Head and Neck Squamous Cell Carcinoma
Conditions
Brief summary
Part1: A mutilpe-center, open-label, Phase II clinical trial to evaluate the efficacy and the safety of HLX10 in combination with HLX07 in patients with advanced advanced head and neck tumors. Part2: A randomized, double-blind, multi-center, phase II clinical study to evaluate the clinical efficacy and safety of HLX10 in combination with HLX07 and chemotherapy versus HLX10 in combination with placebo and chemotherapy in the first-line treatment of R/M HNSCC.
Detailed description
Part 1: This is an open label study. Sample size recommendations for this phase II study are determined according to Simon's two-stage Optimal design. In the first stage, 13 patients will be accrued. The patients will receive 3 mg/kg of HLX10 every two weeks infusion combined with 600 mg HLX07 weekly (stage 1L). These patients will be assessed for treatment response after 8 weeks of first infusion of study drugs. If there are 3 or fewer responsive patients in these 13 patients, additional 13 patients will be accrued. These additional 13 patients will receive 3 mg/kg of HLX10 every two weeks infusion combined with 800 mg HLX07 weekly (Stage 1H). If 3 or fewer responses after eight weeks treatment noted in these 13 patients in stage 1H, the trial will be stopped. If 4 or more patients are responsive to therapy in stage 1, the trial will be continued to stage 2, 30 additional patients will be accrued to reach a total of 43 patients. These additional 30 patients will receive the same dose of regimen as the prior patients. Part 2: This is a randomized, double-blind, multi-center, phase II clinical study to evaluate the clinical efficacy and safety of HLX10 in combination with HLX07 and chemotherapy versus HLX10 in combination with placebo and chemotherapy in the first-line treatment of R/M HNSCC. Approximately 75 first-line R/M HNSCC subjects are planned to be recruited. The sample size calculation is not based on the statistical hypothesis. Eligible subjects after screening will be randomly assigned to the treatment group (group A) or the control group (group B) in a ratio of 2:1, with PD-L1 CPS (≥ 20 and \< 20) as the stratification factor at randomization (Figure 1): Group A: approximately 50 subjects, HLX10 in combination with HLX07 and chemotherapy (cisplatin in combination with 5-FU). Group B: approximately 25 subjects, HLX10 in combination with placebo and chemotherapy (cisplatin in combination with 5-FU). Cisplatin may be replaced with carboplatin when the subject is judged intolerant to cisplatin by the INV. The study will be unblinded overall for ORR analysis approximately 3 months after the first dose of the last subject.
Interventions
DRUGHLX10
Part 1: HLX10 3 mg/kg biweekly. Part 2: HLX10 300 mg every three weeks.
DRUGHLX07
Part 1: HLX07 600 mg weekly (stage 1L). Part 1: HLX07 800 mg weekly (stage 1H). Part 2: HLX07 1000 mg every three weeks.
DRUGHLX07 placebo
HLX07 placebo 1000 mg every three weeks
Cisplatin 100 mg/m2 every three weeks. Cisplatin will be switched to carboplatin in case of intolerance to cisplatin. Up to 6 cycles.
DRUG5-FU
5-FU 1000 mg/m2/day, 1-4 days, every three weeks. Up to 6 cycles.
