Evaluate Safety, Tolerability and PK of HLX55 in Patients With Advanced Solid Tumors With Different cMET Status

Phase 1

• Conditions: Solid Tumor, Adult
• Interventions: Drug: HLX55

• Registration Number: NCT04169178
• Lead Sponsor: Henlix, Inc

Brief Summary

A mutilpe-center, open-label, dose-escalation Phase I clinical trial to evaluate the safety and the tolerability of HLX55 in patients with advanced solid tumors overexpressing/Mutation/Amplification cMET after failure of standard of care.

Detailed Description

This study is an open-label and dose escalation study including dose finding stage and expansion stage.

In dosing finding stage, the study will precede in two phases, (i) a modified accelerated titration design 2A (ATD 2A) phase and (ii) a traditional 3+3 dose escalation phase aimed at exploring the safety and MTD of HLX55. Four dose levels are designed for HLX55 in this stage: 2.5, 5, 15, and 25 mg/kg/3 weeks. The 5 mg/kg/3 weeks will serve as the starting dose.

In the dose-expansion stage, three to five cohorts are planned, and different cohorts will evaluate the efficacy of HLX55 for potential indications. Maximum 20 patients will be accrued in each cohort.

Study Timeline

• Study First Submitted: 2019-11-13
• Study First Submitted QC: 2019-11-18
• Study First Posted: 2019-11-19
• Study Start: 2020-03-03
• Status Verified: 2020-04
• Last Update Submitted: 2020-04-29
• Last Update Posted: 2020-05-01
• Primary Completion: 2022-12
• Study Completion: 2022-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 98

Inclusion Criteria

1. Eligible patients must be 18-years of age or older (or per local regulations) and ≦75 years of age.
2. For dose finding stage: patients with measurable or evaluable advanced or metastatic solid tumours who have failed standard therapy or for whom no standard therapy is available.
3. For dose expansion stage: patients with measurable or evaluable advanced or metastatic solid tumors with histologically confirmed c-MET mutations (MET exon 14 mutations) or amplifications (MET/CEP7 ratio ≥ 2.0 or MET ≥ 5.0 copies) or over-expression (immunohistochemistry [IHC] score ≥ 2+) and have failed standard therapy or for whom no standard therapy is available. Positive c-MET mutation/amplification/over-expression results should be available before the subject can receive HLX55.
4. No prior therapy with MET-targeting biological agents (patients who have received prior therapy with a MET-targeting tyrosine kinase inhibitor [TKI] is allowed.)
5. Must be able to supply adequate tumor tissue. (Adequate tumor biopsy material means (1) newly biopsied or archival tissue biopsied within 60 days before the first dosing, (2) Biopsy materials should be adequate for biomarker analysis (c-MET/Kras/EGFR).
6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 at the time of study entry.
7. Able to provide informed consent.
8. A life expectancy longer than three months.
9. Adequate hematologic functions, as defined by absolute neutrophil counts ≥ 1500/mm3; a haemoglobin level ≥ 9 gm/dL; a platelet count ≥ 100,000/mm3 and an international normalized ratio ≤ 1.5.
10. An adequate hepatic function defined by a total bilirubin level ≤ 1.5 x of upper limit of normal values (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤ 2.5 x of ULN or ≤ 5 x of ULN in known hepatic metastases or with primary hepatocellular carcinoma.
11. Adequate renal function, as defined by the creatinine clearance rate ≥ 50 mL/minute by Cockcroft-Gault formula. In patients with extreme body weights (body mass index [BMI] < 18.5 OR > 30) estimated glomerular filtration rate (eGFR) ≥ 50ml/min calculated by Modification of Diet in Renal Disease (MDRD) formula is acceptable.
12. Adequate cardiac function defined as left ventricular ejection fraction (LVEF) ≥ 50% measured by either cardiac echo or multigated acquisition (MUGA) scan.
13. At least 21days from prior cytotoxic chemotherapy, prior therapy with investigational small molecule agents (or medical device) or radiotherapy, at least 28 days from prior immunotherapy, biological agents or prior major surgery and at least 14 days from prior hormonal therapy and minor surgery before infusion of first dose of HLX55.
14. For patients with hepatocellular carcinoma, their Child-Pugh score must be A.
15. Able to be followed up as required by the study protocol.
16. Female participants must have a negative pregnancy test at screening if of childbearing potential or be of non-childbearing potential.
17. Female participants of childbearing potential and male partners with female partners of childbearing potential must agree to use 2 adequate barrier methods of contraception during the study and for at least 180 days after last dose of study drug.

