60 subjects with advanced solid tumors were received single and then multiple oral doses of SHR7390(2 cycles,each cycle 28days).

SHR7390 is provided as white, film-coated,immediate release tablets containing SHR7390 at dosage strengths of 0.125 mg and 0.5 mg. Multiple tablets of SHR7390 will be administered daily to achieve targeted doses of SHR7390: 0.25 mg-4 mg. Tablets will be orally administered with 240 ml water, once daily, 2 hours after a meal.

SHR7390

RuiHua Xu, MD, PhD

Yi Liu, PhD

This aim of study to assess the safety and tolerability of SHR7390 and to define the maximum tolerated dose (MTD) of SHR7390 in the patients with advanced solid tumors.

To evaluate the pharmacokinetics of SHR7390 in patients with advanced solid tumors.

To study the effects of food on the pharmacokinetic parameters of SHR7390. To assess the antitumor activity of SHR7390 in patients with advanced solid tumors preliminarily and recommend reasonable dosage regimen for the follow-up clinical trial.

This is an open-label, dose escalation study of repeated doses of SHR7390 in the patients with advanced solid tumors that have no targeted agent as standard of therapy.

A study cycle is defined as SHR7390 administered once daily orally for 28 days. Dose limiting toxicities (DLT) will be assessed in the first cycle of treatment. the trial is dose escalation and is designed by Accelerated Titration Designs during initial accelerated phase. when the significant toxicity or DLT is observed in any course of treatment,the accelerated titration trial terminates and subsequent cohort sizes and dose escalation are a conventional design of 3+3 patients. If one adverse event （AE） meets dose limiting toxicity (DLT) criteria at a given dose, 3 additional patients will be enrolled in this dose cohort. If 2 DLTs are determined at a given dose level, this dose will be designated as the MTD.

Additional patients will be enrolled for PK evaluations at different dose levels based on preliminary safety and tolerability. Multiple blood samples at designated time points will be collected for PK evaluations.

The safety, tolerability and AEs will be closely monitored throughout the study duration. The preliminary effectiveness and clinical benefits of SHR7390 will be evaluated as a single agent.

The evaluation of the effects of a high-fat, high-calorie meal on the single-dose pharmacokinetics (PK) of SHR7390.The design to assess food-effect is a randomized, balanced, 2-treatment(fed vs. fasted), separated by an adequate wash-out period.

Phase I Study of SHR7390 in Patients With Advanced Solid Tumors

A Phase I, Open Label, Dose Escalation Study to Evaluate the Safety, Tolerability and Pharmacokinetics of SHR7390 in Patients With Advanced Solid Tumors

to assess safety and tolerability of SHR7390 with a maximum tolerated dose (MTD) of SHR7390 in patients with advanced solid tumors

Jiangsu HengRui Medicine Co., Ltd.

Symptoms and General Pathology

All Conditions

Death

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Poly(ADP-ribose) Polymerase Inhibitors

Fluzoparib

Enzyme Inhibitors

Total 60-100 subjects with advanced solid tumors

In the two-drug combination therapy,subjects were received single oral doses of SHR7390，then accepted two drug combination therapy, SHR7390 is administered multiple daily oral doses of SHR7390 for 28 days for a treatment cycle. At the same time, SHR-1210 was given intravenously per 2 weeks at the 200mg fixed dose.

In the second study part, subjects accepted three drug combination therapy, SHR7390 is administered orally for 21 days and discontinued for 7 days in a 28-day treatment cycle,SHR3162 was administered orally twice a day for 28 days at a fixed dose of 100 mg. At the same time, SHR-1210 was given intravenously per 2 weeks at the 200mg fixed dose

SHR7390 is provided as white, film-coated,immediate release tablets containing SHR7390 at dosage strengths of 0.125 mg,0.5 mg and 2mg. Multiple tablets of SHR7390 will be administered orally to achieve targeted doses of SHR7390: 0.125 mg-4 mg. Tablets will be administered once daily or for 21 days and discontinued for 7 days with 240 ml water after 2 hours of the meal.

SHR-1210 is a humanized anti-PD1 immunoglobulin G4 (IgG4) monoclonal antibody. SHR-1210 is provided as the lyophilized powder,200 mg/vial.SHR-1210 was given with 200mg fixed dose intravenously per 2 weeks at the D1 and D15.Intravenous infusion over 30 min

SHR-1210

SHR3162 is provided as capsules containing SHR3162 at dosage strengths of 10mg,40mg and 100mg. The capsule of SHR3162 will be orally administered with 240ml water twice a day to achieve targeted doses of SHR3162 and the interval of SHR3162 capsules taken twice a day is about 12 hours.

SHR3162

The study consists of the two parts, the first one is SHR7390 combined with SHR-1210, the second one is SHR7390 combined with SHR-1210 and SHR3162. Two parts of the study are separately to assess the safety and tolerability, to define dose limiting toxicity（DLT) and maximum tolerated dose (MTD),to evaluate the pharmacokinetics ,to assess the antitumor activity in patients with advanced solid tumors preliminarily and to recommend reasonable dosage regimen of SHR7390 for the follow-up clinical trial.