Sponsors
Shanghai Henlius Biotech
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Part 1: open label. Part 2: Matters related to the blinding of study treatment will be carried out by the statistics department. The subjects, the INV, the sponsor, and designees are not aware of the randomized allocation. This study will be unblinded overall approximately 3 months after the first administration in the last subject. Unblinding is allowed unless there is an emergency medical condition (emergency treatment is only possible when being informed of the randomized medication) or unblinding is requested by the regulatory authorities. Otherwise, the study should remain blinded. Only when all data have been input into the database, all data queries have been resolved, and subjects have been allocated into analysis sets, can the randomization codes be unblinded.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Part1 Inclusion Criteria: 1. Eligible patients must be 18 years of age or older or per local regulation AND younger than 80 years old age. 2. Patients with histologically-proven recurrent (not amenable to locally curative treatment options) or metastatic, squamous cell carcinoma of the head and neck with previously failed platinum-based chemotherapy and PD-L1 expression (combined positive score ≥ 1) as determined by immunohistochemistry (IHC) stain. (Patient must be able to provide tissue for PD-L1 biomarker analysis from a core or excisional biopsy; fine needle aspirate is not sufficient.: A newly obtained biopsy; within 90 days prior to start of study treatment; is preferred but an archival sample is acceptable.) 3. Lesion must be measurable based on RECIST, version 1.1. 4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 at the time of study entry. 5. Able to provide informed consent. 6. A life expectancy longer than three months. 7. Adequate hematologic functions, as defined by: absolute neutrophil counts (ANC) ≥ 1500/mm3; a hemoglobin (Hb) level ≥ 9 gm/dL; a platelet count ≥ 100,000/mm3. 8. Adequate hepatic function defined by: a total bilirubin level ≤ 1.5x of upper limit of normal (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤ 2.5 x of ULN or ≤ 5x of ULN in known hepatic metastases. 9. Adequate renal function, as defined by the creatinine clearance rate ≥ 50 mL/minute calculated using Cockcroft-Gault formula. In patient with extreme body weight (body mass index \[BMI\] \< 18.5 or \> 30), estimated glomerular filtration rate (GFR) ≥ 50mL/min calculated using Modification of Diet in Renal Disease (MDRD) formula is acceptable. 10. Adequate cardiac function defined as left ventricular ejection fraction (LVEF) ≥ 50% measured by multigated acquisition (MUGA) scan or cardiac ultrasound. 11. Use of effective contraceptive measures if procreative potential exists . 12. At least 28 days from prior major surgery, prior cytotoxic chemotherapy, or prior therapy with investigational agents (or medical device) and curative radiotherapy or palliative radiotherapy to target lesion before the first infusion of investigational product. 13. Able to follow the procedures as required by the study protocol and must agree to provide tumor tissue for programmed cell death 1 (PD-L1) expression analyses, EGFR mutation status, and biomarker assessment.
Exclusion criteria
1. Patients who still have persistent ≥ grade 2 toxicities from prior therapies. 2. Patients with primary nasopharynx cancers. 3. Squamous cell carcinoma of unknown primary in cervical lymph node. 4. Concurrent unstable or uncontrolled medical conditions. Either of the followings: * Active systemic infections currently under treatment with antimicrobial agents; * Poorly controlled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥100 mmHg), or poor compliance with anti-hypertensive agents; * Clinically significant arrhythmia, unstable angina pectoris, congestive heart failure (class III or IV of New York Heart Association \[NYHA\]) or acute myocardial infarction within 12 months; * Uncontrolled diabetes or poor compliance with hypoglycemic agents; * The presence of chronically unhealed wound or ulcers; * Other chronic diseases, which, in the opinion of the investigator, could compromise safety of the patient or the integrity of study. 5. Newly-diagnosed or symptomatic brain metastases (patients with a history of brain metastases must have received definitive surgery or radiotherapy, must be clinically stable, and must not taking steroids for brain edema for at least 14 days to be allowed in the study). Anticonvulsants are allowed. 6. Any concurrent malignancy other than basal cell carcinoma or carcinoma in situ of the cervix. (Patients with a previous malignancy but without evidence of disease for ≥ 3 years can participate). 