A Phase Ib/II Clinical Trial of TQB2922 Injection (Subcutaneous Administration) Combined With Chemotherapy as First-Line Treatment for RAS/BRAF Wild-Type Unresectable Metastatic Colorectal Cancer
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 64
- 试验地点
- 16
- 主要终点
- Recommended phase II dose (RP2D), phase Ib
研究概览
简要总结
This study will assess the safety and anticancer activity of TQB2922 injection given under the skin together with chemotherapy in adults with colorectal cancer that has spread, cannot be removed by surgery, and has no RAS or BRAF mutations. Participants have not received systemic treatment for advanced colorectal cancer, apart from the prior adjuvant treatment allowed by the protocol. TQB2922 is designed to block two proteins involved in cancer growth. The study tests whether adding TQB2922 to chemotherapy can improve tumor response with tolerable side effects. An initial safety stage will help select doses for further study. In the next stage, participants will be randomly assigned in a 2:1 ratio to two TQB2922 dose groups, each receiving mFOLFOX6 chemotherapy (oxaliplatin, calcium folinate, and fluorouracil). The planned TQB2922 doses are 2000 mg and 1600 mg, subject to the initial safety findings. Participants and doctors will know the treatment given. After 6 to 8 treatment cycles, maintenance treatment consists of TQB2922 and fluorouracil, with protocol-specified exceptions. Each participant may remain in the study for up to 24 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
- •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
排除标准
- •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.
- •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 >=
- •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.
研究组 & 干预措施
Phase Ib safety run-in: TQB2922 injection + mFOLFOX6
Nonrandomized safety run-in. TQB2922 starts at 2000 mg; separate 1600 mg and 1200 mg cohorts may be enrolled sequentially if dose reduction is needed for intolerance. TQB2922 is given subcutaneously on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of later 28-day cycles, with oxaliplatin, calcium folinate, and fluorouracil (mFOLFOX6) every 2 weeks. After 6 to 8 cycles, maintenance comprises TQB2922 plus fluorouracil, subject to protocol-permitted exceptions and stopping rules.
干预措施: TQB2922 injection (subcutaneous administration) (Drug)
Phase Ib safety run-in: TQB2922 injection + mFOLFOX6
Nonrandomized safety run-in. TQB2922 starts at 2000 mg; separate 1600 mg and 1200 mg cohorts may be enrolled sequentially if dose reduction is needed for intolerance. TQB2922 is given subcutaneously on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of later 28-day cycles, with oxaliplatin, calcium folinate, and fluorouracil (mFOLFOX6) every 2 weeks. After 6 to 8 cycles, maintenance comprises TQB2922 plus fluorouracil, subject to protocol-permitted exceptions and stopping rules.
干预措施: Calcium folinate (leucovorin calcium) (Drug)
Phase II 2000 mg group: TQB2922 injection + mFOLFOX6
Participants in phase II are randomized 2:1 to the 2000 mg and 1600 mg groups. This group receives TQB2922 2000 mg; final dose selection depends on phase Ib safety and tolerability. TQB2922 is given subcutaneously on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of later 28-day cycles, with oxaliplatin, calcium folinate, and fluorouracil (mFOLFOX6) every 2 weeks. After 6 to 8 cycles, maintenance comprises TQB2922 plus fluorouracil, subject to protocol-permitted exceptions and stopping rules.
干预措施: TQB2922 injection (subcutaneous administration) (Drug)
Phase II 2000 mg group: TQB2922 injection + mFOLFOX6
Participants in phase II are randomized 2:1 to the 2000 mg and 1600 mg groups. This group receives TQB2922 2000 mg; final dose selection depends on phase Ib safety and tolerability. TQB2922 is given subcutaneously on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of later 28-day cycles, with oxaliplatin, calcium folinate, and fluorouracil (mFOLFOX6) every 2 weeks. After 6 to 8 cycles, maintenance comprises TQB2922 plus fluorouracil, subject to protocol-permitted exceptions and stopping rules.
干预措施: Calcium folinate (leucovorin calcium) (Drug)
Phase II 1600 mg group: TQB2922 injection + mFOLFOX6
Participants in phase II are randomized 2:1 to the 2000 mg and 1600 mg groups. This group receives TQB2922 1600 mg; final dose selection depends on phase Ib safety and tolerability. TQB2922 is given subcutaneously on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of later 28-day cycles, with oxaliplatin, calcium folinate, and fluorouracil (mFOLFOX6) every 2 weeks. After 6 to 8 cycles, maintenance comprises TQB2922 plus fluorouracil, subject to protocol-permitted exceptions and stopping rules.
