A Study of HG381 Administered to Patients With Advanced Solid Tumors

Official title

Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of HG381 as Monotherapy in Patients With Advanced Solid Tumors

Overview

This is a Phase I, first in human, open-label, non-randomized, multicenter study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, preliminary efficacy and establish a recommended dose of HG381 administered intravenously (IV) alone in subjects with advanced solid tumors.

Detailed description

The trial consists of a dose escalation phase and a cohort expansion phase.In dose escalation phase, escalating doses of HG381 will be evaluated as guided by the traditional 3+3 design . In cohort expansion phase, subjects will receive HG381 alone at a single dose level determined based on the data form dose escalation phase. In total, approximately 57 subjects will participate in the study, approximately 42 in the dose-escalation cohort, and approximately 15 in the expansion cohort.

Interventions

• Drug HG381
  HG381 is available as white to off-white cake or powder for solution for injection at a unit dose strength of 5 mg per vial. HG381 will be administered as IV injection.

Primary outcome measures

• Number of subjects achieving Dose-limiting toxicity (DLT) [Time frame: Up to Day 21]
• Maximum Tolerated Dose (MTD) [Time frame: Up to 12 months]
• Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [Time frame: Up to 24 months]
• Severity of AEs [Time frame: Up to 24 months]

Secondary outcome measures (6)

• Recommended Phase 2 Dose (RP2D) of HG381 [Time frame: Up to 12 months]
• Best objective response based on RECIST 1.1 [Time frame: Up to 24 months]
• HG381 concentrations in plasma following administration of HG381 alone [Time frame: Cycle 1 Days 1, Cycle 2 Days 1 and Cycle 3 Days 1: pre-infusion and at multiple time points (up to 24 hours) post-infusion (Cycle length=21 days)]
• Maximum observed concentration (Cmax) following administration of HG381 alone [Time frame: Cycle 1 Days 1, Cycle 2 Days 1 and Cycle 3 Days 1: pre-infusion and at multiple time points (up to 24 hours) post-infusion (Cycle length=21 days)]
• Area under the concentration-time curve (AUC) following administration of HG381 alone [Time frame: Cycle 1 Days 1, Cycle 2 Days 1 and Cycle 3 Days 1: pre-infusion and at multiple time points (up to 24 hours) post-infusion (Cycle length=21 days)]
• Apparent terminal phase half-life (t½) following administration of HG381 alone [Time frame: Cycle 1 Days 1, Cycle 2 Days 1 and Cycle 3 Days 1: pre-infusion and at multiple time points (up to 24 hours) post-infusion (Cycle length=21 days)]

Eligibility criteria

Inclusion criteria

• Capable of giving signed informed consent.
• Life expectancy of at least 3 months.
• Histological or cytological documentation of an advanced solid tumor，subjects with advanced/recurrent solid tumors, who have progressed on, be intolerant of, or ineligible for, all available therapies for which clinical benefit has been established.
• Measurable disease per RECIST version 1.1, there is at least one measurable lesion during the screening period.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
• Adequate organ function : Hematologic system: Hemoglobin ≥9 g/dL, Absolute neutrophil count \[ANC\] ≥1.5x10\^9/L, Platelets ≥100x10\^9/L, INR ≤ 1.5 and APTT ≤1.5 x ULN; Hepatic system: Total bilirubin ≤1.5 x ULN, ALT and AST ≤ 2.5 x ULN; Renal system: serum creatinine ≤1.5×ULN or creatinine clearance ≥50 mL/min (calculated by the Cockcroft-Gault formula); Cardiac system: left ventricular ejection fraction (LVEF) ≥50% ; QT interval (QTcF) ≤470 ms for women, and ≤450 ms for men; Endocrine system: Thyroid-stimulating hormone (TSH) is within the normal limits.
• Subjects with fertility must agree to take medically approved effective contraceptive measures during the entire trial period and at least 3 months after the last medication.

