Advanced Tumors, Erdheim-Chester Disease, Melanoma, Non-Small-Cell Lung Cancer, Other RAS/RAF/MEK/ERK Mutated Tumors
Conditions
Keywords
Melanoma, Non-Small-Cell Lung Cancer, Erdheim-Chester Disease, MAPK pathway, ERK1, ERK2
Brief summary
This is a First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, Tolerability and Pharmacokinetics of HH2710 in Patients with Advanced Tumors, composed of a Phase I dose escalation and dose expansion stage and a Phase II dose extension stage.
Detailed description
HH2710 is developed by Shanghai Haihe Pharmaceutical Co., Ltd. HH2710 is a highly potent, selective, reversible, ATP-competitive ERK1/2 inhibitor. This is a first-in-human study of HH2710 and is designed as an open-label, multicenter, Phase I/II study which is composed of a Phase I dose escalation and dose expansion stage and a Phase II dose extension stage.
Interventions
DRUGHH2710
HH2710 is a small molecule that potently inhibits both ERK1 and ERK2 protein kinases in the nanomolar range. The kinase selectivity assessment towards a panel of over 400 protein kinases showed that HH2710 barely inhibited other kinases at a concentration up to 1 μM, except the substantial inhibition against ERK1 (MAPK1), ERK2 (MAPK2) and the MAPK pathway upstream kinases MEK and RAF proteins.
Sponsors
Haihe Biopharma Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provide signed and dated informed consent prior to initiation of any study-related procedures. 2. Male or female patients aged ≥ 18 years. 3. Phase I dose escalation stage: Patients who have been diagnosed with histologically or cytological documented, unresectable/metastatic tumors that are refractory or intolerant to standard therapy or for whom no curative standard therapy exists. \- For LCH/ECD: Eligible patients must have multifocal disease and the diagnosis must be confirmed by pathological evaluation of the affected tissue. 4. Phase I expansion stage and Phase II stage: Histologically or cytologically documented unresectable/metastatic tumors with evidence of genetic mutations affecting MAPK pathway is required. Patients with a BRAF V600 mutation must have progressed on or after standard therapy, including BRAF and/or MEK inhibitors (≤3 lines). Patients entering the Phase 2 portion of the trial will be enrolled in Cohorts 1-4 depending upon their tumor type. * Cohort 1: Patients with BRAF/NRAS (mutation sites as follows: NRAS G13V, NRAS Q61, BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated melanoma; * Cohort 2: Patients with BRAF/NRAS (mutation sites as follows: NRAS G13V, NRAS Q61, BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated non-small cell lung cancer; * Cohort 3: Patients with BRAF V600 mutated Langerhans Cell Histiocytosis Syndrome (LCH)/ Erdheim-Chester disease (ECD); * For LCH/ECD: Eligible patients must have multifocal disease and the diagnosis must be confirmed by pathological evaluation of the affected tissue. * Cohort 4: Patients with RAS/RAF/MEK/ERK mutated tumor types that are not included in other cohorts. 5. Patients in the Phase I dose escalation portion of the trial may have measurable (per RECIST v1.1) or evaluable disease. Patients in the Phase I expansion and Phase II portions of the trial must have measurable disease per RECIST v1.1. 6. Eastern Cooperative Oncology Group (ECOG) performance status≤1. 7. Predicted life expectancy ≥ 3 months; 8. Adequate renal function defined as a creatinine clearance ≥ 60 mL/min; 9. Adequate hepatic function \[total bilirubin ≤ 1.5 x UNL; AST (aspartate aminotransferase) and ALT (alanine aminotransferase) ≤ 3 x UNL or ≤ 5 x UNL if due to liver involvement by tumor\]; 10. Adequate cardiac function, \> institutional lower limit of normal e.g., left ventricular ejection fraction (LVEF) of ≥ 50% as assessed by ultrasound/echocardiography (ECHO) or multi-gated acquisition (MUGA) ; corrected QT interval (QTcF) \< 460 ms (male patients), \< 470 ms (female patients) (using QTc Fridericia's formula. 11. Adequate bone marrow function, patients must not have required blood transfusion or growth factor support ≤ 7 days before sample collection for the following ： • Absolute neutrophil count ≥ 1.5 × 109/L; • Hemoglobin ≥ 9 g/dL; • Platelet count ≥100 × 109/L; • International normalized ratio (INR) ≤ 1.5; • Activated partial prothrombin time (APTT) ≤ 1.5 × ULN; 12. Willing and able to participate in the trial and comply with all study requirements;
Exclusion criteria
1. Gastrointestinal condition which could impair absorption of study medication; 2. Congenital long QT syndrome, or any known history of torsade de pointes (TdP), or family history of unexplained sudden death; 3. Clinically uncontrolled hypertension (after standard antihypertensive treatment, systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg); 4. Undergone a bone marrow or solid organ transplant; 5. Any toxicities from prior treatment that have not recovered to ≤ CTCAE Grade 1 before the start of study drug, with the exception of hair loss or fatigue; 6. Patients who have previously participated in clinical trials of ERK inhibitors drug; 7. Allergic to similar drugs or their excipients; 8. HIV (human immunodeficiency virus) infection, active hepatitis B or hepatitis C patients (HBsAg positive patients also detected HBV (hepatitis