Exclusion Criteria

1. Patients who still have ≥ grade 2 toxicities from prior therapies.

2. Concurrent unstable or uncontrolled medical conditions with either of the followings:

   • Active systemic infections requiring intravenous antibiotic use within 1 week;
   • Poorly controlled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥100 mmHg), or poor compliance with anti-hypertensive agents;
   • Clinically significant arrhythmia requiring anti-arrhythmia therapy, unstable angina pectoris, congestive heart failure (class III or IV of New York Heart Association [NYHA]) or acute myocardial infarction within 6 months;
   • Uncontrolled diabetes or poor compliance with hypoglycemics defined by glycated hemoglobin (HbA1c) ≥ 9.5%;
   • The presence of chronically unhealed wound or ulcers;
   • Uncontrolled hypercalcemia (defined as persistent Ionized (free) Calcium ≥ 6.5 mg/dl despite appropriate management.)
   • Other chronic diseases, which, in the opinion of the investigator, could compromise the safety of the patient or the integrity of the study.

3. Newly-diagnosed or symptomatic brain metastases (patients with a history of brain metastases must have received definitive surgery or radiotherapy, be clinically stable, and not taking steroids for brain edema at least 14 days before infusion of the first dose of HLX55 can be allowed in the study). Anticonvulsants are allowed.

4. 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).

5. Known history of human immunodeficiency virus infection (HIV), hepatitis B virus carrier status (HBV surface antigen positive) and hepatitis C carrier (anti-HCV antibody positive).

6. The patient is the investigator, sub-investigator or anyone directly involved in the conduct of the study.

7. History or current evidence of any condition or disease that could confound the results of the study or, in the opinion of Investigator(s), is not in the best interest of the patient to participate.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
HLX55, dose expansion stage, gastric cancer	HLX55	Participants diagnosed with gastric cancer with will receive HLX55 in recommended phase 2 dose (RP2D) every three weeks.
HLX55, dose finding stage, advanced solid tumor	HLX55	Participants will receive HLX55 at assign dose level, e.g. 2.5, 5, 15 and 25 mg/kg every three weeks followed by a 21-day DLT observation period.
HLX55, dose expansion stage, NSCLC	HLX55	Participants diagnosed with non-small cell lung cancer (NSCLC) with will receive HLX55 in RP2D every three weeks.
HLX55, dose expansion stage, colorectal cancer	HLX55	Participants diagnosed with colorectal cancer (CRC) with will receive HLX55 in RP2D every three weeks.
HLX55, dose expansion stage, other solid cancer	HLX55	Participants diagnosed with other solid cancer with will receive HLX55 in RP2D every three weeks.

Primary Outcome Measures

Name	Time	Method
Dose finding stage-safety	Up to 2 years	Numbers and percentage of patients with adverse events (AEs).
Dose expansion stage-safety	Up to 2 years	Numbers and percentage of patients with adverse events (AEs).
Dose finding stage-MTD or RP2D	Up to 2 years	The maximum tolerated dose and recommended phase 2 dose (RP2D) of HLX55.
Dose expansion stage-efficacy	Up to 2 years	Duration of response (DOR).

Secondary Outcome Measures

Name	Time	Method
Dose finding stage and dose expansion stage-PK profile	Through study completion, up to 2 years.	PK profile of HLX55 including maximum concentration (Cmax), minimum concentration (Cmin), area under concentration (AUC0-tau), half-life (T1/2), clearance (CL) rate and the volume of distribution at steady state (Vss) at different doses.
Dose finding stage and dose expansion stage-serum HGF levels	Cycle 1 to 3 (each cycle is 21 days)	Changes in serum HGF levels before and at different time-points after HLX55 treatment.
Dose finding stage and dose expansion stage-immunogenicity	Up to 2 years	The presence and percentage of anti-HLX55 antibody-positive patients (immunogenicity) by measurement of anti-HLX55 antibodies in serum.

Trial Locations

Locations (4)

Taipei Minicipal Wangfang Hospital; 🇨🇳 Taipei, Taiwan

National Cheng Kung University Hospital; 🇨🇳 Tainan, Taiwan

Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare; 🇨🇳 Taipei county, Taiwan

Tri-Service General Hospital; 🇨🇳 Taipei, Taiwan