therapy for metastatic disease. This objective is clinically relevant as it aims to identify the maximum tolerated dose (MTD) or a recommended dose in the absence of dose-limiting toxicities (DLTs), which is crucial for determining the feasibility of these combinations in further clinical development.
Secondary objectives include:
- Evaluating the initial **antitumor activity** of OMTX705 in combinations and regorafenib monotherapy through other treatment responses and time-to-event efficacy endpoints.
- Assessing the **immunogenicity** of OMTX705.
- Evaluating the **pharmacokinetic** profile of OMTX705 with regorafenib/tislelizumab.
- Further evaluating the **safety** and **tolerability** of the three arms in Part 2.
Participants
The clinical trial involves participants diagnosed with **advanced/metastatic colorectal cancer**. The study population includes both male and female patients aged 18 years and older. Participants are required to have a documented progression to the last line of therapy or, in the opinion of the Investigator, require a change in therapy. The trial population was selected based on specific inclusion criteria, including histologically or cytologically confirmed adenocarcinoma of the colon or rectum, and progression on or after receiving standard systemic therapies for advanced or metastatic disease. Participants must have measurable disease by RECIST 1.1 criteria and an Eastern Cooperative Oncology Group Performance status of 0-1. Adequate bone marrow, hepatic, and renal function are also required. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. The trial includes a vulnerable population, and both genders are represented in the study.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and **efficacy** of OMTX705, an anti-fibroblast activation protein antibody-drug conjugate, in combination with **regorafenib** and **tislelizumab** in patients with advanced or metastatic colorectal cancer. This is a Phase 1b/2 dose-escalation study, structured as a randomized, double-blind, controlled trial. The trial is expected to commence recruitment on August 8, 2025, and conclude by February 4, 2027. The study is divided into two parts: Part 1 focuses on determining the safety, tolerability, and maximum tolerated dose (MTD) of the drug combinations, while Part 2 aims to assess the antitumor activity and overall response rate of the combinations compared to a reference arm of regorafenib monotherapy.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease progression, and previous treatment history. The trial will include regular follow-up visits to monitor safety, collect pharmacokinetic data, and assess treatment efficacy using imaging techniques like CT or MRI scans. The end-of-study visit will evaluate the overall health status of participants and document any adverse events. The expected length of participant involvement is approximately 18 months, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent.
Key elements of the research methodology include the use of **intravenous** administration for OMTX705 and tislelizumab, and **oral** administration for regorafenib. The primary endpoints focus on safety and tolerability, while secondary endpoints include disease control rate, progression-free survival, and overall survival. The trial will also assess the immunogenicity of OMTX705 and its pharmacokinetic profile in combination with the other drugs. Participants must adhere to contraceptive requirements and provide informed consent prior to any study-specific procedures. The trial is not classified as low-intervention and is conducted under rigorous scientific and ethical standards to ensure the validity and reliability of the results.
Treatment
The clinical trial involves the administration of **OMTX705**, an experimental medication developed by ONCOMATRYX BIOPHARM S.L. OMTX705 is formulated as a **concentrate for solution for infusion** and is administered via the **intravenous** route. The specific dosage and frequency of administration are determined based on the trial's dose-escalation protocol, aiming to identify the maximum tolerated dose or a recommended dose for further study phases. Participant compliance with the administration schedule is monitored throughout the trial to ensure adherence to the protocol.
In addition to OMTX705, the trial includes the administration of **Tevimbra**, a commercially available medication containing the active substance **tislelizumab**. Tevimbra is provided as a **100 mg concentrate for solution for infusion** and is also administered **intravenously**. This medication is produced by BEIGENE IRELAND LIMITED and is used in combination with OMTX705 and regorafenib in certain study arms. The administration schedule for Tevimbra is aligned with the trial's protocol to evaluate its combined effect with the other investigational treatments.