B virus) DNA ≥ 103 copies or ≥ 200 IU/ml; HCV antibody test results are positive, and HCV (hepatitis C virus) RNA PCR test results are positive); 9. Uncontrolled or severe intercurrent medical condition: * Unstable angina pectoris ≤3 months prior to starting study drug; * Acute myocardial infarction ≤3 months prior to starting study drug; 10. Symptomatic CNS metastases that are neurologically unstable or requiring increasing doses of steroids to control CNS disease. Note: Controlled CNS metastases are allowed. Radiotherapy or surgery for CNS metastases must have been completed \>2 weeks prior to study entry. No new neurologic deficits on clinical examination and no new findings on CNS imaging are permitted. Steroid use for management of CNS metastases must be at a stable dose for two weeks preceding study entry; 11. Any cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic or immunotherapy, Chinese medicine/Chinese patent medicine with anti-tumor effect, etc.) within 28 days or 5 half-lives, whichever is shorter; 12. Major surgery within 4 weeks prior to first dose; 13. Any use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of HH2710; 14. Pregnant or breast-feeding women; 15. Severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc. * Severe infections within 4 weeks prior to the first dose, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia. * Received therapeutic oral or IV antibiotics within 2 weeks prior to the first dose of study drug. 16. Any important or severe medical illness or abnormal laboratory finding that would increase the risk of participating in this study; 17. A history or current evidence/risk of retinal vein occlusion, central serous retinopathy or choroidneovascularization (CNV) ; 18. Concurrent therapy with any other investigational agent; 19. Concomitant malignancies or previous malignancies with less than 2 years disease-free interval at the time of enrollment; (But basal cell carcinoma skin cancer, cervical CIS(carcinoma in situ), CIS of the breast, localized or low Gleason grade prostate cancer, and \< T2 bladder cancer can be included); 20. Current treatment with agents including vitamins, supplements, and herbal supplements that are metabolized solely through CYP3A4; 21. Severe chronic obstructive pulmonary disease, severe asthma, pneumoconiosis, asbestosis and other occupational lung diseases. 22. A history of acute or chronic pancreatitis, surgery of the pancreas, or any risk factors that may increase the risk of pancreatitis; 23. Contraception: Patients who do not meet the following conditions will be excluded, - For women: Negative pregnancy test for females of child-bearing potential; must be surgically sterile, postmenopausal (defined as no menstrual cycle for at least 12 consecutive months), or compliant with an acceptable contraceptive regimen (2 highly effective forms, such as oral contraceptives, condom with spermicide, etc.) during and for 6 months after the treatment period. Abstinence is not considered an adequate contraceptive regimen; - For men: Must be surgically sterile, or compliant with a contraceptive regimen (as above) during and for a minimum of 6 months after the treatment period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MTD (Maximum Tolerated Dose) | Up to 1 cycle (21 days) | MTD estimation: After the escalation is completed, select the MTD based on the isotonic regression. Specifically, select the MTD for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, select the higher dose level when the isotonic estimate is lower than the target toxicity rate and select the lower dose level when the isotonic estimate is greater than or equal to the target toxicity rate. |
| Number of Participants Who Experienced DLT (Dose Limiting Toxicities) | Up to 1 cycle (21 days) | DLT is defined as: any toxicity meeting the specified criteria and considered at least possibly related to HH2710 (i.e., any toxicity for which a clear alternative etiology such as disease progression has not been identified) should be considered a DLT per National Cancer Institute Common Terminology Criteria for Adverse events (NCI-CTCAE V5.0) standard, which met any of the following, NCI-CTCAE V5.0 will be used for all grading, and compliance of 80% (i.e. 17 of 21 days) in Cycle 1 is required for a patient to be included in the DLT evaluation. For the purpose of dose-escalation decisions, DLTs will be considered and included in the BOIN. |
| Tumor Objective Response Rate (ORR) | Up to 1 cycle (21 days) | ORR=CR+PR. ORR was defined as the percentage of patients who had at least one confirmed response of CR or PR defined by RECIST version 1.1 prior to any evidence of progression, and was calculated and summarized by the treatment group, along with the 95% confidence interval (CI) calculated by the Clopper-Pearson method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Measures -Plasma Elimination Half-life (t1/2) | Single dose, C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h(if available),C1D2, pre-dose(if available) | Terminal half-life, defined as 0.693 (ln2) divided by Lambda z. And t1/2，Lambda z (λz), Vz/F, are only applicable for single dose administration. |
