TQB2922 Injection Given Under the Skin With Chemotherapy as Initial Treatment for Colorectal Cancer That Has Spread

• TQB2922 injection (subcutaneous administration) (Drug): TQB2922 is an investigational bispecific antibody targeting epidermal growth factor receptor and c-Met. Administered subcutaneously at the assigned dose: weekly in cycle 1, then every 2 weeks in 28-day cycles. Phase Ib starts at 2000 mg with possible cohort dose reductions to 1600 mg and 1200 mg. Phase II planned doses are 2000 mg and 1600 mg, subject to phase Ib findings. Continued with fluorouracil during maintenance.
• Oxaliplatin (Drug): Platinum-based antineoplastic component of mFOLFOX6. Oxaliplatin 85 mg/m\^2 by intravenous infusion every 2 weeks during the 6-to-8-cycle treatment phase. Used in all study arms; not listed in the protocol maintenance regimen.
• Calcium folinate (leucovorin calcium) (Drug): Folate component of mFOLFOX6. Calcium folinate 400 mg/m\^2 by intravenous infusion every 2 weeks during the 6-to-8-cycle treatment phase. Used in all study arms; not listed in protocol section 6.2.1 for maintenance.
• Fluorouracil (Drug): Antimetabolite component of mFOLFOX6. Fluorouracil 400 mg/m\^2 by intravenous bolus followed by 2400 mg/m\^2 by continuous intravenous infusion over 46 hours, repeated every 2 weeks. Used in all study arms during treatment and continued with TQB2922 in maintenance.

Primary outcomes

• Recommended phase II dose (RP2D), phase Ib [During the Phase Ib safety run-in period, approximately 28 days.]: Dose(s) of TQB2922 for combination with mFOLFOX6 selected jointly by the investigator and sponsor after assessment of safety, tolerability, pharmacokinetics, and preliminary activity in the phase Ib safety run-in.
• Incidence and severity of adverse events, phase Ib [From informed consent to 30 days after the last dose or start of new anticancer therapy, whichever occurs first; study participation up to 24 months.]: Percentage of participants with adverse events (AEs), with severity graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 6.0. Predose events are handled as specified in protocol section 8.4.1.
• Incidence and severity of serious adverse events, phase Ib [From informed consent to 30 days after the last dose or start of new anticancer therapy, whichever occurs first; study participation up to 24 months.]: Percentage of participants with serious adverse events (SAEs), with severity graded using NCI CTCAE version 6.0. Seriousness is assessed using the criteria in protocol section 8.4.5.
• Incidence and severity of laboratory abnormalities, phase Ib [From informed consent to 30 days after the last dose or start of new anticancer therapy, whichever occurs first; study participation up to 24 months.]: Percentage of participants with laboratory abnormalities and their severity, graded using NCI CTCAE version 6.0 where applicable. Laboratory assessments include hematology, biochemistry, coagulation, urinalysis, and thyroid function.
• Objective response rate (ORR), phase II [From baseline, every 6 weeks (+/-7 days) through week 48 and every 12 weeks (+/-7 days) thereafter; up to 24 months.]: Percentage of participants with a best overall response of complete response (CR) or partial response (PR), assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Disease control rate (DCR), phase II [From baseline, every 6 weeks (+/-7 days) through week 48 and every 12 weeks (+/-7 days) thereafter; up to 24 months.]: Percentage of participants with a best overall response of CR, PR, or stable disease (SD), assessed by the investigator using RECIST version 1.1.
• Progression-free survival (PFS), phase II [From baseline, every 6 weeks (+/-7 days) through week 48 and every 12 weeks (+/-7 days) thereafter; up to 24 months.]: Time from randomization to investigator-assessed disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first.
• Duration of response (DOR), phase II [From baseline, every 6 weeks (+/-7 days) through week 48 and every 12 weeks (+/-7 days) thereafter; up to 24 months.]: Among responders, time from the first documented CR or PR to investigator-assessed disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first.