This is a phase I, open-label,two parts,dose escalation/expansion clinical study.The safety,tolerance,PK and preliminary efficacy of two-drug combination and three-drug combination were evaluated respectively in the patients with advanced solid tumors that have no any targeted agents as the standard therapies.

In the first study part, subjects receiving a single dose of SHR7390 (Run-in) are observed in 7-10 days, then accepted two drug combination therapy, SHR7390 is administered once daily orally for 28 days for a treatment cycle. At the same time, SHR-1210 was given intravenously per 2 weeks at the fixed dose of 200mg.

In the second study part, subjects accepted three drug combination therapy, SHR7390 is administered orally for 21 days and discontinued for 7 days in a 28-day treatment cycle,SHR3162 was administered orally twice a day for 28 days at a fixed dose of 100 mg. At the same time, SHR-1210 was given intravenously per 2 weeks at the fixed dose of 200mg.

Dose limiting toxicities (DLT) in the first study part will be assessed during the Run-in and first cycle of treatment. the dose escalation is designed by Accelerated Titration Designs during initial accelerated phase. when the significant toxicity or DLT is observed in the Run-in and first cycle of treatment,the accelerated titration trial terminates and subsequent dose escalations are become a conventional design of 3+3 patients. If one adverse event （AE） meets dose limiting toxicity (DLT) criteria at a given dose, 3 additional patients will be enrolled in this dose cohort. If 2 DLTs are determined at a given dose level, the previous dose will be designated as the MTD.

Based on preliminary determination of RP2D and sufficient safety data in the first part of the study, the second part of three-drug combination will be carried out. the preset dose of SHR7390 includes RP2D initially determined in the first part of the study and its previous low dose level (for example, RP2D is 0.5 mg/d, while the former low dose is 0.25 mg/d). Dose escalation is a conventional design of 3+3 patients.

Additional patients will be enrolled for pharmacokinetic (PK) evaluations at different dose levels based on preliminary safety and tolerability.Each dose level can expand at least 12 subjects , of which 9-12 subjects are PK subjects. Multiple blood samples at designated time points will be collected for PK evaluations (more than 12 subjects are determined by SMC).

The safety, tolerability and AEs will be closely monitored throughout the study duration. The preliminary effectiveness and clinical benefits of two-drug combination and three-drug combination will be evaluated.

The Study of SHR7390 in Combination With SHR-1210 and SHR3162 in Patients With Advanced Solid Tumors

A Phase I, Open Label, Dose Escalation/Expansion Study to Evaluate the Safety, Tolerability and Pharmacokinetics of SHR7390 Combined With SHR-1210 and SHR3162 in Patients With Advanced Solid Tumors

A DLT is considered at AE related to study drug unless there is a clear, well-documented, alternative explanation for the toxicity. Severity of AEs are graded according to the NCI CTCAE 4.03 for the study, the occurrence of the following drug related AEs during the single dose and the first cycle(35-38 days,two-drug combination) or the first cycle (28 days, three-drug combination) will be considered a DLT by the investigator and SMC.

MTD is the highest dose of SHR7390 in subjects with DLT less than 33.3% during the DLT observation in the dose escalation of two-drug combination.

Assessment of the incidence and severity of treatment-related AEs in all subjects who received at least 1 dose of SHR7390,SHR-1210 and SHR3162.

Pharmacokinetics profile of SHR7390:Time to peak (Tmax) of plasma concentration

Pharmacokinetics profile of SHR7390: Maximum plasma concentration (Cmax)

Pharmacokinetics profile of SHR7390: Halflife (T1/2)

Pharmacokinetics profile of SHR7390: Clearance/ bioavailability (CL/F)

Pharmacokinetics profile of SHR7390: apparent volume of distribution/bioavailability (Vd/F)

Pharmacokinetics profile of SHR7390: Area under curve (AUC)

Pharmacokinetics profile of SHR7390: Accumulation index (Rac)

Pharmacokinetics profile of SHR7390:blood concentration

Pharmacokinetics profile of SHR7390:plasma concentration

Pharmacokinetics profile of SHR3162: plasma concentration

Pharmacokinetics profile of SHR-1210: serum concentration

Subjects will be assessed using RECIST v1.1. The primary aim is to demonstrate clinically meaningful improvement in ORR.

When the dose escalation is accomplished, RP2D will be identified by the characterization of safety.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase I Study of SHR7390 in Patients With Advanced Solid Tumors	NCT02968485	Solid Tumor	SHR7390	18 Years - 70 Years	Jiangsu HengRui Medicine Co., Ltd.
Phase I Study of SHR7390 in Patients With Advanced Solid Tumors	NCT02968485	Solid Tumor	SHR7390	18 Years - 70 Years	Jiangsu HengRui Medicine Co., Ltd.
The Study of SHR7390 in Combination With SHR-1210 and SHR3162 in Patients With Advanced Solid Tumors	NCT03182673	Solid Tumor	SHR7390 SHR-1210 SHR3162	18 Years - 70 Years	Jiangsu HengRui Medicine Co., Ltd.
The Study of SHR7390 in Combination With SHR-1210 and SHR3162 in Patients With Advanced Solid Tumors	NCT03182673	Solid Tumor	SHR7390 SHR-1210 SHR3162	18 Years - 70 Years	Jiangsu HengRui Medicine Co., Ltd.

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