A Multicenter, Randomized, Open-Label Phase 3 Study of APG-157 as Neoadjuvant Therapy or as Induction and Maintenance Therapy in Locally Advanced Head and Neck Squamous Cell Carcinoma
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 826
研究概览
简要总结
This Phase 3, multicenter, randomized, open-label study evaluates APG-157 in adults with newly diagnosed locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Two independently powered cohorts are enrolled based on treatment pathway. Cohort A evaluates APG-157 administered as neoadjuvant therapy before curative-intent surgery in participants with resectable oral cavity or oropharyngeal cancer who are medically ineligible for perioperative pembrolizumab. Cohort B evaluates APG-157 administered as induction therapy before definitive chemoradiotherapy and as maintenance therapy after chemoradiotherapy in participants with unresectable or medically inoperable disease. Participants are randomized 1:1 within each cohort to receive APG-157-based treatment or standard-of-care therapy. The primary hypothesis is that APG-157 given before definitive surgery followed by (chemo)radiotherapy improves event-free survival (EFS) compared to surgery and adjuvant (chemo)radiotherapy alone (Cohort A), and that APG-157 given as induction therapy prior to definitive chemoradiotherapy (CRT) followed by maintenance APG-157 improves EFS compared to definitive CRT alone (Cohort B).
详细描述
This Phase 3, multicenter, randomized, open-label study evaluates APG-157 in adults with newly diagnosed locally advanced head and neck squamous cell carcinoma (LA-HNSCC). The study consists of two independently powered cohorts designed to evaluate APG-157 in distinct treatment settings. Cohort A enrolls participants with resectable oral cavity or oropharyngeal squamous cell carcinoma who are objectively medically ineligible for perioperative pembrolizumab according to protocol-defined criteria. Participants are randomized 1:1 to receive APG-157 administered orally at 600 mg/day for 6 weeks prior to curative-intent surgical resection followed by protocol-directed adjuvant therapy, or standard-of-care surgery followed by adjuvant therapy alone. Cohort B enrolls participants with unresectable or medically inoperable locally advanced oropharyngeal squamous cell carcinoma. Participants are randomized 1:1 to receive APG-157 induction therapy for 4 weeks before definitive chemoradiotherapy, followed by APG-157 maintenance therapy initiated within 60 days after chemoradiotherapy and continued for up to 1 year, or standard-of-care definitive chemoradiotherapy alone.The primary objective is to determine whether APG-157-based treatment improves event-free survival compared with standard-of-care treatment. Key secondary objectives include overall survival, objective response, pathological response, ctDNA clearance, safety, treatment feasibility, and patient-reported outcomes.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Cohort A (Resectable Disease)
- •Adults ≥18 years
- •Histologically or cytologically confirmed, previously untreated locally advanced head and neck squamous cell carcinoma (LA-HNSCC) of the oral cavity or oropharynx.
- •Resectable disease appropriate for curative-intent surgery.
- •Stage III-IVA disease according to AJCC criteria:
- •Oropharynx, p16-positive: Stage III (T4, N0-N3, M0)
- •Oropharynx, p16-negative: Stage III or IVa (T3-T4, N0-N2, M0)
- •Oral cavity: Stage III or IVa (T3-T4, N0-N2, M0)
- •Objectively medically ineligible for perioperative pembrolizumab according to protocol-defined objective criteria.
- •HPV/p16 testing available for stratification.
- •Measurable or evaluable disease.
- •Life expectancy ≥12 months.
- •ECOG Performance Status ≤
- •Negative pregnancy test for women of childbearing potential and agreement to use effective contraception.
- •Ability to comply with study procedures.
- •Cohort B (Unresectable / Medically Inoperable Disease)
- •Adults ≥18 years
- •Histologically or cytologically confirmed, previously untreated LA-HNSCC of the oropharynx. Disease not suitable for curative-intent surgery.
- •Stage III-IVA disease according to AJCC criteria:
- •p16-positive Stage III (T4, N0-N3, M0) with >10 pack-year smoking history
- •p16-negative Stage III or IVa (T3-T4, N0-N2, M0)
- •HPV/p16 testing available for stratification.
