Overview

The primary objective of this study is to evaluate the safety and tolerability of TYK-00540, with dose-escalation stage and dose-expansion stage.

Eligibility

Inclusion Criteria:

1. Age ≥18 years.
2. In the Single-agent escalation phase, subjects should fulfill the following criterion at Screening: Histologically or cytologically confirmed locally advanced/metastatic solid tumors that do not have, failed or intolerated standard of care (SOC).In the single-agent expansion phase, subjects should fulfill the following criteria at Screening: Cohort 1: Histologically or cytologically confirmed platinum-resistant HGSOC (Platinum-resistant: responds at first to treatment with drugs that contain platinum, but then comes back within 6 months period; only female subjects will be enrolled). Cohort 2: Histologically or cytologically confirmed locally advanced/metastatic TNBC who have received two lines of standard of care (SOC) regimens, including:
   1. Any prior treatment can be considered as one of the SOC regimens if executed on patients with the receptor status of triple-negative no matter the previous pathological type;
   2. For patients whose treatment have been changed due to intolerability to toxicity, the intolerable regimens can be included as one of the prior standards of care regimens;
   3. For neoadjuvant and/or adjuvant chemotherapy, if relapse or disease progression to locally advanced or metastatic disease occurs during treatment or within 12 months after discontinuation of treatment (at least 2 cycles have been completed), it will be considered as one of the SOC regimens;
   4. For patients with documented germline BRCA1/BRCA2 mutations, if they have been treated with an approved PARP inhibitor, then the PARP inhibitor can be considered as one of the 2 lines of prior SOC regimens required.