| Pharmacokinetic Measures - Plasma Clearance Rate Constant, Lambda z (λz) | Single dose, C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h(if available),C1D2, pre-dose(if available) | Terminal phase rate constant, determined by linear regression of at least 3 points on the terminal phase of the log-linear plasma concentration-time curve. The correlation coefficient (r2) for the goodness of the fit of the regression line through the data points has to be 0.85 or higher for the value to be considered reliable. If the WinNonlin data points are not on the linear portion of the terminal slope, the data points will be selected manually prior to calculation of Lambda\_z. And t1/2，Lambda z (λz), Vz/F，these 3 PK parameters are only applicable for single dose administration. |
| Pharmacokinetic Measures - Peak Time (Tmax) | C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose. | Measure of time to reach maximum (peak) plasma concentration(s) |
| Pharmacokinetic Measures - Apparent Volume of Distribution (Vz/F) | Single dose, C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h(if available),C1D2, pre-dose(if available) | The apparent volume of distribution during terminal phase (associated with λz)(volume). And t1/2，Lambda z (λz), Vz/F，these 3 PK parameters are only applicable for single dose administration. |
| Pharmacokinetic Measures - Apparent Clearance (CL/F) | C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h ;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose. | Measure apparent total clearance(s) from plasma after oral |
| Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose. | Measure the maximum (peak) plasma concentration(s) |
| Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose. | Measure the variation of concentration in blood plasma as a function of time |
Countries
China, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HH2710 25mg BID administered orally，25mg QD at C1D1, then 25mg BID from C1D2 (21 days/cycle. | 3 |
| HH2710 50mg BID administered orally，50mg BID (21 days/cycle) | 3 |
| HH2710 100mg BID administered orally，100mg BID(21 days/cycle)。 | 4 |
| HH2710 200mg BID administered orally，200mg BID(21 days/cycle)。 | 7 |
| HH2710 300mg QD administered orally，300mg QD (21 days/cycle) | 4 |
| HH2710 400mg QD administered orally，400mg QD (21 days/cycle) | 4 |
| HH2710 600mg QD administered orally，600mg QD (21 days/cycle) | 8 |
| HH2710 800mg QD administered orally，800mg QD (21 days/cycle) | 4 |
| Total | 37 |
Baseline characteristics
| Characteristic | HH2710 300mg QD | HH2710 600mg QD | HH2710 800mg QD | Total | HH2710 25mg BID | HH2710 50mg BID | HH2710 100mg BID | HH2710 200mg BID | HH2710 400mg QD |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 3 Participants | 2 Participants | 11 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 5 Participants | 2 Participants | 26 Participants | 3 Participants | 2 Participants | 3 Participants | 5 Participants | 2 Participants |
| Age, Continuous | 55 years | 62 years | 54 years | 57 years | 53 years | 51 years | 55 years | 57 years | 63 years |
| BMI | 31.58 kg/m2 STANDARD_DEVIATION 10.449 | 24.20 kg/m2 STANDARD_DEVIATION 5.182 | 25.58 kg/m2 STANDARD_DEVIATION 1.193 | 25.61 kg/m2 STANDARD_DEVIATION 5.705 | 26.57 kg/m2 STANDARD_DEVIATION 8.693 | 22.80 kg/m2 STANDARD_DEVIATION 5.237 | 26.38 kg/m2 STANDARD_DEVIATION 4.597 | 24.80 kg/m2 STANDARD_DEVIATION 2.749 | 24.53 kg/m2 STANDARD_DEVIATION 6.856 |
| ECOG Performance Status 0 | 0 Participants | 2 Participants | 1 Participants | 6 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| ECOG Performance Status 1 | 4 Participants | 6 Participants | 3 Participants | 31 Participants | 2 Participants | 3 Participants | 3 Participants | 7 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 7 Participants | 4 Participants | 36 Participants | 3 Participants | 3 Participants | 4 Participants | 7 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 168.05 cm | 167.50 cm | 167.75 cm | 167.40 cm | 170.10 cm | 173.40 cm | 173.30 cm | 161.40 cm | 161.90 cm |
| Location of metastases at baseline Adrenal | 0 sites | 0 sites | 0 sites | 1 sites | 1 sites | 0 sites | 0 sites | 0 sites | 0 sites |
| Location of metastases at baseline Axillary Lymph Nodes | 0 sites | 1 sites | 1 sites | 5 sites | 0 sites | 0 sites | 1 sites | 1 sites | 1 sites |
| Location of metastases at baseline Bladder | 0 sites | 1 sites | 0 sites | 2 sites | 0 sites | 0 sites | 0 sites | 1 sites | 0 sites |
| Location of metastases at baseline Bone | 0 sites | 3 sites | 1 sites | 10 sites | 1 sites | 1 sites | 1 sites | 2 sites | 1 sites |
| Location of metastases at baseline Bone, Lumbar Vertebrae | 0 sites | 1 sites | 0 sites | 1 sites | 0 sites | 0 sites | 0 sites | 0 sites | 0 sites |
| Location of metastases at baseline Bone, Sacrum | 0 sites | 1 sites | 0 sites | 2 sites | 0 sites | 1 sites | 0 sites | 0 sites | 0 sites |
| Location of metastases at baseline Brain | 0 sites | 1 sites | 0 sites | 3 sites | 0 sites | 0 sites | 0 sites | 2 sites | 0 sites |
| Location of metastases at baseline Cervical Lymph Node | 0 sites | 1 sites | 0 sites | 4 sites | 0 sites | 0 sites | 0 sites | 3 sites | 0 sites |
| Location of metastases at baseline Colon | 0 sites | 0 sites | 0 sites | 1 sites | 1 sites | 0 sites | 0 sites | 0 sites | 0 sites |
| Location of metastases at baseline Kidney | 0 sites | 1 sites | 1 sites | 3 sites | 1 sites | 0 sites | 0 sites | 0 sites | 0 sites |