干预措施: TQB2922 injection (subcutaneous administration) (Drug)
Phase II 1600 mg group: TQB2922 injection + mFOLFOX6
Participants in phase II are randomized 2:1 to the 2000 mg and 1600 mg groups. This group receives TQB2922 1600 mg; final dose selection depends on phase Ib safety and tolerability. TQB2922 is given subcutaneously on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of later 28-day cycles, with oxaliplatin, calcium folinate, and fluorouracil (mFOLFOX6) every 2 weeks. After 6 to 8 cycles, maintenance comprises TQB2922 plus fluorouracil, subject to protocol-permitted exceptions and stopping rules.
干预措施: Calcium folinate (leucovorin calcium) (Drug)
Phase II 1600 mg group: TQB2922 injection + mFOLFOX6
Participants in phase II are randomized 2:1 to the 2000 mg and 1600 mg groups. This group receives TQB2922 1600 mg; final dose selection depends on phase Ib safety and tolerability. TQB2922 is given subcutaneously on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of later 28-day cycles, with oxaliplatin, calcium folinate, and fluorouracil (mFOLFOX6) every 2 weeks. After 6 to 8 cycles, maintenance comprises TQB2922 plus fluorouracil, subject to protocol-permitted exceptions and stopping rules.
干预措施: Fluorouracil (Drug)
Phase Ib safety run-in: TQB2922 injection + mFOLFOX6
Nonrandomized safety run-in. TQB2922 starts at 2000 mg; separate 1600 mg and 1200 mg cohorts may be enrolled sequentially if dose reduction is needed for intolerance. TQB2922 is given subcutaneously on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of later 28-day cycles, with oxaliplatin, calcium folinate, and fluorouracil (mFOLFOX6) every 2 weeks. After 6 to 8 cycles, maintenance comprises TQB2922 plus fluorouracil, subject to protocol-permitted exceptions and stopping rules.
干预措施: Oxaliplatin (Drug)
Phase II 2000 mg group: TQB2922 injection + mFOLFOX6
Participants in phase II are randomized 2:1 to the 2000 mg and 1600 mg groups. This group receives TQB2922 2000 mg; final dose selection depends on phase Ib safety and tolerability. TQB2922 is given subcutaneously on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of later 28-day cycles, with oxaliplatin, calcium folinate, and fluorouracil (mFOLFOX6) every 2 weeks. After 6 to 8 cycles, maintenance comprises TQB2922 plus fluorouracil, subject to protocol-permitted exceptions and stopping rules.
干预措施: Oxaliplatin (Drug)
Phase Ib safety run-in: TQB2922 injection + mFOLFOX6
Nonrandomized safety run-in. TQB2922 starts at 2000 mg; separate 1600 mg and 1200 mg cohorts may be enrolled sequentially if dose reduction is needed for intolerance. TQB2922 is given subcutaneously on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of later 28-day cycles, with oxaliplatin, calcium folinate, and fluorouracil (mFOLFOX6) every 2 weeks. After 6 to 8 cycles, maintenance comprises TQB2922 plus fluorouracil, subject to protocol-permitted exceptions and stopping rules.
干预措施: Fluorouracil (Drug)
Phase II 2000 mg group: TQB2922 injection + mFOLFOX6
Participants in phase II are randomized 2:1 to the 2000 mg and 1600 mg groups. This group receives TQB2922 2000 mg; final dose selection depends on phase Ib safety and tolerability. TQB2922 is given subcutaneously on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of later 28-day cycles, with oxaliplatin, calcium folinate, and fluorouracil (mFOLFOX6) every 2 weeks. After 6 to 8 cycles, maintenance comprises TQB2922 plus fluorouracil, subject to protocol-permitted exceptions and stopping rules.
干预措施: Fluorouracil (Drug)
Phase II 1600 mg group: TQB2922 injection + mFOLFOX6
Participants in phase II are randomized 2:1 to the 2000 mg and 1600 mg groups. This group receives TQB2922 1600 mg; final dose selection depends on phase Ib safety and tolerability. TQB2922 is given subcutaneously on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of later 28-day cycles, with oxaliplatin, calcium folinate, and fluorouracil (mFOLFOX6) every 2 weeks. After 6 to 8 cycles, maintenance comprises TQB2922 plus fluorouracil, subject to protocol-permitted exceptions and stopping rules.
干预措施: Oxaliplatin (Drug)
结局指标
主要结局
Recommended phase II dose (RP2D), phase Ib
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- 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).)
- 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).)
- 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 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).)
- 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).)
- 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).)
- 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 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).)
- 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).)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)