Overview

This is a single-center, single-arm phase Ib / II clinical trial, which was included with two phase. The main purpose of the phase Ib part was to determine the dose-limiting toxicity ( DLT ), maximum tolerated dose ( MTD ), and recommended dose ( RP2D ) of Fluzoparib combined with Dalpiciclib in patients with locally advanced or metastatic sarcoma. The phase II part is mainly to observe the efficacy and safety of Fluzoparib combined with Dalpiciclib.

Eligibility

Inclusion Criteria:1.Patients aged 12 to 75 years, male and female ; 2.Eastern Cooperative

        Oncology Group ( ECOG ) physical status score was 0-2 ; 3.Locally advanced or metastatic
        sarcomas ( including osteosarcoma, Ewing sarcoma, undifferentiated sarcoma, liposarcoma,
        leiomyosarcoma, fibrosarcoma and synovial sarcoma ) confirmed by histopathology, and at
        least one measurable lesion without local treatment ( according to RECIST v1.1, the long
        diameter of the measurable lesion mesured by spiral CT scan should be≥ 10 mm or the short
        diameter of the lymph node lesion should be ≥ 15 mm ) ; 4.Life expectancy≥ 12 weeks ; 5.The
        main organ function is basically normal and meets the program requirements :
        a)Blood examination : (without blood transfusion within 14 days before screening, without
        using granulocyte colony stimulating factor [ G-CSF ], or other methods to correct bone
        marrow suppression within 7 days ) ,Blood indicators should meet: i.hemoglobin ≥ 90 g / L ;
        ii.neutrophil count ≥ 1.5 × 109 / L ; iii.Platelet count ≥ 75 × 109 / L ; b)b. Biochemical
        examination : ( no albumin transfusion within 14 days ) indicators should meet: i.albumin ≥
        29 g / L ; ii.Alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) ≤ 2.5
        times the upper limit of normal ( ULN ) ; iii.total bilirubin ( TBIL ) ≤ 1.5 times ULN ;
        iv.Creatinine Cr ≤ 1.5 times ULN or Cr clearance > 50 mL / min; v.Urine protein < 2 +. If
        Urine protein ≥ 2 +, an 24 hours ( h ) urine protein quantification test should be taken,
        and 24h urine protein quantification < 1.0 g is allowed to include ) ; c)Coagulation
        function : activated partial thromboplastin time ( APTT ) and international normalized
        ratio ( INR ) ≤ 1.5 × ULN ( for those who regularly use anticoagulant therapy such as low
        molecular weight heparin or warfarin and INR meets the expected requirement are allowed to
        include ) ; d)Thyroid stimulating hormone ( TSH ) ≤ ULN ; If not, T3 and T4 levels should
        be examined, and only with normal T3 and T4 level is allowed to include.
        e)Echocardiography : left ventricular ejection fraction ( LVEF ) ≥ 60 %. 6.Non-surgical
        sterilization or women of childbearing age who are required to use a medically approved
        contraceptive (such as an intrauterine device, contraceptive pill or condom) during the
        study treatment period and for 6 months after the study treatment period ends; Female
        patients of childbearing age who were not surgically sterilized must have a negative serum
        or urine HCG test within 7 days prior to study enrollment; And must be non-lactation
        period; For male patients with a partner of a woman of childbearing age, effective
        contraceptive methods should be used during the trial period and within 6 months after the
        last Fluzoparib or Dalpiciclib administration.
        Understand the research procedures and methods, volunteer to participate in the experiment,
        and sign the informed consent. And fully understand the trial content, process and possible
        adverse reactions.
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        Exclusion Criteria:1.Plan to receive any other antitumor therapy during this trial;
        2.Within 4 weeks of the first administration of the drug in this study, the patient has
        received radiotherapy for sarcoma, or received compound names such as Fluzoparib,
        Dalpiciclib, drug administration or cell therapy in other clinical trials; 3.Imaging
        diagnosis showed the presence of tumor lesions in the brain; 4.Active malignancies other
        than sarcoma within 5 years or at the same time. Cured localized tumors, such as skin basal
        cell carcinoma, skin squamous cell carcinoma, superficial bladder carcinoma, prostate
        carcinoma in situ, cervical carcinoma in situ, breast carcinoma in situ, etc., could be
        included in the group.
        5.Patients with clinical symptoms of ascites requiring puncture or drainage, or patients
        who have received ascites drainage within the past 3 months, except those who only show a
        small amount of ascites without clinical symptoms on imaging; Uncontrolled or medium or
        above pleural effusion and pericardial effusion; There is evidence of abdominal gas
        accumulation that cannot be explained by puncture or recent surgical procedures 6.Have a
        history of epilepsy, or a history of seizures within 12 months prior to the first
        administration of the study drug (including a history of transient ischemic attack,
        cerebral stroke (except imaging only found ischemic focus but no corresponding clinical
        history), brain trauma with disturbance of consciousness requiring hospitalization);
        7.Previous treatment with PARP or CDK4/6 inhibitors, including but not limited to
        Fluzoparib and Dalpiciclib; 8.Allergic constitution, including severe drug allergy or drug
        allergic reaction history; Known allergies or intolerances to Fluzoparib, Dalpiciclib or
        their excipients; 9.Severe infections (CTC AE ≥grade 2), such as severe pneumonia,
        bacteremia, and infection complications requiring hospitalization, occurred within 4 weeks
        prior to the first use of the study drug; Baseline chest imaging suggests active pulmonary
        inflammation, signs and symptoms of infection within 2 weeks prior to the first use of the
        study drug, or the need for oral or intravenous use of the drug · Antibiotic therapy
        (excluding the use of prophylactic antibiotics); 10.Drugs that may affect P-gp should not
        be discontinued during the study； 11.Had use of a potent/moderate-acting drug that inhibits
        or induces the liver drug metabolizing enzyme CYP3A4 14 days prior to initial
        administration； 12.Inability to swallow, chronic diarrhea, intestinal obstruction, or other
        factors affecting drug administration and absorption; 13.A history of myelodysplastic
        syndrome (MDS)/acute myeloid leukemia (AML), or other malignancies (other than carcinoma in
        situ with complete response and malignancies determined by the investigator to be slow in
        progression) within 5 years prior to the initial administration of the study; 14.Combined
        with other viral infection (anti-HCV, anti-HIV positive, HBsAg positive) or syphilis
        infection; 15.A history of immunodeficiency (including HIV test positive, other acquired or
        congenital immunodeficiency diseases) or a history of organ transplantation; 16.A known
        history of psychotropic drug abuse, alcoholism and drug use; A concomitant disease (such as
        poorly controlled hypertension, severe diabetes, thyroid disease, and psychosis) or any
        other condition that, in the investigator's judgment, seriously endangers the patient's
        safety or affects the patient's ability to complete the study.
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