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

NCT04198818 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: HH2710-G101
• Study Type: interventional
• Target: 37
• Locations: 2 countries
• Sites: 3

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.

Conditions

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

Keywords

Melanoma; Non-Small-Cell Lung Cancer; Erdheim-Chester Disease; MAPK pathway; ERK1; ERK2

Outcome Measures

Primary Outcomes (3)

• 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.

  Up to 1 cycle (21 days)

• 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.

  Up to 1 cycle (21 days)

• 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.

  Up to 1 cycle (21 days)

Secondary Outcomes (7)

• 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.

• 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 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 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 - 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)

Study Arms (1)

Dose escalation study of HH2710

EXPERIMENTAL

to determine the MTD of HH2710 and/or Recommended Phase II dose (RP2D).

Drug: HH2710

Interventions

HH2710 DRUG

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.

Dose escalation study of HH2710

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 \[total bilirubin ≤ 1.5 x UNL; AST (aspartate aminotransferase) and ALT (alanine aminotransferase) ≤ 3 x UNL or ≤ 5 x UNL if due to liver involvement by tumor\];

You may not qualify if:

• 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;

Sponsors & Collaborators

• Haihe Biopharma Co., Ltd.: lead

Study Sites (3)

Horizon Oncology Research, LLC

Lafayette, Indiana, 47905, United States

Location

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Shanghai East hospital

Shanghai, China

Location

MeSH Terms

Conditions

Melanoma; Carcinoma, Non-Small-Cell Lung; Erdheim-Chester Disease

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Medical Officer
• Organization: Haihe Biopharma Co., Ltd

fugen.li@haihepharma.com

86-(021)-20568888

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 11, 2019
• First Posted: December 13, 2019
• Study Start: January 7, 2020
• Primary Completion: March 31, 2023
• Study Completion: March 31, 2023
• Last Updated: July 19, 2024
• Results First Posted: July 19, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2); CN (1)