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

NCT03182673 | Terminated Phase 1

• 1 other identifier: SHR7390-I-102-AST
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Solid Tumor

Keywords

advanced solid tumor; Protein Kinase MEK inhibitor (MEKi); Programmed Death 1(PD-1); Safety; Pharmacokinetics; PARP inhibitor

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity(DLT)

  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.

  up to 24 months

Secondary Outcomes (14)

• The assessment of Treatment-related Adverse Events

  Up to 24 months

• Time to peak (Tmax) of plasma concentration

  up to 24 months

• Maximum plasma concentration (Cmax)

  up to 24 months

• Halflife (T1/2)

  up to 24 months

• Clearance/ bioavailability (CL/F)

  up to 24 months

Study Arms (1)

SHR7390, SHR-1210 and SHR3162

EXPERIMENTAL

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

Drug: SHR7390; Biological: SHR-1210; Drug: SHR3162

Interventions

SHR7390 DRUG

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.

Also known as: MEKi

SHR7390, SHR-1210 and SHR3162

SHR-1210 BIOLOGICAL

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

Also known as: PD-1

SHR7390, SHR-1210 and SHR3162

SHR3162 DRUG

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.

Also known as: parp inhibitor

SHR7390, SHR-1210 and SHR3162

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• To be included to participate in this study each patient must:
• years of age, both male and female;
• The invalid standard treatment or non standard and effective treatment in patients with advanced solid tumors diagnosed by pathology;
• （1) in the phase of dose escalation , the subjects with RAS or BRAF mutation status and microsatellite stability （MSS）are not restricted.
• （2）in the phase of dose expansion，the subjects with RAS or BRAF mutations and microsatellite stability (MSS) are included necessarily.
• （3) the subjects included in the phase of dose expansion must have at least one measurable target lesion with RECIST V 1.1.
• (4) If they in the phase of dose expansion are unable to provide the results of previous RAS/BRAF mutation and microsatellite stability,subjects must provide previous cancer tissues（paraffin blocks or pathological 8-10 white sections）, or fresh biopsy specimens.
• \. The Eastern Cooperative Oncology Group （ECOG） General status (performance status, PS) of 0-1;
• \. The expected lifetime ≥ 3 months;
• \. The organ function must meet the following requirements:
• Adequate bone marrow reserve: including neutrophil absolute count,platelets and hemoglobin;
• Liver: serum albumin ≥ 2.8 g/dl; bilirubin≤1.5 upper limit of normal value (ULN), Alanine aminotransferase（ALT）and aspartate aminotransferase（AST）≤ 2.5 upper limit of normal value (ULN),if there is liver metastasis, the ALT or AST≤5xULN;
• Kidneys: creatinine clearance ≥ 50 mL/min (Cockcroft-Gault of the standard formula）；
• Heart: left ventricular ejection fraction ≥ 50%; normal Electrocardiograph (ECG) and corrected QT interval（QTc）;male QTc\<450ms，female QTc\<470ms
• \. The lesion of the patients caused by other treatments has been restored(≤1 grade，except alopecia and other adverse events that the investigators judged to be tolerable）。The time interval between previous treatment and the first use of study drugs：nitrosourea or mitomycin\> 6 weeks; cytotoxic drugs, monoclonal antibodies, radiotherapy or surgery\> 4 weeks; TKI targeted drugs\> 2 weeks;endocrine therapy\> 1 week；

You may not qualify if:

• Previous treatment with any other tumor immune checkpoint inhibitors within 2 months before the first use of study drugs；previous treatment with other MEK inhibitors or PARP inhibitors (the previous treatment of PARP inhibitors is only excluded in the second part of the study).
• Use of other investigational anti-cancer drugs or the termination of the investigational drugs within the last four weeks.
• The subjects had active autoimmune diseases, a history of immunodeficiency disease and autoimmune diseases, or a history of disease or syndrome with systemic steroid hormones or immunosuppressive drugs(such as asthma, idiopathic pulmonary fibrosis, institutional pneumonia, bronchiolitis obliterans, and drug pneumonia,idiopathic pneumonia or interstitial pneumonia, colitis, hepatitis, pituitary inflammation, vasculitis, nephritis,hyperthyroidism, hypothyroidism, but not limited to these diseases or syndromes），or other acquired (HIV) and congenital immunodeficiency diseases, or a history of organ transplantation (including allogeneic bone marrow transplantation).
• Known severe hypersensitivity or other hypersensitivity to chimeric or humanized antibodies or fusion proteins; known to be allergic or hypersensitive to components of SHR-1210，SHR7390 or SHR3162.
• The subjects were known to have tumor metastases of central nervous system or meningeal metastases, or a history of primary tumors of CNS.
• Presence of a factor that influences the oral drug (such as inability to swallow) or presence of active gastrointestinal disease or other diseases that will interfere significantly with the absorption, distribution, metabolism, or excretion of drug.
• History of the retinopathy or the sensory retinal detachment. As assessed by ophthalmologist, presence of the risk factors of study treatment that may cause retinal vein thrombosis/occlusion (RVO), central serous chorioretinopathy (CSCR),or neovascular and macular degeneration.
• The intraocular pressure \> 21mmHg or glaucoma was diagnosed within 4 weeks
• The evidence of severe or uncontrollable pleural effusion, peritoneal effusion or pericardial effusion. The clinical treatment is required, such as periodic drainage.
• The evidence of severe or uncontrolled systemic diseases (e.g. chronic lung, liver, kidney, or heart diseases).
• Unstable angina pectoris or new angina pectoris within recent three months.Presence of arrhythmia, myocardial ischemia with long-term drug treatment.III-IV stage heart failure as defined by the New York Heart Association (NYHA). Presence of acute myocardial infarction events and congestive heart failure within the first six months before screening.
• Medical treatment for an acute stage of infection or active TB.
• Hepatitis B virus（HBV) or hepatitis C virus (HCV) infection stage with abnormal liver function.
• Pregnant or lactating women or intending to become pregnant during the study period.
• Living attenuated vaccines within one months of the initial use of the drug, or a living attenuated vaccine is expected during the study period.

Sponsors & Collaborators

• Jiangsu HengRui Medicine Co., Ltd.: lead

Study Sites (1)

The Cancer Center,Sun Yat-sen University

Guangzhou, Guangdong, 510060, China

Location

MeSH Terms

Interventions

camrelizumab; fluzoparib; Poly(ADP-ribose) Polymerase Inhibitors

Intervention Hierarchy (Ancestors)

Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Antineoplastic Agents; Therapeutic Uses

Study Officials

• RuiHua Xu, MD, PhD

  The Cancer Center,Sun Yat-sen University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: SHR7390,SHR-1210 and SHR3162

Study Record Dates

• First Submitted: June 7, 2017
• First Posted: June 9, 2017
• Study Start: July 24, 2017
• Primary Completion: June 12, 2019
• Study Completion: June 12, 2019
• Last Updated: September 1, 2022

Record last verified: 2018-02

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)