Exclusion criteria

• Chemotherapy, radiotherapy, biological therapy, endocrine therapy, immunotherapy and other anticancer therapy within 4 weeks.
• Concurrent medical condition requiring the use of other systemic immunosuppressive treatment within 4 weeks before the first dose of study treatment.
• Receipt of any live vaccine within 4 weeks of the start of study treatment.
• Receipt of unmarketed clinical trial drugs or treatments within 4 weeks of the start of study treatment.
• Receipt of surgery or interventional treatment (excluding tumor biopsy, puncture, etc.) within 4 weeks of the start of study treatment.
• History or evidence of cardiovascular and cerebrovascular diseases risk.
• Subjects with uncontrolled diabetes.
• Symptomatic central nervous system (CNS) metastases or asymptomatic CNS metastases that have required steroids within 2 weeks prior to first dose of study treatment.
• Currently or in the past suffering from malignant tumors.
• Uncontrollable pleural effusion, pericardial effusion or ascites still need to be drained frequently after appropriate intervention.
• Active or suspected autoimmune disease.
• History of idiopathic pulmonary fibrosis, interstitial lung disease, or organizing pneumonia, or evidence of active, non-infectious pneumonitis.
• Toxicity from previous treatment including: Toxicity Grade ≥3 related to prior immunotherapy and that led to study treatment discontinuation; Toxicity related to prior treatment that has not resolved to Grade ≤ 1.
• Subjects who have acute bacterial, viral or fungal infections and require systemic anti-infective treatment.
• Positive test for syphilis antibodies or human immunodeficiency virus (HIV) antibodies.
• Subjects who are allergic to test drugs and excipients.
• Women who are pregnant or breastfeeding.
• Known drug or alcohol abuse.
• Patients with mental or neurological diseases.
• Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation.
• Subjects who have a history of serious systemic disease or any other reason are not suitable to participate in this trial as judged by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• HitGen Inc. — Chengdu

Publications

• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12. PMID 30207593
• Zhu Y, An X, Zhang X, Qiao Y, Zheng T, Li X. STING: a master regulator in the cancer-immunity cycle. Mol Cancer. 2019 Nov 4;18(1):152. doi: 10.1186/s12943-019-1087-y. PMID 31679519
• Liu S, Cai X, Wu J, Cong Q, Chen X, Li T, Du F, Ren J, Wu YT, Grishin NV, Chen ZJ. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science. 2015 Mar 13;347(6227):aaa2630. doi: 10.1126/science.aaa2630. Epub 2015 Jan 29. PMID 25636800
• Barber GN. STING: infection, inflammation and cancer. Nat Rev Immunol. 2015 Dec;15(12):760-70. doi: 10.1038/nri3921. PMID 26603901
• Abe T, Barber GN. Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-kappaB activation through TBK1. J Virol. 2014 May;88(10):5328-41. doi: 10.1128/JVI.00037-14. Epub 2014 Mar 5. PMID 24600004
• Ramanjulu JM, Pesiridis GS, Yang J, Concha N, Singhaus R, Zhang SY, Tran JL, Moore P, Lehmann S, Eberl HC, Muelbaier M, Schneck JL, Clemens J, Adam M, Mehlmann J, Romano J, Morales A, Kang J, Leister L, Graybill TL, Charnley AK, Ye G, Nevins N, Behnia K, Wolf AI, Kasparcova V, Nurse K, Wang L, Puhl AC, Li Y, Klein M, Hopson CB, Guss J, Bantscheff M, Bergamini G, Reilly MA, Lian Y, Duffy KJ, Adams PMID 30405246
• Sivick KE, Desbien AL, Glickman LH, Reiner GL, Corrales L, Surh NH, Hudson TE, Vu UT, Francica BJ, Banda T, Katibah GE, Kanne DB, Leong JJ, Metchette K, Bruml JR, Ndubaku CO, McKenna JM, Feng Y, Zheng L, Bender SL, Cho CY, Leong ML, van Elsas A, Dubensky TW Jr, McWhirter SM. Magnitude of Therapeutic STING Activation Determines CD8+ T Cell-Mediated Anti-tumor Immunity. Cell Rep. 2019 Oct 15;29(3):7 PMID 31618645
• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026. PMID 19097774

Identifiers

NCT: NCT04998422 · HG381CN101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