| Location of metastases at baseline Liver | 4 sites | 5 sites | 3 sites | 26 sites | 3 sites | 2 sites | 2 sites | 4 sites | 3 sites |
| Location of metastases at baseline Lung | 3 sites | 7 sites | 4 sites | 25 sites | 0 sites | 3 sites | 2 sites | 5 sites | 1 sites |
| Location of metastases at baseline Meninges | 0 sites | 0 sites | 0 sites | 1 sites | 0 sites | 0 sites | 0 sites | 1 sites | 0 sites |
| Location of metastases at baseline Omentum | 0 sites | 0 sites | 0 sites | 1 sites | 0 sites | 0 sites | 0 sites | 0 sites | 1 sites |
| Location of metastases at baseline Other | 1 sites | 3 sites | 3 sites | 24 sites | 3 sites | 2 sites | 4 sites | 6 sites | 2 sites |
| Location of metastases at baseline Pancreas | 0 sites | 0 sites | 0 sites | 1 sites | 0 sites | 0 sites | 0 sites | 0 sites | 1 sites |
| Location of metastases at baseline Pericardial Effusion (Malignant) | 0 sites | 1 sites | 0 sites | 1 sites | 0 sites | 0 sites | 0 sites | 0 sites | 0 sites |
| Location of metastases at baseline Peritoneum | 1 sites | 0 sites | 0 sites | 5 sites | 0 sites | 0 sites | 0 sites | 1 sites | 3 sites |
| Location of metastases at baseline Pleura | 0 sites | 1 sites | 1 sites | 4 sites | 0 sites | 0 sites | 0 sites | 2 sites | 0 sites |
| Location of metastases at baseline Pleural Effusion (Malignant) | 0 sites | 0 sites | 0 sites | 1 sites | 0 sites | 0 sites | 0 sites | 1 sites | 0 sites |
| Location of metastases at baseline Spleen | 0 sites | 0 sites | 1 sites | 2 sites | 0 sites | 1 sites | 0 sites | 0 sites | 0 sites |
| Location of metastases at baseline Stomach | 0 sites | 0 sites | 0 sites | 1 sites | 0 sites | 0 sites | 0 sites | 0 sites | 1 sites |
| Location of metastases at baseline Thoracic Lymph Nodes | 0 sites | 0 sites | 0 sites | 2 sites | 0 sites | 0 sites | 1 sites | 1 sites | 0 sites |
| Number of metastases at baseline 1 | 2 Participants | 1 Participants | 1 Participants | 6 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Number of metastases at baseline 2 | 1 Participants | 1 Participants | 0 Participants | 7 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 2 Participants |
| Number of metastases at baseline 3 | 1 Participants | 0 Participants | 1 Participants | 6 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of metastases at baseline >3 | 0 Participants | 6 Participants | 2 Participants | 13 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants |
| Number of metastases at baseline Missing | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 0 Participants |
| Number of prior lines or regimens of therapy Adjuvant | 1 number of lines or regimens | 3 number of lines or regimens | 1 number of lines or regimens | 8 number of lines or regimens | 0 number of lines or regimens | 0 number of lines or regimens | 0 number of lines or regimens | 3 number of lines or regimens | 0 number of lines or regimens |
| Number of prior lines or regimens of therapy First Line | 2 number of lines or regimens | 7 number of lines or regimens | 1 number of lines or regimens | 26 number of lines or regimens | 2 number of lines or regimens | 2 number of lines or regimens | 3 number of lines or regimens | 6 number of lines or regimens | 3 number of lines or regimens |
| Number of prior lines or regimens of therapy Neo-adjuvant | 0 number of lines or regimens | 0 number of lines or regimens | 1 number of lines or regimens | 2 number of lines or regimens | 0 number of lines or regimens | 0 number of lines or regimens | 0 number of lines or regimens | 1 number of lines or regimens | 0 number of lines or regimens |
| Number of prior lines or regimens of therapy Other | 1 number of lines or regimens | 1 number of lines or regimens | 2 number of lines or regimens | 10 number of lines or regimens | 1 number of lines or regimens | 1 number of lines or regimens | 1 number of lines or regimens | 2 number of lines or regimens | 1 number of lines or regimens |
| Number of prior lines or regimens of therapy Palliative | 1 number of lines or regimens | 0 number of lines or regimens | 0 number of lines or regimens | 1 number of lines or regimens | 0 number of lines or regimens | 0 number of lines or regimens | 0 number of lines or regimens | 0 number of lines or regimens | 0 number of lines or regimens |
| Number of prior lines or regimens of therapy Second Line | 2 number of lines or regimens | 5 number of lines or regimens | 0 number of lines or regimens | 23 number of lines or regimens | 2 number of lines or regimens | 2 number of lines or regimens | 3 number of lines or regimens | 6 number of lines or regimens | 3 number of lines or regimens |
| Number of prior lines or regimens of therapy Third Line | 1 number of lines or regimens | 4 number of lines or regimens | 1 number of lines or regimens | 19 number of lines or regimens | 2 number of lines or regimens | 2 number of lines or regimens | 3 number of lines or regimens | 3 number of lines or regimens | 3 number of lines or regimens |
