Head and Neck Squamous Cell Carcinoma
Conditions
Keywords
Becotatug Vedotin, EGFR ADC, Pucotenlimab, HX008, Neoadjuvant Therapy, Recurrent Head and Neck Cancer, GATEWAY, Immunotherapy Progression, Salvage Surgery, Major Pathological Response
Brief summary
This is a prospective, single-arm, multi-center, Phase II clinical trial evaluating the efficacy and safety of neoadjuvant becotatug vedotin (an anti-EGFR antibody-drug conjugate) combined with pucotenlimab (HX008, an anti-PD-1 monoclonal antibody) in patients with resectable recurrent head and neck squamous cell carcinoma (rHNSCC) who have progressed on prior PD-1/PD-L1 inhibitor and platinum-based therapy. A total of 42 EGFR-positive patients will be enrolled using Simon's two-stage design across 11 centers in China (Stage 1: 25 patients; Stage 2: 17 additional patients with 5% dropout). Enrolled patients will receive 3 cycles of neoadjuvant becotatug vedotin (2.3 mg/kg, IV, Q3W) plus pucotenlimab (3 mg/kg, IV, Q3W), followed by salvage surgery (3-4 weeks later), adjuvant radiotherapy +/- chemotherapy per NCCN/CSCO guidelines, and pucotenlimab maintenance therapy (3 mg/kg, Q3W) for up to 12 cycles or until disease progression or unacceptable toxicity. The primary endpoint is major pathological response (MPR) rate. The null hypothesis MPR rate is 14% (historical data) and the target MPR rate is 30% (alpha=0.05, power=0.8, one-sided). Secondary endpoints include objective response rate (ORR), pathological complete response (pCR), survival outcomes, quality of life, and safety.
Detailed description
Recurrent head and neck squamous cell carcinoma (rHNSCC) remains a significant clinical challenge, with recurrence rates of 40-60% after curative treatment. Salvage surgery is the standard of care, yet approximately 50% of patients experience re-recurrence within 2 years. For patients who have progressed on prior PD-1 inhibitor and platinum-based therapy, effective treatment options are extremely limited. Becotatug vedotin is a novel anti-EGFR antibody-drug conjugate (ADC) that has demonstrated significant anti-tumor activity in HNSCC, with an ORR of 40% in Phase Ia/Ib and 43% in the post-immunotherapy Phase II study. Pucotenlimab (HX008) is a PD-1 inhibitor with an extended half-life (T1/2 = 21.76 days). Phase I/II data showed the combination achieved ORR of 60% in HNSCC with manageable toxicity. This study investigates neoadjuvant becotatug vedotin plus pucotenlimab in resectable rHNSCC after immunotherapy progression. TREATMENT REGIMEN: 1. Neoadjuvant: Becotatug vedotin 2.3 mg/kg IV + Pucotenlimab 3 mg/kg IV, Q3W, 3 cycles 2. Surgery: Salvage surgery 3-4 weeks after neoadjuvant completion 3. Adjuvant: IMRT (60-66 Gy/30f) +/- platinum-based chemotherapy per NCCN/CSCO 4. Maintenance: Pucotenlimab 3 mg/kg IV Q3W for 12 cycles or until progression/toxicity Simon's two-stage design: Stage 1 (25 patients, \>=3 MPR required) to Stage 2 (17 additional, total 42). H0 MPR=14%, H1 MPR=30% (alpha=0.05, power=0.8).
Interventions
Becotatug vedotin as one of the drugs used in neoadjuvant therapy.
DRUGPucotenlimab
Pucotenlimab as one of the drugs used in neoadjuvant therapy.