**Stivarga**, containing the active substance **regorafenib**, is another non-experimental treatment used in this study. Manufactured by BAYER AG, Stivarga is available as **40 mg film-coated tablets** and is administered **orally**. It serves as a standard-of-care therapy in the trial, either as a monotherapy in the reference arm or in combination with OMTX705 and/or Tevimbra in other study arms. The dosing schedule for Stivarga is consistent with its approved usage guidelines, and participant adherence is monitored to ensure accurate assessment of its efficacy and safety in combination with the investigational treatments.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the overall response rate (ORR) as determined by the Investigator, using the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). This will be conducted in Part 2 of the trial. Secondary efficacy endpoints will include additional response-associated metrics such as disease control rate (DCR), which encompasses complete response (CR), partial response (PR), and stable disease (SD) for durations of 6, 12, and 21 weeks. The duration of response and time to response will also be evaluated. Time-to-event efficacy endpoints will include progression-free survival (PFS) and the proportion of participants without progression or death at 3, 6, and 12 months. Overall survival (OS) and the proportion of participants alive at 3, 6, 12, and 18 months will be measured. Changes in carcinoembryonic antigen (CEA) tumor biomarker levels from baseline will be monitored, and other abnormal standard serum biomarkers will be followed as applicable.
In addition to efficacy, the trial will assess the immunogenicity of **OMTX705** by quantifying anti-drug antibodies (ADAs) against OMTX705 and determining the percentage of ADA-positive participants. The pharmacokinetic (PK) profile of OMTX705 in combination with regorafenib and tislelizumab will be evaluated by measuring blood drug concentrations of total OMTX705, conjugated antibody, and unconjugated payload (TAM470). Non-compartmental analysis will be used to derive main PK parameters such as maximum observed concentration (Cmax), time of first occurrence of Cmax (Tmax), and area under the analyte concentration versus time curve from time 0 to time t (AUC0-t).
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- Male and female patients aged 18 years and older.
- 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.
- 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. Fluoropyrimidine, oxaliplatin, and irinotecan 2. Anti-VEGF therapy (e.g., bevacizumab) 3. Anti-EGFR therapy (e.g., cetuximab, panitumumab) if RAS (KRAS/NRAS) wild type 4. BRAF 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
- Microsatellite stable or pMMR CRC per previous local assessment.
- Known extended RAS and BRAF status as per local SoC.
- 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.
- Easter Cooperative Oncology Group Performance (ECOG) performance status 0-1.
- Adequate bone marrow, hepatic and renal function: 1. Total 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. Aspartate 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.
- Women of childbearing potential (WOCBP) and men with sexual partners who are WOCBP must be willing to adhere to contraceptive requirements.
- Suitable venous access for safe drug administration and the study-required drug concentration and pharmacodynamics sampling.
- A valid archival tumor sample as defined in Section 7.20.1.
- 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).
Exclusion Criteria
- 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.
- 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).
- 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.
- 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).
- Major surgical procedure or significant traumatic injury ≤28 days prior to the planned first dose of OMTX705
- Cardiac arrhythmias that require anti-arrhythmic therapy (excluding controlled atrial fibrillation). Note: pacemakers, beta-blockers, or digoxin are permitted.
- Uncontrolled hypertension: systolic BP >140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management.
- Patients with a history of arterial aneurysms or artery dissection.
- 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
- 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
- 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.
- History of organ allograft (including corneal transplant).
- Non-healing wound, ulcer, or bone fracture including fistulae (e.g., Chron’s disease)
- Renal failure that requires hematological (hemo-) or peritoneal dialysis
- 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.
- 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.
- 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
- 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
- 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.
- 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.
- Patients with previous history or evidence of liver cirrhosis.
- 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.
- 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.
- Women who are pregnant, breastfeeding, or trying to become pregnant.
- Male patients wishing to father children, planning for future sperm banking, or expressing concerns about sterility.
- 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.
- 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.
- 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.
- 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.
- 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).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 08 Aug 2025 | 69 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Stivarga 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | — | — | PRD1713388 |
Tevimbra 100 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | — | — | PRD11015696 |
OMTX705 | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | — | — | PRD11296025 |