Secondary outcomes

• Peak concentration (Cmax), phase Ib [Within 2 hours before dosing on specified days of Cycles 1, 2, 4 and 8; through 72 hours after dosing on Day 1 of Cycle 1 and through 168 hours after dosing on Day 1 of Cycle 4 (28-day cycles; sampling windows specified in the description).]: Maximum observed concentration of TQB2922. Estimated by noncompartmental analysis in participants undergoing intensive pharmacokinetic (PK) sampling. C denotes cycle and D denotes day.
• Area under the concentration-time curve from time zero to the last quantifiable concentration (AUC0-t), phase Ib [Within 2 hours before dosing on specified days of Cycles 1, 2, 4 and 8; through 72 hours after dosing on Day 1 of Cycle 1 and through 168 hours after dosing on Day 1 of Cycle 4 (28-day cycles; sampling windows specified in the description).]: Area under the TQB2922 concentration-time curve from time zero to the last quantifiable concentration. Estimated by noncompartmental analysis in participants undergoing intensive pharmacokinetic (PK) sampling. C denotes cycle and D denotes day.
• Time to peak concentration (Tmax), phase Ib [Within 2 hours before dosing on specified days of Cycles 1, 2, 4 and 8; through 72 hours after dosing on Day 1 of Cycle 1 and through 168 hours after dosing on Day 1 of Cycle 4 (28-day cycles; sampling windows specified in the description).]: Time to the maximum observed TQB2922 concentration. Estimated by noncompartmental analysis in participants undergoing intensive pharmacokinetic (PK) sampling. C denotes cycle and D denotes day.
• Terminal elimination rate constant (lambda z), phase Ib [Within 2 hours before dosing on specified days of Cycles 1, 2, 4 and 8; through 72 hours after dosing on Day 1 of Cycle 1 and through 168 hours after dosing on Day 1 of Cycle 4 (28-day cycles; sampling windows specified in the description).]: Terminal elimination rate constant estimated from the TQB2922 concentration-time profile. Estimated by noncompartmental analysis in participants undergoing intensive pharmacokinetic (PK) sampling. C denotes cycle and D denotes day.
• Elimination half-life (t1/2), phase Ib [Within 2 hours before dosing on specified days of Cycles 1, 2, 4 and 8; through 72 hours after dosing on Day 1 of Cycle 1 and through 168 hours after dosing on Day 1 of Cycle 4 (28-day cycles; sampling windows specified in the description).]: Time required for the TQB2922 concentration to decrease by half in the terminal elimination phase. Estimated by noncompartmental analysis in participants undergoing intensive pharmacokinetic (PK) sampling. C denotes cycle and D denotes day.
• Apparent clearance (CL/F), phase Ib [Within 2 hours before dosing on specified days of Cycles 1, 2, 4 and 8; through 72 hours after dosing on Day 1 of Cycle 1 and through 168 hours after dosing on Day 1 of Cycle 4 (28-day cycles; sampling windows specified in the description).]: Apparent clearance of TQB2922 following subcutaneous administration. F denotes bioavailability. Estimated by noncompartmental analysis in participants undergoing intensive pharmacokinetic (PK) sampling. C denotes cycle and D denotes day.
• Apparent terminal volume of distribution (Vz/F), phase Ib [Within 2 hours before dosing on specified days of Cycles 1, 2, 4 and 8; through 72 hours after dosing on Day 1 of Cycle 1 and through 168 hours after dosing on Day 1 of Cycle 4 (28-day cycles; sampling windows specified in the description).]: Apparent volume of distribution of TQB2922 during the terminal phase following subcutaneous administration. Estimated by noncompartmental analysis in participants undergoing intensive pharmacokinetic (PK) sampling. C denotes cycle and D denotes day.
• Extrapolated percentage of AUC0-infinity (%AUCextrap), phase Ib [Within 2 hours before dosing on specified days of Cycles 1, 2, 4 and 8; through 72 hours after dosing on Day 1 of Cycle 1 and through 168 hours after dosing on Day 1 of Cycle 4 (28-day cycles; sampling windows specified in the description).]: Percentage of the total TQB2922 AUC extrapolated from the last quantifiable concentration to infinity. Estimated by noncompartmental analysis in participants undergoing intensive pharmacokinetic (PK) sampling. C denotes cycle and D denotes day.
