RAS/BRAF Wild Type Colorectal Cancer
Conditions
Brief summary
This is a multicenter, open Phase Ib/II clinical study evaluating the safety and efficacy of TQB2922 in combination with TAS-102±bevacizumab in subjects with RAS/BRAF wild-type unresectable locally advanced or metastatic colorectal cancer that has failed treatment with oxaliplatin, fluorouracil-based and irinotecan.
Interventions
DRUGTQB2922 injection ± TAS-102 tablets
TQB2922 is an anti-EGFR/c-Met bispecific antibody, subtype Immunoglobulin G1 (IgG1). TQB2922 blocks the activation of EGFR and c-Met signalling pathway by binding to EGFR and c-Met on the surface of tumour cells, thus preventing tumour growth and progression. At the same time, TQB2922 can target EGFR and c-Met on the surface of tumour cells through antibody-dependent cytotoxicity (ADCC) and antibody-dependent cell phagocytosis by natural killer cells and macrophages, thus killing tumour cells.
DRUGTQB2922 injection+TAS-102 tablets ± Bevacizumab
TQB2922 is an anti-EGFR/c-Met bispecific antibody, subtype IgG1. TQB2922 blocks the activation of EGFR and c-Met signalling pathway by binding to EGFR and c-Met on the surface of tumour cells, thus preventing tumour growth and progression. At the same time, TQB2922 can target EGFR and c-Met on the surface of tumour cells through antibody-dependent cytotoxicity (ADCC) and antibody-dependent cell phagocytosis by natural killer cells and macrophages, thus killing tumour cells.
Sponsors
Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Subjects voluntarily enrolled in the study, signed the informed consent and had good compliance; * Age: 18-75 years old (including boundaries at the time of signing the informed consent); * Eastern Cooperative Oncology Group (ECOG) score: 0-1; * Expected survival of more than 3 months; * Unresectable locally advanced or metastatic colorectal cancer diagnosed by histological/cytological pathology; * Disease progression or intolerable after prior treatment with oxaliplatin, fluorouracil-based and irinotecan and treated with cetuximab or bevacizumab; * Patients with genetic testing showing wild-type for both rat sarcoma (RAS) and B-type rapid response protein kinase (BRAF); * Presence of at least 1 measurable lesion according to RECIST 1.1 criteria; * Laboratory tests meet the criteria; * Female subjects of childbearing potential must agree to use contraception (e.g., Intrauterine Device (IUD), birth control pills, or condoms) for the duration of the study and for 6 months after the end of the study; must have a negative serum pregnancy/urine pregnancy test * within 7 days prior to study entry and must not be breastfeeding; male subjects must agree to use contraception for the duration of the study and for 6 months after the end of the study.
Exclusion criteria
* Patients who have had previous confirmation of microsatellite high instability/mismatch repair defects (MSI-H/dMMR) by immunohistochemistry (IHC), next-generation sequencing (NGS) or polymerase chain reaction (PCR); * Presence of a disease that interferes with intravenous administration, intravenous blood collection, or multiple factors that interfere with oral administration of medications (e.g., inability to swallow, chronic diarrhoea and intestinal obstruction); * Active inflammatory bowel disease (ulcerative colitis, Crohn's disease) within 28 days prior to first dose; * The presence or current concurrent presence of other malignancies within 2 years prior to the first dose. * Unresolved toxic reactions above Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 due to any prior therapy, excluding alopecia, fatigue and peripheral neuropathy; * Major surgical treatment, incisional biopsy or significant traumatic injury within 28 days prior to first dose; * The presence of a long-standing unhealed wound or fracture; * Cerebrovascular accident (including temporary ischaemic attack, cerebral haemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism within 6 months prior to the first dose; * Have a history of psychotropic substance abuse and are unable to quit or have a mental disorder; * Subjects with any severe and/or uncontrolled medical condition, including: * Unsatisfactory control of blood pressure (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg, at least 2 measurements taken at intervals of more than 24h); * Myocardial infarction, unstable angina pectoris, stable angina pectoris ≥ Grade 2, heart failure ≥ Grade 2 (New York Heart Association (NYHA) classification), arrhythmia ≥ Grade 2; * Active or uncontrolled severe bacterial, viral, or systemic fungal infection (≥ CTC AE grade 2 infection) within 28 days prior to first dose; patients with active tuberculosis within 1 year prior to enrolment. * Active viral hepatitis with poor control. Subjects will be screened if they meet the following requirements: Hepatitis B surface antigen (HBsAg) positive subjects with Hepatitis B virus (HBV) DNA quantification \<2000 IU/ml (or 1\*10 4 copy/ml) or at least 1 week of anti-HBV treatment with a 10-fold (1 log) or greater reduction in viral index prior to study entry. Subject is willing to remain on anti-HBV therapy for the entire duration of the study; HCV-infected patients (HCV Ab or HCV RNA positive) who are judged to be stable by the investigator or who are on antiviral therapy at the time of enrolment and who continue to receive approved antiviral therapy during the study; * Subjects with a history of (non-infectious) interstitial lung disease requiring systemic steroid therapy, or current interstitial lung disease/interstitial pneumonia; or subjects with Screening Imaging suggestive of suspected interstitial lung disease/interstitial pneumonia that cannot be ruled out; * History of immunodeficiency, including being human immunodeficiency virus (HIV) positive or having other acquired, congenital immunodeficiency diseases; * Poorly controlled diabetes mellitus (fasting blood glucose (FBG) \> 10 mmol/L); and * Active syphilis infection. * Known tumour-associated spinal cord compression, cancerous meningitis, with symptoms of brain metastases, or symptoms controlled for less than 4 weeks; * Imaging suggestive of tumour invasion of large blood vessels or, in the judgement of the investigator, there is a high probability of tumour rupture or invasion of vital blood vessels during the study period leading to fatal haemorrhage; * Failure to control a plasma (thoracic, abdominal, or pericardial) effusion that requires repeated drainage; * Local radiotherapy within 2 weeks or \>30% bone marrow irradiation radiotherapy for bone metastases within 4 weeks prior to first dose. * Chemotherapy, targeted therapy, immunotherapy, or other antineoplastic agents within 4 weeks prior to the first dose, or who are still on drug 5. treatment, or subjects who are still within 5 half-lives of the drug (whichever occurs first); * Prior use of epidermal growth factor receptor/c-mesenchymal epidermal transforming factor (EGFR/c-Met) dual-antibody drugs; * Received treatment with a proprietary Chinese medicine with an anti-tumour indication as specified in the National Drug * Administration (NMPA) approved drug insert within 1 week prior to study treatment. * History of live attenuated vaccination within 2 weeks prior to the first dose or planned live attenuated vaccination during the study period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting toxicity (DLT) | Baseline up to 48 weeks | One or more unacceptable toxic reactions following administration of the drug, resulting in the inability to continue increasing the dose or prolonging the dosing cycle. |
| Objective Response Rate (ORR) | Complete response time was achieved, evaluation is expected to take 1 years. | Proportion of patients with tumour volume reduction to a pre-specified value that maintains the minimum timeframe requirement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | Complete response time was achieved, evaluation is expected to take 1 years. | The proportion of subjects who achieved complete response (CR), partial response (PR), or stable disease (SD) was assessed. |
| Recommended Phase 2 Dose | Baseline up to 48 weeks | The dose recommended for Phase 2 trials based on Phase 1 safety, tolerability, and pharmacokinetic data. |
| Elimination Half-life | Baseline up to 48 weeks | The time required for the plasma concentration of a drug to decrease by 50% during the elimination phase, reflecting metabolic and excretory rates. |
| Area Under the Curve | Baseline up to 48 weeks | The integral of the drug concentration-time curve in plasma, representing total systemic drug exposure. |
| Apparent Clearance | Baseline up to 48 weeks | The apparent volume of plasma cleared of the drug per unit time, typically expressed in L/h. |
| Maximum tolerated dose (MTD) | Baseline up to 48 weeks | If dose limiting toxicity (DLT) occurs in 2 or more subjects in a given dose group, the dose level in the previous dose group is considered MTD. |
| Trough Concentration | Baseline up to 48 weeks | The plasma drug concentration measured at the end of a dosing interval (before next administration), used to assess accumulation risk. |
| Duration of Response | Complete response time was achieved, evaluation is expected to take 1 years. | Time from first documented objective response (e.g., tumor shrinkage) to disease progression or death. |
| Progression-Free Survival | 1 year of assessment is expected from the start of enrolment to the first occurrence of disease progression or death from any cause | Time from enrollment to disease progression or death from any cause, evaluating treatment's disease control ability. |
| Incidence of Anti-Drug Antibody | Baseline up to 48 weeks | The proportion of patients developing antidrug antibodies during treatment, indicating immunogenicity risk. |
| Apparent Volume of Distribution in Terminal Phase | Baseline up to 48 weeks | The apparent volume in which a drug is distributed during the terminal phase, calculated based on plasma concentration, indicating tissue distribution extent. |
| Incidence of adverse event (AE) and serious adverse event (SAE) | Baseline up to 48 weeks | The incidence and severity of adverse events were determined according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 rating scale |
Countries
China
Contacts
Primary ContactSuxia Luo, Master
Backup ContactShegan Gao, Doctor
Outcome results
None listed