A First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, Tolerability and Pharmacokinetics of HH2710 in Patients With Advanced Tumors
Overview
- Phase
- Phase 1
- Intervention
- HH2710
- Conditions
- Advanced Tumors
- Sponsor
- Haihe Biopharma Co., Ltd.
- Enrollment
- 37
- Locations
- 3
- Primary Endpoint
- MTD (Maximum Tolerated Dose)
- Status
- Terminated
- Last Updated
- last year
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provide signed and dated informed consent prior to initiation of any study-related procedures.
- •Male or female patients aged ≥ 18 years.
- •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.
- •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.
Exclusion Criteria
- •Gastrointestinal condition which could impair absorption of study medication;
- •Congenital long QT syndrome, or any known history of torsade de pointes (TdP), or family history of unexplained sudden death;
- •Clinically uncontrolled hypertension (after standard antihypertensive treatment, systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg);
- •Undergone a bone marrow or solid organ transplant;
- •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;
- •Patients who have previously participated in clinical trials of ERK inhibitors drug;
- •Allergic to similar drugs or their excipients;
- •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);
- •Uncontrolled or severe intercurrent medical condition:
- •Unstable angina pectoris ≤3 months prior to starting study drug;
Arms & Interventions
Dose escalation study of HH2710
to determine the MTD of HH2710 and/or Recommended Phase II dose (RP2D).
Intervention: HH2710
Outcomes
Primary Outcomes
MTD (Maximum Tolerated Dose)
Time Frame: 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)
Time Frame: 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)
Time Frame: 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 Outcomes
- 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.)
- 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))
- 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))
- 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.)
- 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))
- 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.)
- 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.)