7. Pregnancy (confirmed by serum beta human chorionic gonadotropin \[ßHCG\]) or breast-feeding. 8. Known history of human immunodeficiency virus infection (HIV). 9. Patient who has an active or a documented history of autoimmune disease. 10. Patient who has active hepatitis B (HBV DNA titer \> 100 IU/mL or \> 500 copies/mL) or hepatitis C (defined as anti-HCV antibody reactive and/ or detectable HCV RNA \> 15 IU/L). 11. Patient who has a history of interstitial lung disease. 12. Have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of autoimmune disease. 13. Patients who have failed systemic anti-EGFR monoclonal antibody therapies (who have PD or PFS less than 3 months during anti EGFR treatment) or have been received more than 3 lines of systemic chemotherapy regimens. 14. Patients who previously have severe allergic reaction to anti-EGFR monoclonal antibody (CTCAE grade ≥3). 15. Patients who have previously received immune check point therapy, including but not limit to anti-PD1 and anti-PDL1. 16. The patient is the investigator, sub-investigator or any one directly involved in the conduct of the study. 17. Patient has a history or current evidence of any condition or disease that could confound the results of the study, or study or is not the best interest of the patient to participate, in the opinion of Investigator. Part2 Inclusion Criteria: 1. Histologically or cytologically confirmed R/M HNSCC that is considered incurable by local therapies. 2. Have not received any systemic anti-tumor therapy for R/M HNSCC. Patients who have received systemic anti-tumor therapy (including anti-EGFR antibody drugs) as part of comprehensive treatment at the locally advanced stage are allowed to be enrolled if the systemic therapy has been completed for at least 6 months before signing the informed consent form (ICF). * Tumor types to be included: primary cancers of the oropharynx, oral cavity, hypopharynx, and larynx. * Patients with primary nasopharyngeal cancer are not allowed to be enrolled. * Willing and able to provide the written ICF to participate in this study. 3. Age ≥ 18 years at the time of signing the ICF. 4. Have measurable lesion as assessed by the INV per RECIST v1.1. Previously irradiated lesions may be considered measurable if progression has been confirmed in such lesions. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at the time of enrollment. 6. Normal major organ functions. 7. Able to provide tissue samples from needle biopsy or excisional biopsy (fine-needle aspiration is unacceptable) for determination of EGFR and PD-L1 expression. Patients with oropharyngeal cancer are required to provide additional tissue samples for HPV (P16) status testing. Tissue samples should be re-collected if the quantity is not adequate. 8. Female subjects with childbearing potential must be tested negative for serum pregnancy test within 7 days prior to the first dose. 9. Female subjects with childbearing potential should agree to use two methods of contraception, undergo sterilization, or avoid heterosexual sex during the treatment and until 180 days after the last dose. Subjects with childbearing potential refer to those who have not undergone sterilization or have stopped menstruating for less than 1 year. Subjects are allowed to choose abstinence as a contraceptive measure if abstinence is their normal lifestyle. 10. Male subjects should agree to take adequate contraceptive measures from the first dose until 180 days after the last dose. Subjects are allowed to choose abstinence as a contraceptive measure if abstinence is their normal lifestyle.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part1: Efficacy-ORR | at 16 weeks after first dose | Objective Response Rate (ORR) |
| Part1: Safety-adverse event profile | up to one year | The proportion of patients suffered from drug related toxicities. |
| Part2: Efficacy-ORR (IRRC) | at 3 months after first dose | Objective Response Rate (ORR) assessed by the Independent Radiological Review Committee (IRRC) per RECIST v1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| clearance rate (CL) | up to one year | — |
| volume of distribution (Vss) | up to one year | — |
| area under concentration (AUC0-tau) | up to one year | — |
| maximum concentration (Cmax) | up to one year | — |
| Efficacy-PFS | up to one year | Progression-free survival (PFS) |
| Efficacy-OS | up to one year | Overall survival (OS) |
| The number of presence patients that develop of anti-durg antibody (immunogenicity). | up to one year | — |
| Efficacy-Best ORR | up to one year | Best response rate (Best ORR) |
| trough concentration (Ctrough) | up to one year | — |
| half-life (T1/2) | up to one year | — |
Countries
China
Outcome results
None listed