| Number of prior lines or regimens of therapy Third Line More | 1 number of lines or regimens | 3 number of lines or regimens | 0 number of lines or regimens | 14 number of lines or regimens | 1 number of lines or regimens | 2 number of lines or regimens | 3 number of lines or regimens | 2 number of lines or regimens | 2 number of lines or regimens |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 5 Participants | 2 Participants | 18 Participants | 1 Participants | 1 Participants | 1 Participants | 7 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 0 Participants | 5 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 2 Participants | 14 Participants | 1 Participants | 2 Participants | 2 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 1 Participants | 19 Participants | 2 Participants | 0 Participants | 2 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 3 Participants | 18 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 1 Participants |
| Tumor Current Stage, n (%) Stage III | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Current Stage, n (%) Stage IIIB | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Tumor Current Stage, n (%) Stage IV | 3 Participants | 7 Participants | 4 Participants | 31 Participants | 3 Participants | 1 Participants | 3 Participants | 6 Participants | 4 Participants |
| Tumor Current Stage, n (%) Stage IVA | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Tumor Current Stage, n (%) Unknown | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Histology type, n (%) Adenocarcinoma | 4 Participants | 4 Participants | 3 Participants | 25 Participants | 2 Participants | 3 Participants | 1 Participants | 5 Participants | 3 Participants |
| Tumor Histology type, n (%) Carcinoid Carcinoid Carcinoid | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Tumor Histology type, n (%) Endometrioid | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Tumor Histology type, n (%) Invasive Ductal Carcinoma | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Tumor Histology type, n (%) Melanoma | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Histology type, n (%) other | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Tumor Histology type, n (%) Squamous Cell Carcinoma | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Weight | 88.30 kg STANDARD_DEVIATION 23.527 | 69.21 kg STANDARD_DEVIATION 17.96 | 74.38 kg STANDARD_DEVIATION 20.852 | 72.44 kg STANDARD_DEVIATION 17.098 | 78.97 kg STANDARD_DEVIATION 24.568 | 68.83 kg STANDARD_DEVIATION 12.744 | 78.75 kg STANDARD_DEVIATION 13.55 | 65.29 kg STANDARD_DEVIATION 7.37 | 65.15 kg STANDARD_DEVIATION 17.241 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 1 / 3 | 1 / 4 | 4 / 7 | 1 / 4 | 2 / 4 | 6 / 8 | 2 / 4 |
| other Total, other adverse events | 2 / 3 | 3 / 3 | 4 / 4 | 7 / 7 | 4 / 4 | 4 / 4 | 8 / 8 | 3 / 4 |
| serious Total, serious adverse events | 1 / 3 | 2 / 3 | 1 / 4 | 3 / 7 | 3 / 4 | 1 / 4 | 5 / 8 | 1 / 4 |
Outcome results
Primary
MTD (Maximum Tolerated Dose)
MTD estimation: After the escalation is completed, select the MTD based on the isotonic regression. Specifically, select the MTD for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, select the higher dose level when the isotonic estimate is lower than the target toxicity rate and select the lower dose level when the isotonic estimate is greater than or equal to the target toxicity rate.
Time frame: Up to 1 cycle (21 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | MTD (Maximum Tolerated Dose) | NA mg |
Primary
Number of Participants Who Experienced DLT (Dose Limiting Toxicities)
DLT is defined as: any toxicity meeting the specified criteria and considered at least possibly related to HH2710 (i.e., any toxicity for which a clear alternative etiology such as disease progression has not been identified) should be considered a DLT per National Cancer Institute Common Terminology Criteria for Adverse events (NCI-CTCAE V5.0) standard, which met any of the following, NCI-CTCAE V5.0 will be used for all grading, and compliance of 80% (i.e. 17 of 21 days) in Cycle 1 is required for a patient to be included in the DLT evaluation. For the purpose of dose-escalation decisions, DLTs will be considered and included in the BOIN.
Time frame: Up to 1 cycle (21 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Number of Participants Who Experienced DLT (Dose Limiting Toxicities) | 0 Participants |
| HH2710 50mg BID | Number of Participants Who Experienced DLT (Dose Limiting Toxicities) | 0 Participants |
| HH2710 100mg BID | Number of Participants Who Experienced DLT (Dose Limiting Toxicities) | 0 Participants |
| HH2710 200mg BID | Number of Participants Who Experienced DLT (Dose Limiting Toxicities) | 0 Participants |
| HH2710 300mg QD | Number of Participants Who Experienced DLT (Dose Limiting Toxicities) | 0 Participants |
| HH2710 400mg QD | Number of Participants Who Experienced DLT (Dose Limiting Toxicities) | 0 Participants |
| HH2710 600mg QD | Number of Participants Who Experienced DLT (Dose Limiting Toxicities) | 0 Participants |
| HH2710 800mg QD | Number of Participants Who Experienced DLT (Dose Limiting Toxicities) | 2 Participants |
Primary
Tumor Objective Response Rate (ORR)
ORR=CR+PR. ORR was defined as the percentage of patients who had at least one confirmed response of CR or PR defined by RECIST version 1.1 prior to any evidence of progression, and was calculated and summarized by the treatment group, along with the 95% confidence interval (CI) calculated by the Clopper-Pearson method.
