HLX301 (TIGIT×PDL1 Bispecific) in Patients With Locally Advanced or Metastatic Solid Tumors

This Phase 1/2, multicenter, first-in-human, open-label, dose-escalation, dose expansion, and clinical expansion study will evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor efficacy of HLX301 administered as a single-agent by IV infusion every 2 weeks to patients with locally advanced or metastatic solid malignancies, who have failed or are intolerant to standard therapy, or for whom no standard therapy is available. This study has three parts: phase 1a dose escalation, phase 1b dose expansion, and phase 2 clinical expansion.

Up to 150 patients will be included in this study. Up to 30 DLT evaluable patients will be enrolled in phase 1a (dose escalation), 40 per-protocol treated patients in phase 1b (dose expansion), and 80 per-protocol treated patients in phase 2.

Phase 1a uses the Bayesian optimal interval (BOIN) design, to investigate the safety and determine the MTD of HLX301. BOIN design combines rule-based and model-based design, allowing for flexibility of dose escalation and de-escalation, and high patient enrollment in doses closest to the target toxicity rate (pre-defined as 30% in this study). This study will also evaluate safety profiles at different dose levels, PK parameters, pharmacodynamic markers, immunogenicity, and the preliminary efficacy of the drug.

Following dose escalation and determination of the MTD, additional patients with NSCLC will be enrolled in phase 1b dose expansion to further evaluate PK and pharmacodynamic characteristics, and preliminary efficacy in order to determine the RP2D.

The phase 2 clinical expansion will include patients with various cancer types, including:

20 per-protocol treated patients with non-small cell lung cancer (NSCLC) 20 per-protocol treated patients with gastric/esophagogastric junction adenocarcinoma (GC/EGJ) 20 per-protocol treated patients with head and neck squamous cell carcinoma (HNSCC) 20 per-protocol treated patients with urothelial carcinoma (UC)

Eligibility Criteria:
Inclusion Criteria:

* 1. Patients who meet the following criteria will be enrolled:

  1. Phase 1a dose escalation: patients must have histologically or cytologically confirmed malignant solid tumors which are advanced or metastatic, have failed prior standard treatment, and be intolerant or ineligible for standard therapy (with the exception of hepatocellular carcinoma, which meets diagnostic criteria by dynamic CT/MRI).
  2. Phase 1b dose expansion: patients must have a histological or cytological diagnosis of Non-Small Cell Lung Cancer which is advanced or metastatic, have failed prior standard treatment, and be intolerant or ineligible for standard therapy.
  3. Phase 2 clinical expansion: patients must have histological confirmed or cytological diagnosis of PD-L1 expressing, i.e., TPS ≥1% non-small cell lung cancer, CPS ≥1 gastric/esophagogastric junction adenocarcinoma, CPS ≥1 head and neck squamous cell carcinoma, or CPS ≥10 urothelial carcinoma, have failed at least one or two prior systemic anti-tumor regimens, and be intolerant or ineligible for standard therapy.
* 2. Age ≥ 18 years, or legally an adult as per local regulations.
* 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
* 4. Measurable disease according to RECIST Version 1.1
* 5. Able to provide informed consent.
* 6. A life expectancy longer than three months.
* 7. Adequate hematologic parameters, defined as white blood cell count ≥ 3000/mm3 and absolute neutrophil counts ≥ 1500/mm3; hemoglobin≥ 10 gm/dL; platelet count ≥ 100,000/mm3 without platelet transfusion within 14 days.
* 8. Adequate hepatic function, defined as serum albumin ≥ 3.0 g/dL; serum total bilirubin ≤ 1.5x upper limit of normal (ULN); serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN (AST and ALT ≤ 5 × ULN for patients with known liver metastasis or primary hepatocellular carcinoma); Child-Pugh score A in HCC.
* 9. Adequate renal function, defined as serum creatinine ≤ 1.5x upper limit of normal (ULN).
* 10. Adequate cardiac function defined as left ventricular ejection fraction (LVEF) ≥ 50% measured by cardiac ultrasound or MUGA scan; normal ECG or ECG without any clinically significant findings.

Exclusion Criteria:

* 1. Received prior anti-TIGIT therapy.
* 2. Patients who still have persistent ≥ grade 2 toxicities from prior therapies.
* 3. Concurrent unstable or uncontrolled medical conditions including, but not limited to, the following:

  1. Ongoing or active systemic infections requiring antibiotic treatment
  2. Clinically significant arrhythmia, unstable angina pectoris, class III or IV congestive heart failure as per the New York Heart Association, or acute myocardial infarction in the past 6 months
  3. Unhealed wound or ulcers persisting ≥ 3 months
  4. Psychiatric illness or a social situation that would preclude study compliance
  5. Any other diseases, metabolic dysfunction, physical examination findings, or laboratory results raising reasonable suspicion of a disease or condition that contraindicates use of the investigational drug, that may affect interpretation of results, or that may place the patient at high risk of treatment complications.
* 4. Active CNS metastasis indicated by clinical symptoms, cerebral edema, steroid requirements (not including maintenance low dose steroids), or progressive growth.
* 5. History of any secondary malignancy in the past 3 years with the exception of curatively treated non-melanoma skin cancer or treated cervical carcinoma in situ.
* 6. Active or a history of (in the past 2 years) of autoimmune disease or syndrome requiring systemic steroid or immunosuppressive agents.
* 7. History of interstitial lung disease.
* 8. Hepatitis B virus infection (HBsAg or anti-HBc positive, and HBV-DNA positive), hepatitis C virus infection (anti-HCV positive, and HCV-RNA positive), or co-infection with hepatitis B and hepatitis C (positive HBsAg or anti-HBc, and positive anti-HCV).
* 9. Human immunodeficiency virus (HIV) infection.
* 10. Major surgery, treatment with anti-cancer or investigational agents, or radiotherapy in the 28 days prior to the first study dosing.
* 11. Treatment with immune check point inhibitors (anti-PD-1 or anti-PD-L1) in the 42 days prior to the first study dosing.
* 12. Pregnancy or breast-feeding.
* 13. Patients of reproductive age who are unable to use effective contraceptive measures in the period from the first dose of study drug to 180 days following the last dose of study drug. Female patients who have been amenorrheic for at least 12 months, have had a hysterectomy or oophorectomy, or have been surgically sterilized do not require contraception.