             In the combination-agent escalation and combination expansion phase (Cohort 3),
             subjects should fulfill the following criteria at Screening: ER+/HER2-breast cancer
             with who have relapsed or progressed after treatment with CDK4/6 inhibitors (no prior
             treatment of fulvestrant or other SERDs, SERCA; no contraindications to the use of
             fulvestrant; for locally advanced or metastatic disease stages, the number of
             chemotherapy lines≤ 1). Note: Histologically-confirmed breast carcinoma expressing
             positive ER (≥1% tumor cells expressing ER as positive on IHC staining, recommended by
             ASCO/CAP Guideline Update 2020. For the purposes of the expansion study, only ER+ IHC
             staining ≥10% will be considered ER+ in this cohort. Negative HER2 is defined as IHC 0
             or 1+, or IHC 2+ but confirmed by the negative ISH, recommended by ASCO/CAP Guideline
             2018.
          3. Subjects in the escalation phase should have measurable or evaluable lesions at
             baseline; Measurable lesions required in the expansion phase (RECIST 1.1).
          4. ECOG performance status is 0 to 1 and there is no deterioration in the 2 weeks prior
             to the first dose.
          5. Life expectancy of at least 3 months.
          6. Adequate organ functions, defined as: ALT or AST ≤ 2.5×the upper limit of normal (ULN)
             or ≤ 5 ×ULN with documented liver involvement (such as liver metastasis or a primary
             biliary tumor) and Total bilirubin ≤ 1.5 ×ULN (subjects with Gilbert's Disease may be
             enrolled with Sponsor approval); Absolute neutrophil count (ANC) ≥ 1.5×109/L, Platelet
             count ≥ 80 ×109/L and Hemoglobin (Hb) ≥ 9 mg/dL, not requiring growth factor and
             transfusion support for at least 14 days prior to screening; Adequate renal function,
             creatinine clearance ≥ 60 mL/min (According to the Cockcroft and Gault formula).
             Coagulation function: International normalized ratio (INR) ≤ 1.5 ×ULN and activated
             partial thromboplastin time (APTT) ≤ 1.5 × ULN. Left ventricular ejection fraction
             (LVEF) ≥50%.
          7. Willing and able to provide written informed consent approved by institutional review
             board (IRB) or independent ethics committee (IEC).
          8. Willingness of men and women of reproductive potential to observe conventional and
             effective birth control for the duration of treatment and 6 months following the last
             dose of study treatment; this may include barrier methods such as condom or diaphragm
             with spermicidal gel.
        Exclusion Criteria:
          1. Known allergy to any excipients of TYK-00540 tablets (for combination-agent escalation
             phase and combination expansion phase, known contraindications to fulvestrant should
             also be considered).
          2. Subjects with prior therapy of: Systemic anti-tumor treatment such as standard
             chemotherapy, macromolecular targeted drugs and immunological drug therapy within 28
             days prior to the first dose; reception of endocrine therapy, small molecule targeted
             drugs and oral fluorouracil within 14 days before the first dose; reception of
             nitrosoureas and mitomycin within 6 weeks prior to the first dose Major surgery
             (except minor surgeries such as appendicitis and tumor biopsy) within 4 weeks prior to
             the planned start of TYK-00540. Subjects who have taken proton pump inhibitors (PPIs)
             within 7 days prior to the first dose of TYK-00540, or require continuation of therapy
             during the study. Subjects who were receiving and need to continue treatment with
             medications known to prolong the QTc interval or potentially cause Torsade de pointe
             ventricular tachycardia during the treatment. Participation in other clinical trials
             (excluding non-interventional drug clinical trials) within 28 days prior to the first
             dose; Prior allogeneic bone marrow transplantation.
          3. Subjects with other malignancies or a history of other malignant tumors, except for
             cured basal cell carcinoma of the skin or squamous cell carcinoma, carcinoma in situ
             of the cervix, papillary thyroid cancer, carcinoma in situ of the breast duct, or
             other malignant tumors that have survived for more than 5 years.
          4. Any unresolved toxicities from prior therapy greater than NCI CTCAE Grade 1 at the
             time of starting study treatment with the exception of Grade 2 alopecia and prior
             platinum-therapy related neuropathy.
          5. Patients with primary central nervous system (CNS) tumors or CNS metastases that have
             failed local therapy. Patients who are asymptomatic or clinically stable and do not
             require steroids and other treatments for CNS metastases ≥ 28 days and are
             radiographically stable during the screening period may be enrolled.
          6. The subject has symptoms of spinal cord compression due to the tumor.
          7. Uncontrollable or poorly controlled effusion of chest, abdomen, pelvis, or
             pericardium.
          8. Any baseline 12-lead ECG abnormalities which may impair the safety of subjects (such
             as baseline QTc interval ≥ 470 msec, complete left bundle branch block (LBBB), acute
             or unspecified myocardial infarction, active myocardial ischemic ST-T segment changes
             with clinical significance, second- or third-degree atrioventricular (AV) block, or
             severe bradycardia or tachycardia).
          9. Have had any of the following in the past 6 months: myocardial infarction, long QT
             syndrome, torsades de pointes, arrhythmias (double-bundle branch block, such as right
             bundle branch block (RBBB) with left anterior or posterior branch block, third-degree
             atrioventricular block) , unstable angina, coronary/peripheral artery bypass grafting,
             symptomatic chronic heart failure (CHF), Grade III or IV cardiac function as defined
             by the New York Heart Association, cerebrovascular accident, transient cerebral
             ischemia, symptomatic pulmonary embolism, and/or other clinically significant
             thromboembolic disease episodes. NCI CTCAE ≥ Grade 2 persistent arrhythmia, any grade
             of atrial fibrillation (asymptomatic uncomplicated atrial fibrillation was required to
             be of ≥Grade 2). Enrollment of patients who have an implanted cardiac rhythm
             device/pacemaker with QTcF > 470 msec needs to be discussed by the investigators and
             sponsor.
         10. Subjects with any other disease or medical condition that is unstable or could affect
             their safety or study compliance, any serious or uncontrolled systemic disease,
             including uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or
             diastolic blood pressure > 100 mmHg). Uncontrolled diabetes, active bleeding, ocular
             lesions, and other serious mental, neurological, cardiovascular or respiratory system
             diseases.
         11. Known active infections, including human immunodeficiency virus (HIV), hepatitis B
             virus (HBV), and hepatitis C virus (HCV) infection, except for asymptomatic chronic
             HBV or HCV carriers. Active HBV, HCV, or HIV infections are defined as:
               1. Hepatitis B surface antigen (HBsAg) positive and HBV-DNA ≥ 2000 cps/mL or 500
                  IU/mL; HBsAg-negative, anti-HBc-positive patients are at high risk of HBV
                  reactivation who require suppressive antiviral therapy prior to initiation of
                  cancer therapy;
               2. Anti-HCV antibody positive and HCV-RNA > upper normal limit defined by sites;
               3. Anti-HIV antibody positive with uncontrolled opportunistic infections; anti-HIV
                  antibody positive with CD4+ count< 350 cells/uL that requires HIV therapy prior
                  to the cancer treatment; other conditions allowing concurrent ART but the therapy
                  not tolerated and that the toxicities confused with investigational drug
                  toxicities.
         12. History of positively diagnosed interstitial lung disease or interstitial pneumonia
             (ILD), drug-induced ILD, or radiation pneumonitis requiring hormone therapy, or any
             evidence of active ILD (e.g., acute onset or progressive pneumonitis/pulmonary
             fibrosis at baseline), or the pulmonary symptoms which are not suitable for enrollment
             in the investigator's judgment or the high-risk factors which may cause interstitial
             lung disease and are not suitable for enrollment.
         13. Clinically significant gastrointestinal abnormalities at screening that may affect the
             intake, transport or absorption of drugs (such as dysphagia, uncontrollable nausea and
             vomiting, active gastric ulcer, ulcerative colitis, Crohn's disease, chronic diarrhea,
             intestinal obstruction, gastric diseases requiring long-term administration of PPIs
             without a cure, etc.).
         14. Clinically significant hypercoagulability.
         15. Pregnant and lactating women.
         16. Subjects who, in the opinion of the investigator, would not be suitable for
             participation in this study (e.g., not in line with the treatment of the subject's
             best benefit, subject compliance, etc.).