Time frame: Up to 1 cycle (21 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Tumor Objective Response Rate (ORR) | 0 percentage of patients |
| HH2710 50mg BID | Tumor Objective Response Rate (ORR) | 0 percentage of patients |
| HH2710 100mg BID | Tumor Objective Response Rate (ORR) | 0 percentage of patients |
| HH2710 200mg BID | Tumor Objective Response Rate (ORR) | 0 percentage of patients |
| HH2710 300mg QD | Tumor Objective Response Rate (ORR) | 0 percentage of patients |
| HH2710 400mg QD | Tumor Objective Response Rate (ORR) | 0 percentage of patients |
| HH2710 600mg QD | Tumor Objective Response Rate (ORR) | 0 percentage of patients |
| HH2710 800mg QD | Tumor Objective Response Rate (ORR) | 0 percentage of patients |
Secondary
Pharmacokinetic Measures - Apparent Clearance (CL/F)
Measure apparent total clearance(s) from plasma after oral
Time frame: C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h ;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose.
Population: AUC0-t, t1/2, Lambda z and CL/F of some patients could not be calculated because of insufficient sampling time points after Tmax point during the elimination phase. So the participates analyzed for AUC0-t, t1/2, Lambda z (λz) and CL/F is less than participates of dosing administration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Single Dose Administration | 8.2 L/h | Standard Deviation 5.6 |
| All Participants | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Multiple-dose Administration | 5.1 L/h | Standard Deviation 3.2 |
| HH2710 50mg BID | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Multiple-dose Administration | 5.9 L/h | Standard Deviation 0.1 |
| HH2710 50mg BID | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Single Dose Administration | 14.7 L/h | Standard Deviation 9.5 |
| HH2710 100mg BID | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Single Dose Administration | 9.3 L/h | Standard Deviation 4.7 |
| HH2710 100mg BID | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Multiple-dose Administration | 5.5 L/h | Standard Deviation 1.2 |
| HH2710 200mg BID | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Single Dose Administration | 13.6 L/h | Standard Deviation 19.3 |
| HH2710 200mg BID | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Multiple-dose Administration | 21.3 L/h | Standard Deviation 18.8 |
| HH2710 300mg QD | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Single Dose Administration | 26.5 L/h | Standard Deviation 21.2 |
| HH2710 300mg QD | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Multiple-dose Administration | 18.9 L/h | Standard Deviation 7 |
| HH2710 400mg QD | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Single Dose Administration | 23.3 L/h | Standard Deviation 21.6 |
| HH2710 400mg QD | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Multiple-dose Administration | 18.5 L/h | Standard Deviation 8.7 |
| HH2710 600mg QD | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Single Dose Administration | 14.4 L/h | Standard Deviation 5 |
| HH2710 600mg QD | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Multiple-dose Administration | 6.8 L/h | Standard Deviation 2.8 |
| HH2710 800mg QD | Pharmacokinetic Measures - Apparent Clearance (CL/F) | Single Dose Administration | 4.1 L/h | Standard Deviation 1.6 |
Secondary
Pharmacokinetic Measures - Apparent Volume of Distribution (Vz/F)
The apparent volume of distribution during terminal phase (associated with λz)(volume). And t1/2，Lambda z (λz), Vz/F，these 3 PK parameters are only applicable for single dose administration.
Time frame: Single dose, C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h(if available),C1D2, pre-dose(if available)
Population: AUC0-t, t1/2, Lambda z and CL/F of some patients could not be calculated because of insufficient sampling time points after Tmax point during the elimination phase. So the participates analyzed for AUC0-t, t1/2, Lambda z (λz) and CL/F is less than participates of dosing administration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Participants | Pharmacokinetic Measures - Apparent Volume of Distribution (Vz/F) | 126.5 L | Standard Deviation 30.4 |
| HH2710 50mg BID | Pharmacokinetic Measures - Apparent Volume of Distribution (Vz/F) | 218.9 L | Standard Deviation 32.3 |
| HH2710 100mg BID | Pharmacokinetic Measures - Apparent Volume of Distribution (Vz/F) | 151.9 L | Standard Deviation 104.7 |
| HH2710 200mg BID | Pharmacokinetic Measures - Apparent Volume of Distribution (Vz/F) | 454 L | Standard Deviation 505 |
| HH2710 300mg QD | Pharmacokinetic Measures - Apparent Volume of Distribution (Vz/F) | 353 L | Standard Deviation 311.6 |
| HH2710 400mg QD | Pharmacokinetic Measures - Apparent Volume of Distribution (Vz/F) | 385 L | Standard Deviation 328 |
| HH2710 600mg QD | Pharmacokinetic Measures - Apparent Volume of Distribution (Vz/F) | 184 L | Standard Deviation 82 |
| HH2710 800mg QD | Pharmacokinetic Measures - Apparent Volume of Distribution (Vz/F) | 122 L | Standard Deviation 42 |
Secondary
Pharmacokinetic Measures - Peak Plasma Concentration (Cmax)
Measure the maximum (peak) plasma concentration(s)
Time frame: C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose.
