Residual Disease Interception in Locoregionally-Advanced High Risk HPV+ and HPV- HNSCC
This is a phase II, open-label study to assess the efficacy of AZD2936 in terms of molecular residual disease (MRD) clearance and treatment outcome in patients with MRD after definitive treatment for high risk locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). MRD is defined as ctDNA detection in plasma after definitive treatment. Approximately 100 patients are expected to be enrolled.
• Age ≥ 18 years at the time of screening or age of consent according to law.
• Written informed consent and any locally required authorization (e.g., data privacy) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Weight ≥ 35 kg.
• Must have a life expectancy of at least 12 weeks.
• Histological or cytological confirmed LA-HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx. Patients with locoregionally advanced unknown head and neck primary but tumor tested to be p16-positive are eligible.
• High-risk HPV negative LA-HNSCC patients (stage III-IVB according to AJCC/UICC 8th Edition) OR high-risk HPV positive LA-HNSCC patients (stage III according to AJCC/UICC 8th Edition).
• Archival tumor formalin-fixed, paraffin-embedded (FFPE) specimens for correlative biomarker studies are required (1 H\&E and 10 unstained 5 microns slides). If surgery is going to be performed after signing consent, then tumor FFPE from that surgery is allowed.
• Patient is a candidate for definitive treatment: either surgery followed by radiation or chemoradiation, OR definitive radiation, OR definitive chemoradiation.
⁃ Objective radiological tumor response according to CT or MRI at 8-12 weeks after definitive therapy (surgery followed by radiation or chemoradiation, OR definite radiation, OR definite chemoradiation)
⁃ ECOG performance status of 0 or 1 at randomization.
⁃ Tumor must express PD-L1 (CPS ≥1) as determined by the local laboratory using the PD-L1 IHC 22C3 pharmDx assay.
⁃ Detection of ctDNA in plasma samples collected in Part B in either:
• both samples collected at approximately week 5 (4-6) and at week 10 (8-12) OR
∙ only in the week 10 (8-12) sample NOTE: If ctDNA results at Week 10 are equivocal, a new sample should be collected and analyzed to confirm results within 4 weeks.
⁃ Adequate organ and marrow functions as defined in Table 4.Table 4 (4.1.2-2): Criteria for Adequate Organ and Marrow Function
⁃ Parameter Value Hematological Hemoglobin ≥ 9 g/dL Absolute neutrophil count ≥ 1,500 µ/L Platelet count ≥ 100,000 µ/L Hepatic- Total bilirubin ≤ 1.5 × ULN
‣ 3 × ULN is allowed in the presence of documented Gilbert's syndrome Alanine transaminase and Aspartate transaminase ≤ 3 × ULN
⁃ Renal Serum creatinine or Calculated creatinine clearance Serum creatinine \< 1.5 x ULN or CrCl ≥ 40 mL/minute ULN = upper limit normal. a Hematological criteria cannot be met with ongoing or recent blood transfusions (within 28 days prior to the scheduled first dose of study treatment) or require growth factor support (within 21 days prior to the scheduled first dose of study treatment).
⁃ b As determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance.
⁃ Body mass index ≥ 17.
⁃ Females of childbearing potential who are sexually active with a nonsterilized male partner must use at least one highly effective method of contraception (see Section 8.1.1 for definition of females of childbearing potential and for a description of highly effective methods of contraception) from screening to 4 months after the final dose of study treatment. It is strongly recommended for the male partner of a female subject to also use male condom plus spermicide throughout this period. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
⁃ Nonsterilized male subjects who are sexually active with a female partner of childbearing potential must use a male condom with spermicide from screening to 4 months after receipt of the final dose of study treatment. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. It is strongly recommended for the female partner of a male subject to also use a highly effective method of contraception throughout this period, as described in Section 8.1.2. In addition, male subjects must refrain from sperm donation while on study and for 4 months after the final dose of study treatment.
⁃ Objective radiological tumor response according to CT or MRI at 8-12 weeks after definitive therapy (surgery followed by radiation or chemoradiation, OR definitive radiation, OR definitive chemoradiation)
⁃ No detection of ctDNA in plasma samples analysed in the week 10 (8-12) sample collected in Part B.