A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of HH2710 in Patient With Advanced Tumors

Study Overview
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Brief Summary
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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
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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.

Official Title
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A First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, Tolerability and Pharmacokinetics of HH2710 in Patients With Advanced Tumors

Conditions
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Advanced Tumors, Melanoma, Non-Small-Cell Lung Cancer, Erdheim-Chester Disease, Other RAS/RAF/MEK/ERK Mutated Tumors

Intervention / Treatment
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* Drug: HH2710


Participation Criteria
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Eligibility Criteria
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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. 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. Eastern Cooperative Oncology Group (ECOG) performance status≤1. Predicted life expectancy ≥ 3 months; Adequate renal function defined as a creatinine clearance ≥ 60 mL/min; 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]; 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. 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; Willing and able to participate in the trial and comply with all study requirements; 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; Acute myocardial infarction ≤3 months prior to starting study drug; 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; 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; Major surgery within 4 weeks prior to first dose; Any use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of HH2710; Pregnant or breast-feeding women; 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. Any important or severe medical illness or abnormal laboratory finding that would increase the risk of participating in this study; A history or current evidence/risk of retinal vein occlusion, central serous retinopathy or choroidneovascularization (CNV) ; Concurrent therapy with any other investigational agent; 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); Current treatment with agents including vitamins, supplements, and herbal supplements that are metabolized solely through CYP3A4; Severe chronic obstructive pulmonary disease, severe asthma, pneumoconiosis, asbestosis and other occupational lung diseases. A history of acute or chronic pancreatitis, surgery of the pancreas, or any risk factors that may increase the risk of pancreatitis; 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalaltion study of HH2710<br>to determin the MTD of HH2710 and/or Recommended Phase II dose (RP2D). | Drug: HH2710<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD (Maximum Tolerated Dose) | To determine the maximum tolerable dose. | About 2 years | 
| DLT (Dose limiting toxicities) | Incidence rate of dose limiting toxicities. | About 2 years | 
| Tumor Objective Response Rate (ORR) | Tumor objective response rate (ORR) based on RECIST version 1.1. | About 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic measures - Peak plasma concentration (Cmax) | Measure the maximum (peak) plasma concentration(s) | About 2 years | 
| Pharmacokinetic measures - Peak time (Tmax) | Measure of time to reach maximum (peak) plasma concentration(s) | About 2 years | 
| 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 | About 2 years | 
| Pharmacokinetic measures -Plasma elimination half-life (t1/2) | Measure elimination half-life, when administered in combination | About 2 years | 
| Pharmacokinetic measures - Plasma clearance rate constant (λz), | Measure the clearance rate constant | About 2 years | 
| Pharmacokinetic measures - Apparent clearance (CL/F) | Measure apparent total clearance(s) from plasma after oral | About 2 years | 
| Pharmacokinetic measures - Apparent volume of distribution (Vz/F) | Measure apparent volume of distribution during terminal phase after | About 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, Non-Small-Cell Lung Cancer, Erdheim-Chester Disease, MAPK pathway, ERK1, ERK2