Population: Pharmacokinetic data of HH2710 following a single and multiple dosing administration was evaluated in 35 and 25 patients, respectively.All patients received at least one dose of the study treatment and were included in the FAS and SAS. 35 patients were included in PKS. and group analysis is based on dose administration group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Single Dose Administration | 281 ng/mL | Standard Deviation 37.1 |
| All Participants | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Multiple-dose Administration | 920 ng/mL | Standard Deviation 77.2 |
| HH2710 50mg BID | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Single Dose Administration | 382 ng/mL | Standard Deviation 59.7 |
| HH2710 50mg BID | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Multiple-dose Administration | 1038 ng/mL | Standard Deviation 22 |
| HH2710 100mg BID | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Single Dose Administration | 826 ng/mL | Standard Deviation 66.1 |
| HH2710 100mg BID | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Multiple-dose Administration | 2115 ng/mL | Standard Deviation 17.1 |
| HH2710 200mg BID | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Multiple-dose Administration | 2130 ng/mL | Standard Deviation 61.2 |
| HH2710 200mg BID | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Single Dose Administration | 1440 ng/mL | Standard Deviation 70.2 |
| HH2710 300mg QD | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Single Dose Administration | 1389 ng/mL | Standard Deviation 131.1 |
| HH2710 300mg QD | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Multiple-dose Administration | 1112 ng/mL | Standard Deviation 42.6 |
| HH2710 400mg QD | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Single Dose Administration | 1926 ng/mL | Standard Deviation 82.5 |
| HH2710 400mg QD | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Multiple-dose Administration | 1933 ng/mL | Standard Deviation 83.3 |
| HH2710 600mg QD | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Multiple-dose Administration | 6519 ng/mL | Standard Deviation 6519 |
| HH2710 600mg QD | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Single Dose Administration | 3462 ng/mL | Standard Deviation 45.6 |
| HH2710 800mg QD | Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) | Single Dose Administration | 5313 ng/mL | Standard Deviation 88 |
Secondary
Pharmacokinetic Measures - Peak Time (Tmax)
Measure of time to reach maximum (peak) plasma concentration(s)
Time frame: C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose.
Population: Pharmacokinetic data of HH2710 following a single and multiple dosing administration was evaluated in 35 and 25 patients, respectively.All patients received at least one dose of the study treatment and were included in the FAS and SAS. 35 patients were included in PKS. and group analysis is based on dose administration group.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| All Participants | Pharmacokinetic Measures - Peak Time (Tmax) | Single Dose Administration | 1 h |
| All Participants | Pharmacokinetic Measures - Peak Time (Tmax) | Multiple-dose Administration | 1 h |
| HH2710 50mg BID | Pharmacokinetic Measures - Peak Time (Tmax) | Single Dose Administration | 2 h |
| HH2710 50mg BID | Pharmacokinetic Measures - Peak Time (Tmax) | Multiple-dose Administration | 1.5 h |
| HH2710 100mg BID | Pharmacokinetic Measures - Peak Time (Tmax) | Single Dose Administration | 2.5 h |
| HH2710 100mg BID | Pharmacokinetic Measures - Peak Time (Tmax) | Multiple-dose Administration | 2 h |
| HH2710 200mg BID | Pharmacokinetic Measures - Peak Time (Tmax) | Multiple-dose Administration | 3 h |
| HH2710 200mg BID | Pharmacokinetic Measures - Peak Time (Tmax) | Single Dose Administration | 2 h |
| HH2710 300mg QD | Pharmacokinetic Measures - Peak Time (Tmax) | Single Dose Administration | 4 h |
| HH2710 300mg QD | Pharmacokinetic Measures - Peak Time (Tmax) | Multiple-dose Administration | 8 h |
| HH2710 400mg QD | Pharmacokinetic Measures - Peak Time (Tmax) | Single Dose Administration | 2.5 h |
| HH2710 400mg QD | Pharmacokinetic Measures - Peak Time (Tmax) | Multiple-dose Administration | 6 h |
| HH2710 600mg QD | Pharmacokinetic Measures - Peak Time (Tmax) | Multiple-dose Administration | 4 h |
| HH2710 600mg QD | Pharmacokinetic Measures - Peak Time (Tmax) | Single Dose Administration | 2 h |
| HH2710 800mg QD | Pharmacokinetic Measures - Peak Time (Tmax) | Single Dose Administration | 7 h |
Secondary
Pharmacokinetic Measures - Plasma Clearance Rate Constant, Lambda z (λz)
Terminal phase rate constant, determined by linear regression of at least 3 points on the terminal phase of the log-linear plasma concentration-time curve. The correlation coefficient (r2) for the goodness of the fit of the regression line through the data points has to be 0.85 or higher for the value to be considered reliable. If the WinNonlin data points are not on the linear portion of the terminal slope, the data points will be selected manually prior to calculation of Lambda\_z. And t1/2，Lambda z (λz), Vz/F，these 3 PK parameters are only applicable for single dose administration.
