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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04198818
Recruitment Status : Recruiting
First Posted : December 13, 2019
Last Update Posted : September 22, 2022
Sponsor:
Information provided by (Responsible Party):
Haihe Biopharma Co., Ltd.

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.

Condition or disease Intervention/treatment Phase
Advanced Tumors Melanoma Non-Small-Cell Lung Cancer Erdheim-Chester Disease Other RAS/RAF/MEK/ERK Mutated Tumors Drug: HH2710 Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, Tolerability and Pharmacokinetics of HH2710 in Patients With Advanced Tumors
Actual Study Start Date : January 7, 2020
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024


Arm Intervention/treatment
Experimental: Dose escalaltion study of HH2710
to determin the MTD of HH2710 and/or Recommended Phase II dose (RP2D).
Drug: HH2710
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.




Primary Outcome Measures :
  1. MTD (Maximum Tolerated Dose) [ Time Frame: About 2 years ]
    To determine the maximum tolerable dose.

  2. DLT (Dose limiting toxicities) [ Time Frame: About 2 years ]
    Incidence rate of dose limiting toxicities.

  3. Tumor Objective Response Rate (ORR) [ Time Frame: About 2 years ]
    Tumor objective response rate (ORR) based on RECIST version 1.1.


Secondary Outcome Measures :
  1. Pharmacokinetic measures - Peak plasma concentration (Cmax) [ Time Frame: About 2 years ]
    Measure the maximum (peak) plasma concentration(s)

  2. Pharmacokinetic measures - Peak time (Tmax) [ Time Frame: About 2 years ]
    Measure of time to reach maximum (peak) plasma concentration(s)

  3. Pharmacokinetic measures - Plasma concentration timecurve from time 0 to time (t) (AUC0-t) [ Time Frame: About 2 years ]
    Measure the variation of concentration in blood plasma as a function of time

  4. Pharmacokinetic measures -Plasma elimination half-life (t1/2) [ Time Frame: About 2 years ]
    Measure elimination half-life, when administered in combination

  5. Pharmacokinetic measures - Plasma clearance rate constant (λz), [ Time Frame: About 2 years ]
    Measure the clearance rate constant

  6. Pharmacokinetic measures - Apparent clearance (CL/F) [ Time Frame: About 2 years ]
    Measure apparent total clearance(s) from plasma after oral

  7. Pharmacokinetic measures - Apparent volume of distribution (Vz/F) [ Time Frame: About 2 years ]
    Measure apparent volume of distribution during terminal phase after



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04198818


Contacts
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Contact: Harb Wael Abou, M.D. 765-446-5111 Wharb@horizonbioadvance.com

Locations
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United States, Indiana
Horizon Oncology Research, LLC Recruiting
Lafayette, Indiana, United States, 47905
Contact: Albany Costantine, MD       coalbany@gmail.com   
United States, Michigan
Barbara Ann Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Anthony F. Shields, M.D.,PH.D.    313-576-8735    shieldsa@karmanos.org   
China
Shanghai East hospital Recruiting
Shanghai, China
Contact: Jin Li, M.D.    +86-021-38804518 ext 22229    lijin@csco.org.cn   
Principal Investigator: Jin Li, M.D.         
Sponsors and Collaborators
Haihe Biopharma Co., Ltd.
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Responsible Party: Haihe Biopharma Co., Ltd.
ClinicalTrials.gov Identifier: NCT04198818    
Other Study ID Numbers: HH2710-G101
First Posted: December 13, 2019    Key Record Dates
Last Update Posted: September 22, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Haihe Biopharma Co., Ltd.:
Melanoma
Non-Small-Cell Lung Cancer
Erdheim-Chester Disease
MAPK pathway
ERK1
ERK2
Additional relevant MeSH terms:
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Neoplasms
Carcinoma, Non-Small-Cell Lung
Melanoma
Erdheim-Chester Disease
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Histiocytosis, Non-Langerhans-Cell
Histiocytosis
Lymphatic Diseases