- •Presence of evaluable tumor burden.
- •Eligible to receive definitive chemoradiotherapy.
- •Life expectancy ≥12 months.
- •ECOG Performance Status ≤
- •Adequate organ function.
- •Contraception requirements met.
- •Ability to comply with study procedures.
排除标准
- •Cohort A Specific:
- •Stage I-II disease
- •Stage IVb or Ivc disease
- •T4b unresectable disease
- •N3 disease where applicable
- •Medically eligible for perioperative pembrolizumab
- •Cohort B Specific:
- •Stage I-II disease
- •Disease not appropriate for curative-intent CRT
- •Active autoimmune disease requiring systemic therapy
- •Prior solid organ or allogeneic stem cell transplant
- •Ongoing immunosuppression >10 mg/day prednisone equivalent
- •Common Exclusion Criteria:
- •Primary tumor arising from the nasopharynx, hypopharynx, larynx, paranasal sinus, or unknown primary site.
- •Prior treatment for current head and neck squamous cell carcinoma.
- •Prior malignancy unless protocol exceptions met
- •Distant metastatic disease
- •Live vaccine within 30 days
- •Known hypersensitivity to APG-157 or its components.
- •Unresolved clinically significant toxicity
- •Recent participation in another investigational study
- •Active uncontrolled infection
- •Significant uncontrolled cardiovascular disease
- •Pregnancy or breastfeeding.
- •QTcF >500 msec or congenital long QT syndrome
- •Any condition compromising safety, compliance, or study interpretation
- •Randomization ratio: 1:1 within each cohort
- •Stratification Factors:
- •HPV/p16 status,
- •Planned platinum strategy,
- •PD-L1 CPS category
- •HPV/p16 status
- •Planned platinum strategy
- •Geographic region.
研究组 & 干预措施
Cohort A - APG-157
APG-157 600 mg/day (200 mg orally three times daily)for 6 weeks prior to curative-intent surgery followed by protocol-directed adjuvant therapy.
干预措施: Radiation/Chemotherapy (Radiation)
Cohort A - Control
Standard-of-care surgery and adjuvant therapy; Participants undergo curative-intent surgery followed by protocol-directed adjuvant therapy
干预措施: Radiation/Chemotherapy (Radiation)
Cohort B - APG-157
APG-157 induction therapy and standard-of-care definitive chemoradiotherapy followed by APG-157 maintenance therapy. Participants receive APG-157 600 mg/day for 4 weeks (200 mg orally three times daily) prior to definitive chemoradiotherapy, followed by APG-157 maintenance therapy for up to 1 year
干预措施: Radiation/Chemotherapy (Radiation)
Cohort B - Control
Standard-of-Care Chemoradiotherapy. Participants receive definitive upfront chemoradiotherapy
干预措施: Radiation/Chemotherapy (Radiation)
Cohort A - APG-157
APG-157 600 mg/day (200 mg orally three times daily)for 6 weeks prior to curative-intent surgery followed by protocol-directed adjuvant therapy.
干预措施: APG-157 (Drug)
Cohort B - APG-157
APG-157 induction therapy and standard-of-care definitive chemoradiotherapy followed by APG-157 maintenance therapy. Participants receive APG-157 600 mg/day for 4 weeks (200 mg orally three times daily) prior to definitive chemoradiotherapy, followed by APG-157 maintenance therapy for up to 1 year
干预措施: APG-157 (Drug)
Cohort A - APG-157
APG-157 600 mg/day (200 mg orally three times daily)for 6 weeks prior to curative-intent surgery followed by protocol-directed adjuvant therapy.
干预措施: Surgery (Procedure)
Cohort A - Control
Standard-of-care surgery and adjuvant therapy; Participants undergo curative-intent surgery followed by protocol-directed adjuvant therapy
干预措施: Surgery (Procedure)
结局指标
主要结局
未指定
次要结局
- Patient-Reported Outcomes(Baseline through approximately 36 months.)
- Patient-Report Outcomes(Baseline through approximately 36 months)