Sponsors
Sun Yat-sen University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single Group Assignment
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 2. Age 18-75 years at time of consent 3. Histologically or cytologically confirmed recurrent head and neck squamous cell carcinoma 4. Disease progression after prior treatment including both PD-1/PD-L1 inhibitor and platinum-based therapy (combined or sequential) 5. EGFR protein expression positive by immunohistochemistry (IHC), with no EGFR-targeted therapy within 6 months prior to enrollment 6. Willing to provide archived tumor tissue or undergo fresh tumor biopsy for EGFR testing 7. At least one measurable extracranial lesion per RECIST v1.1; previously treated lesions must demonstrate clear progression 3 or more months after last local treatment 8. Resectable disease with no distant metastasis, as assessed by a multidisciplinary team 9. Adequate organ function within 7 days prior to enrollment: ANC at least 2.0 x 10\^9/L, platelet count at least 100 x 10\^9/L; total bilirubin less than 1.5 x ULN, ALT/AST less than 2.5 x ULN; serum creatinine less than 1.5 x ULN 10. Signed informed consent prior to any study-specific procedures 11. Life expectancy greater than 3 months 12. Effective contraception during study and for 6 months after last dose
Exclusion criteria
1. History of other malignancies (except cured basal cell carcinoma or cervical carcinoma in situ) 2. Comorbidities requiring long-term immunosuppressive therapy or corticosteroids at immunosuppressive doses 3. Immunodeficiency or history of organ transplantation (including interstitial pneumonia, hepatitis, nephritis, hyperthyroidism, hypothyroidism) 4. HIV/AIDS; untreated active hepatitis B (HBV-DNA at least 500 IU/mL); hepatitis C (HCV-RNA above detection limit); or HBV/HCV co-infection 5. High-dose systemic corticosteroids within 4 weeks prior to enrollment 6. Pregnant or lactating women; fertile patients not using effective contraception 7. Laboratory values not meeting inclusion criteria within 7 days 8. Significantly impaired cardiac, hepatic, pulmonary, renal, or bone marrow function 9. Severe uncontrolled comorbidities or active infections 10. Concurrent participation in other clinical trials 11. Refusal or inability to sign informed consent 12. Other contraindications to study treatment as determined by the investigator 13. Psychiatric disorders or mental illness resulting in lack of legal capacity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathological Response Rate (MPR) | At time of surgery, approximately 12 weeks after enrollment | Proportion of patients with less than or equal to 10% viable tumor cells in the surgically resected specimen after neoadjuvant therapy, assessed by central pathology review. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 12-Month Progression-Free Survival Rate | 12 months after end of treatment | Proportion of patients alive without disease progression at 12 months after completion of study treatment. |
| Incidence of Adverse Events (AEs) | Through study completion, up to 90 days after last dose | Safety assessed per NCI CTCAE v5.0. Incidence and severity of all AEs, treatment-emergent AEs, and immune-related AEs. |
| Incidence of Serious Adverse Events (SAEs) | Through study completion, up to 90 days after last dose | Incidence of serious adverse events assessed per CTCAE v5.0. |
| Quality of Life - DASS-21 | Baseline, during treatment, and follow-up through 12 months | Depression, Anxiety, and Stress Scale (21-item version). |
| Quality of Life - PTGI | Baseline and follow-up through 12 months | Post-Traumatic Growth Inventory. |
| Quality of Life - EORTC QLQ-C30 | Baseline, during treatment, and follow-up through 12 months | EORTC Quality of Life Questionnaire Core 30. |
| Stigma Scale | Baseline and follow-up through 12 months | Chronic disease stigma assessment. |
| Duration of Response (DoR) | Up to 60 months | Time from first documented CR or PR to disease progression or death. |
| Median Progression-Free Survival (mPFS) | Up to 60 months from enrollment | Time from enrollment to disease progression per RECIST v1.1 or death from any cause. |
| Objective Response Rate (ORR) | After 3 cycles of neoadjuvant therapy, approximately 9 weeks | Proportion of patients achieving complete response (CR) or partial response (PR) per RECIST v1.1. |
| Pathological Complete Response Rate (pCR) | At time of surgery | Proportion of patients with no residual viable tumor cells in the surgically resected specimen. |
| 6-Month Progression-Free Survival Rate | 6 months after end of treatment | Proportion of patients alive without disease progression at 6 months after completion of study treatment. |
| Median Overall Survival (mOS) | Up to 60 months from enrollment | Time from enrollment to death from any cause. |
Countries
China
Contacts
CONTACTXuekui Liu, MD, PhD
CONTACTChunyan Chen, MD, PhD
STUDY_CHAIRXuekui Liu, MD, PhD
Sun Yat-Sen University Cancer Center
STUDY_CHAIRChunyan Chen, MD, PhD
Sun Yat-Sen University Cancer Center
Outcome results
None listed