• Objective response rate (ORR), phase Ib [From baseline, every 6 weeks (+/-7 days) through week 48 and every 12 weeks (+/-7 days) thereafter; up to 24 months.]: Percentage of participants with a best overall response of complete response (CR) or partial response (PR), assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Disease control rate (DCR), phase Ib [From baseline, every 6 weeks (+/-7 days) through week 48 and every 12 weeks (+/-7 days) thereafter; up to 24 months.]: Percentage of participants with a best overall response of CR, PR, or stable disease (SD), assessed by the investigator using RECIST version 1.1.
• Progression-free survival (PFS), phase Ib [From baseline, every 6 weeks (+/-7 days) through week 48 and every 12 weeks (+/-7 days) thereafter; up to 24 months.]: Time from first dose to investigator-assessed disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first.
• Duration of response (DOR), phase Ib [From baseline, every 6 weeks (+/-7 days) through week 48 and every 12 weeks (+/-7 days) thereafter; up to 24 months.]: Among responders, time from the first documented CR or PR to investigator-assessed disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first.
• Incidence of anti-drug antibodies (ADA), phase Ib [Within 2 hours before dosing on Day 1 of Cycles 1, 2, 4 and 8; at end of treatment; and 90 days (+/-7 days) after the last dose. Additional samples for protocol-specified reactions.]: Percentage of participants with anti-TQB2922 antibodies detected by a validated assay. ADA-positive samples undergo neutralizing-antibody testing. C denotes cycle and D denotes day.
• Incidence and severity of adverse events, phase II [From informed consent to 30 days after the last dose or start of new anticancer therapy, whichever occurs first; study participation up to 24 months.]: Percentage of participants with adverse events (AEs), with severity graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 6.0. Predose events are handled as specified in protocol section 8.4.1.
• Incidence and severity of serious adverse events, phase II [From informed consent to 30 days after the last dose or start of new anticancer therapy, whichever occurs first; study participation up to 24 months.]: Percentage of participants with serious adverse events (SAEs), with severity graded using NCI CTCAE version 6.0. Seriousness is assessed using the criteria in protocol section 8.4.5.
• Incidence and severity of laboratory abnormalities, phase II [From informed consent to 30 days after the last dose or start of new anticancer therapy, whichever occurs first; study participation up to 24 months.]: Percentage of participants with laboratory abnormalities and their severity, graded using NCI CTCAE version 6.0 where applicable. Laboratory assessments include hematology, biochemistry, coagulation, urinalysis, and thyroid function.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Voluntary participation with written informed consent and good compliance.
* Age 18 to 75 years, inclusive, at informed consent.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Life expectancy greater than 12 weeks.
* Histologically or cytologically confirmed unresectable metastatic colorectal cancer, staged according to the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) TNM classification, 8th edition (2017).
* RAS/BRAF wild-type status confirmed in tumor tissue.
* At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
* Adequate laboratory results: hemoglobin >=90 g/L; absolute neutrophil count >=1.5 x 10\^9/L; platelets >=100 x 10\^9/L; total bilirubin <=1.5 times the upper limit of normal (ULN); alanine aminotransferase and aspartate aminotransferase <=2.5 x ULN, or <=5 x ULN with liver metastases; creatinine clearance >=60 mL/min calculated using the modified Cockcroft-Gault formula; urine protein <=1+, or, if >=2+, 24-hour urine protein <1 g measured within 7 days; prothrombin time, activated partial thromboplastin time, and international normalized ratio <=1.5 x ULN in participants not receiving anticoagulation; thyroid-stimulating hormone <=ULN, or, if abnormal, normal triiodothyronine and thyroxine (or their free fractions).
* Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days before enrollment. Participants of reproductive potential must agree to effective contraception during the study and for 6 months after study completion, following protocol section 5.4.4

