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

Phase 3Not Yet RecruitingNCT07667296

Aveta Biomics, Inc.826 enrolled

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).

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.

Study Type

Interventions

APG-157DRUG

APG-157 is a ﬁrst-in-class investigational drug product, formulated as 100 mg soft hydrogel pastille to dissolve in the mouth

SurgeryPROCEDURE

Definitive Surgery

Radiation/ChemotherapyRADIATION

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/ChemotherapyRADIATION

Definitive radiotherapy with concurrent protocol-specified platinum-based chemotherapy.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria Cohort A (Resectable Disease) 1. Adults ≥18 years 2. Histologically or cytologically confirmed, previously untreated locally advanced head and neck squamous cell carcinoma (LA-HNSCC) of the oral cavity or oropharynx. 3. Resectable disease appropriate for curative-intent surgery. 4. 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) 5. Objectively medically ineligible for perioperative pembrolizumab according to protocol-defined objective criteria. 6. HPV/p16 testing available for stratification. 7. Measurable or evaluable disease. 8. Life expectancy ≥12 months. 9. ECOG Performance Status ≤2. 10. Negative pregnancy test for women of childbearing potential and agreement to use effective contraception. 11. Ability to comply with study procedures. Cohort B (Unresectable / Medically Inoperable Disease) 1. Adults ≥18 years 2. Histologically or cytologically confirmed, previously untreated LA-HNSCC of the oropharynx. Disease not suitable for curative-intent surgery. 3. 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) 4. HPV/p16 testing available for stratification. 5. Presence of evaluable tumor burden. 6. Eligible to receive definitive chemoradiotherapy. 7. Life expectancy ≥12 months. 8. ECOG Performance Status ≤2. 9. Adequate organ function. 10. Contraception requirements met. 11. 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.

Outcomes

Primary Outcomes

Event-Free Survival (EFS)

EFS is defined as the time from randomization to the earliest occurrence of a protocol-defined EFS event, including radiographic and/or clinical disease progression that precludes initiation or completion of planned definitive curative-intent therapy; locoregional recurrence, progression, or distant metastasis following definitive treatment, confirmed by imaging, pathology, salvage intervention with viable tumor or other protocol-defined assessments, where applicable, or death from any cause. EFS will be analyzed by blinded independent central review (BICR) using RECIST v1.1 and protocol-defined pathology criteria, as applicable. The primary analysis will be conducted in the intent-to-Treat ( ITT) population using stratified log-rank testing and Cox proportional hazards models.

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 Outcomes

Overall Survival (OS)

Overall survival is defined as the time from randomization until death from any cause.

Time frame: Time from randomization until death from any cause; assessed up to approximately 60 months.

Objective Response Rate (ORR)

Proportion of participants achieving confirmed response (CR) or partial response (PR) according to RECIST v1.1 as assessed by BICR.

Time frame: • Cohort A: Week 6 and pre-surgery assessment • Cohort B: Week 4 and pre-CRT assessment

ctDNA Clearance Rate

Change in circulating tumor DNA (ctDNA) levels over time and proportion of participants achieving ctDNA clearance from the baseline assessed using a tumor-informed assay.

Time frame: Baseline through protocol-defined follow-up assessments up to approximately 36 months.

Clinically Meaningful Pathological Response(Cohort A):

Proportion of participants achieving ≤50% residual viable tumor in the resected specimen as assessed by BICR.

Time frame: At definitive surgery (approximately 6-9 weeks after randomization).

Major Pathologic Response (MPR) (Cohort A)

Proportion of participants achieving ≤10% residual viable tumor in the resected specimen as assessed by BICR.

Time frame: At definitive surgery.

Composite Pathologic Response (Cohort A)

Composite assessment including: * Pathologic tumor response category * Surgical margin status * Extranodal extension status * Clinical-to-pathologic downstaging

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

EuroQol-5 Dimension, 5-Level (EQ-5D-5L). Change from baseline in the EQ-5D-5L Health Utility Index score. The Health Utility Index is derived from responses to the five EQ-5D-5L dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) using a country-specific value set. Scores typically range from less than 0 (health states considered worse than death) to 1.0 (full health), with higher scores indicating better health-related quality of life.

Time frame: Baseline through approximately 36 months.

Patient-Report Outcomes

European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30). Change from baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life Scale score. The Global Health Status/Quality of Life Scale is transformed to a 0 to 100 scale, with higher scores indicating better global health status and quality of life.

Time frame: Baseline through approximately 36 months

Ability to Initiate Definitive Therapy

Proportion of participants able to initiate protocol-defined definitive curative-intent therapy within protocol-specified timing windows (Within 21 days after the last dose of APG-157 prior to definitive surgery (Cohort A) or definitive chemoradiotherapy (Cohort B))

Time frame: Up to 21 days after last dose of APG-157