Time frame: Single dose, C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h(if available),C1D2, pre-dose(if available)
Population: AUC0-t, t1/2, Lambda z and CL/F of some patients could not be calculated because of insufficient sampling time points after Tmax point during the elimination phase. So the participates analyzed for AUC0-t, t1/2, Lambda z (λz) and CL/F is less than participates of dosing administration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Participants | Pharmacokinetic Measures - Plasma Clearance Rate Constant, Lambda z (λz) | 6.1 1/h | Standard Deviation 3.7 |
| HH2710 50mg BID | Pharmacokinetic Measures - Plasma Clearance Rate Constant, Lambda z (λz) | 6.4 1/h | Standard Deviation 3.7 |
| HH2710 100mg BID | Pharmacokinetic Measures - Plasma Clearance Rate Constant, Lambda z (λz) | 3 1/h | Standard Deviation 2.6 |
| HH2710 200mg BID | Pharmacokinetic Measures - Plasma Clearance Rate Constant, Lambda z (λz) | 2.2 1/h | Standard Deviation 1.2 |
| HH2710 300mg QD | Pharmacokinetic Measures - Plasma Clearance Rate Constant, Lambda z (λz) | 8 1/h | Standard Deviation 1 |
| HH2710 400mg QD | Pharmacokinetic Measures - Plasma Clearance Rate Constant, Lambda z (λz) | 6 1/h | Standard Deviation 1.6 |
| HH2710 600mg QD | Pharmacokinetic Measures - Plasma Clearance Rate Constant, Lambda z (λz) | 5.4 1/h | Standard Deviation 3.7 |
| HH2710 800mg QD | Pharmacokinetic Measures - Plasma Clearance Rate Constant, Lambda z (λz) | 3.3 1/h | Standard Deviation 0.2 |
Secondary
Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t)
Measure the variation of concentration in blood plasma as a function of time
Time frame: C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose.
Population: Pharmacokinetic data of HH2710 following a single and multiple dosing administration was evaluated in 35 and 25 participates, respectively. But the AUC0-t, t1/2, Lambda z (λz) and CL/F of some patients could not be calculated because of insufficient sampling time points after Tmax point during the elimination phase. So the participates analyzed for AUC0-t, t1/2, Lambda z (λz) and CL/F is less than participates of dosing administration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Multiple-dose Administration | 16619 h*ng/mL | Standard Deviation 108.2 |
| All Participants | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Single Dose Administration | 2858 h*ng/mL | Standard Deviation 58.4 |
| HH2710 50mg BID | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Multiple-dose Administration | 13738 h*ng/mL | — |
| HH2710 50mg BID | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Single Dose Administration | 3139 h*ng/mL | Standard Deviation 52.6 |
| HH2710 100mg BID | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Single Dose Administration | 7683 h*ng/mL | Standard Deviation 61 |
| HH2710 100mg BID | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Multiple-dose Administration | 34387 h*ng/mL | Standard Deviation 23.5 |
| HH2710 200mg BID | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Multiple-dose Administration | 29611 h*ng/mL | Standard Deviation 91.5 |
| HH2710 200mg BID | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Single Dose Administration | 16027 h*ng/mL | Standard Deviation 67 |
| HH2710 300mg QD | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Multiple-dose Administration | 17572 h*ng/mL | Standard Deviation 39.6 |
| HH2710 300mg QD | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Single Dose Administration | 11369 h*ng/mL | Standard Deviation 87.9 |
| HH2710 400mg QD | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Single Dose Administration | 20546 h*ng/mL | Standard Deviation 66.7 |
| HH2710 400mg QD | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Multiple-dose Administration | 28267 h*ng/mL | Standard Deviation 69.8 |
| HH2710 600mg QD | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Single Dose Administration | 37032 h*ng/mL | Standard Deviation 25.8 |
| HH2710 600mg QD | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Multiple-dose Administration | 64857 h*ng/mL | Standard Deviation 95.3 |
| HH2710 800mg QD | Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) | Single Dose Administration | 79134 h*ng/mL | Standard Deviation 64 |
Secondary
Pharmacokinetic Measures -Plasma Elimination Half-life (t1/2)
Terminal half-life, defined as 0.693 (ln2) divided by Lambda z. And t1/2，Lambda z (λz), Vz/F, are only applicable for single dose administration.
Time frame: Single dose, C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h(if available),C1D2, pre-dose(if available)
Population: AUC0-t, t1/2, Lambda z and CL/F of some patients could not be calculated because of insufficient sampling time points after Tmax point during the elimination phase. So the participates analyzed for AUC0-t, t1/2, Lambda z (λz) and CL/F is less than participates of dosing administration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Participants | Pharmacokinetic Measures -Plasma Elimination Half-life (t1/2) | 16 h | Standard Deviation 12 |
| HH2710 50mg BID | Pharmacokinetic Measures -Plasma Elimination Half-life (t1/2) | 15.6 h | Standard Deviation 12.6 |
| HH2710 100mg BID | Pharmacokinetic Measures -Plasma Elimination Half-life (t1/2) | 12.2 h | Standard Deviation 6.5 |
| HH2710 200mg BID | Pharmacokinetic Measures -Plasma Elimination Half-life (t1/2) | 37.9 h | Standard Deviation 16.7 |
| HH2710 300mg QD | Pharmacokinetic Measures -Plasma Elimination Half-life (t1/2) | 8.8 h | Standard Deviation 1.1 |
| HH2710 400mg QD | Pharmacokinetic Measures -Plasma Elimination Half-life (t1/2) | 12.4 h | Standard Deviation 3.5 |
| HH2710 600mg QD | Pharmacokinetic Measures -Plasma Elimination Half-life (t1/2) | 8.9 h | Standard Deviation 2.9 |
| HH2710 800mg QD | Pharmacokinetic Measures -Plasma Elimination Half-life (t1/2) | 20.9 h | Standard Deviation 1.1 |