APG-157 in Locally Advanced Head and Neck Squamous Cell Carcinoma

Official title

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

Overview

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).

Detailed description

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.

Interventions

• Drug APG-157
  APG-157 is a first-in-class investigational drug product, formulated as 100 mg soft hydrogel pastille to dissolve in the mouth
• Procedure Surgery
  Definitive Surgery
• Radiation Radiation/Chemotherapy
  Protocol-specified risk-adapted postoperative radiotherapy, with concurrent platinum-based chemotherapy (e.g., cisplatin or carboplatin) administered when indicated based on pathological risk factors
• Radiation Radiation/Chemotherapy
  Definitive radiotherapy with concurrent protocol-specified platinum-based chemotherapy.

Primary outcome measures

• Event-Free Survival (EFS) [Time frame: From randomization until the first occurrence of a protocol-defined EFS event, death, withdrawal from study follow-up, or study completion, assessed for up to approximately 36 months.]

Secondary outcome measures (10)

• Overall Survival (OS) [Time frame: Time from randomization until death from any cause; assessed up to approximately 60 months.]
• Objective Response Rate (ORR) [Time frame: • Cohort A: Week 6 and pre-surgery assessment • Cohort B: Week 4 and pre-CRT assessment]
• ctDNA Clearance Rate [Time frame: Baseline through protocol-defined follow-up assessments up to approximately 36 months.]
• Clinically Meaningful Pathological Response(Cohort A): [Time frame: At definitive surgery (approximately 6-9 weeks after randomization).]
• Major Pathologic Response (MPR) (Cohort A) [Time frame: At definitive surgery.]
• Composite Pathologic Response (Cohort A) [Time frame: At definitive surgery.]
• Incidence of Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Treatment Discontinuations Due to Adverse Events [Time frame: From first dose through 30 days after last study treatment.]
• Patient-Reported Outcomes [Time frame: Baseline through approximately 36 months.]
• Patient-Report Outcomes [Time frame: Baseline through approximately 36 months]
• Ability to Initiate Definitive Therapy [Time frame: Up to 21 days after last dose of APG-157]

Eligibility criteria

Inclusion criteria

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 ≤2.
• 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 ≤2.
• Adequate organ function.
• Contraception requirements met.
• Ability to comply with study procedures.

Exclusion criteria

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:

Cohort A:

• HPV/p16 status,
• Planned platinum strategy,
• PD-L1 CPS category

Cohort B:

• HPV/p16 status
• Planned platinum strategy
• Geographic region.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07667296 · AVTA30-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