Exclusion Criteria:

* Known high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR).
* Other malignancy within 3 years before the first dose or a concurrent malignancy. Protocol-permitted exceptions include other malignancies treated by surgery alone with 5 consecutive years of disease-free survival, and cured cervical carcinoma in situ, nonmelanoma skin cancer, or superficial bladder tumors (Ta, Tis, or T1).
* Disease affecting intravenous administration or venous blood collection, or factors affecting oral medication, such as inability to swallow, chronic diarrhea, or intestinal obstruction.
* Toxicities from prior treatment not recovered to grade <=1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 6.0. Exceptions include grade 2 alopecia, peripheral neurotoxicity, or anemia; asymptomatic laboratory abnormalities without clinical significance; stable hypothyroidism on hormone replacement; and other toxicities judged not to pose a safety risk.
* Major surgery or significant traumatic injury within 4 weeks before the first dose, expected major surgery during the study (except protocol-permitted surgery), or a persistently unhealed wound or fracture.
* Poorly controlled active viral hepatitis. Hepatitis B surface antigen-positive participants may be screened if hepatitis B virus (HBV) DNA is <2000 IU/mL (or 1 x 10\^4 copies/mL), or if at least 1 week of anti-HBV treatment before study start has reduced viral load at least 10-fold, and they agree to anti-HBV treatment throughout the study. Participants positive for hepatitis C virus (HCV) antibody or HCV RNA may be screened if judged stable by the investigator, or if receiving antiviral treatment at enrollment and continuing approved antiviral treatment during the study.
* History of noninfectious pneumonitis/interstitial lung disease requiring steroids, or current noninfectious pneumonitis/interstitial lung disease; or hospitalization or therapeutic antibiotics for active infection within 4 weeks before study treatment, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
* History of psychiatric drug abuse that cannot be discontinued, or a psychiatric disorder.
* Planned or previous allogeneic bone marrow transplantation or solid organ transplantation.
* History of hepatic encephalopathy.
* Significant cardiovascular disease, including any of the following: New York Heart Association (NYHA) class II or higher cardiac dysfunction or left ventricular ejection fraction <50%; clinically significant ventricular arrhythmia or arrhythmia requiring continuous antiarrhythmic therapy; unstable angina; myocardial infarction within 12 months; Fridericia-corrected QT interval >450 ms in men or >470 ms in women (an abnormal value may be assessed by the mean of 3 measurements at least 2 minutes apart); personal or family history of congenital long QT syndrome; arterial or venous thrombosis within 6 months before the first dose; systolic blood pressure >=150 mmHg and/or diastolic blood pressure >=90 mmHg despite standard treatment, or prior hypertensive encephalopathy/crisis; clinically significant tumor bleeding/perforation or grade >=3 bleeding within 1 month before treatment; bleeding/coagulation disease while receiving warfarin, aspirin, or other antiplatelet agents (except maintenance aspirin <=100 mg/day or clopidogrel <=75 mg/day); or other bleeding signs/history judged unsuitable by the investigator.
* Poorly controlled diabetes with fasting blood glucose >10 mmol/L.
* Active or uncontrolled serious infection of CTCAE grade >=2.
* Renal failure requiring hemodialysis or peritoneal dialysis.
* History of immunodeficiency, including human immunodeficiency virus (HIV) positivity or another acquired or congenital immunodeficiency.
* Use of immunosuppressants or systemic or absorbable topical steroids for immunosuppression, with continued use required within 7 days before the first dose; except prednisone <10 mg/day or an equivalent glucocorticoid dose.
* Epilepsy requiring treatment.
* Any of the following cancer-related conditions or treatments: chemotherapy/immunotherapy within 3 weeks, radiotherapy/small-molecule targeted therapy within 2 weeks, or treatment within 5 drug half-lives before the first dose (the shortest interval, as stated in the protocol); Chinese patent medicines with a National Medical Products Administration (NMPA)-approved anticancer indication within 2 weeks before the first dose; uncontrolled, symptomatic, or repeatedly drained pleural, peritoneal, or pericardial effusions (small, asymptomatic imaging-only effusions without drainage or treatment in the preceding 2 weeks are allowed); known central nervous system metastases and/or carcinomatous meningitis (except asymptomatic cases, or treated stable cases without imaging evidence of new/enlarging brain metastases for at least 2 weeks after brain-metastasis treatment and off steroids/anticonvulsants for at least 14 days before study treatment); or severe bone damage/spinal cord compression from bone metastases, including weight-bearing pathological fractures within 6 months or anticipated soon, or poorly controlled severe bone pain.
* Known allergy to excipients of the study drug.
* Prior antiangiogenic or anti-epidermal growth factor receptor (EGFR) targeted treatment, including bevacizumab, cetuximab, panitumumab, or aflibercept.
* Prior systemic treatment for advanced colorectal cancer. Adjuvant treatment is permitted if completed >12 months before study start for oxaliplatin-containing chemotherapy, or >6 months for chemotherapy without oxaliplatin, measured from the last chemotherapy dose.
* Receipt of another investigational anticancer drug within 4 weeks before the first dose.
* Any other condition that, in the investigator's judgment, seriously compromises safety or the ability to complete the study.