Evaluate the Safety and Clinical Activity of HH2853
- Conditions
- FL LymphomaEpithelioid SarcomaAdvanced Solid TumorPeripheral T Cell Lymphoma
- Interventions
- Drug: HH2853 Tablets
- Registration Number
- NCT04390737
- Lead Sponsor
- Haihe Biopharma Co., Ltd.
- Brief Summary
This is an open-label, multicenter, first-in-human phase I/II study which is composed of 3 parts: phase I dose escalation, phase I dose extension and phase II. HH2853 will be administered orally on a continuous BID schedule on a continuous 28-day treatment cycle.
- Detailed Description
Phase I:
Phase I dose escalation The accelerated titration (ATD) incorporated with Bayesian Optimal Interval design (BOIN) will be used to assess the DLT, safety, tolerability, MTD and furthermore, to establish the RP2D. DLT assessment is only applicable to phase I dose escalation.
Eligible patients will be enrolled in the ascending dose until MTD/RP2D is established.
Phase I dose extension During the dose escalation phase, a dose extension with additional patients will be included in order to further evaluate the tolerability, pharmacokinetics, and efficacy at doses that have been evaluated as safe. The number of patients to be enrolled in each dose extension cohort is up to 15, but the final number of dose level can be determined and the final patient number at each dose level can be adjusted slightly based on available safety, efficacy, PK, and PD data upon agreement from sponsor and investigators (e.g. safety evaluation meeting). For phase I dose extension, approximately 30 patients will be enrolled based on initial estimate, but the final total number of patients will depend on the number of dose levels extended and patient number at each dose level.
The total number of patients is estimated to be approximately 60 patients for phase I dose escalation and dose extension, but the final total number of patients will depend upon the number of dose cohorts to reach MTD/RP2D, and patient number at each dose level.
Phase II（China Only）:
Phase II is planned after the completion of phase I. Up to approximately 193 patients will be enrolled as outlined below:
* Cohort 1: Relapsed/Refractory FL (n≈56)
* Cohort 2: Epithelioid sarcoma (n≈77)
* Cohort 3: Relapsed/Refractory PTCL, other relapsed/refractory Non-Hodgkin's lymphomas with EZH2 mutation, or advanced solid tumors with specific genetic alterations, including EZH2 mutation, INI1 deficiency, BAP1 deficiency, ARID1A mutation, or/and SMARCA4 mutation (n≈60)
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 254
Not provided
- Any cancer-directed therapy within 28 days or five half-lives prior to first dose; Small molecule anticancer therapy within 2 weeks or five half-lives; Local radiotherapy within 14 days of first dose.
- Symptomatic CNS metastases that are neurologically unstable or requiring increasing doses of steroids to control CNS disease.
- Patients with prior transplant are excluded;
- Major surgery within 4 weeks prior to first dose;
- A prohibited medication or expected to require any of these medications during treatment with study drug within 2 weeks of first dose;
- HIV (human immunodeficiency virus) infection, active hepatitis B or hepatitis C patients (HBsAg positive patients with HBV (hepatitis B virus) DNA ≥ 10^3 copies or ≥ 200 IU/mL; HCV antibody test results are positive, and HCV (hepatitis C virus) RNA PCR test results are positive).
- Concomitant malignancies or previous malignancies
- Concurrent use of therapeutic warfarin is allowed. However, anticoagulants that do not have reversal agents available are prohibited except low molecular weight heparin and direct oral anticoagulants.
- Any toxicities from prior treatment that have not recovered to ≤ CTCAE Grade 1
- There were ≥ 3 lesions with punctate bleeding, any active bleeding, intratumoral bleeding, known bleeding tendencies, or treatment with antiplatelet/antithrombotic drugs.
- Gastrointestinal condition which could impair absorption of study medication;
- Psychological, familial, sociological or geographical conditions that do not permit compliance with the protocol;
- Cardiac exclusion criteria:
1.History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 3 months prior to first dose of study drug; 2.Fridericia's corrected QT interval (QTcF) > 450 ms (for male) and > 470 ms (for female) on ECG conducted during screening; 3.Congenital long QT syndrome, or any known history of torsade de pointes (TdP), or family history of unexplained sudden death; 4.History or current evidence of serious uncontrolled ventricular arrhythmias; 5.Symptomatic congestive heart failure (Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system) within the previous 3 months; 6.Left ventricular ejection fraction (LVEF) < 50%; 14. Any evidence of serious active infections requiring antibiotics; 15. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug or their excipients; 16. Pregnant or breast-feeding female; 17. Contraception: 18. Other serious illness or medical conditions at the Investigator's discretion, that may influence study results 19. Previously received treatment with EZH2 or EZH1/2 inhibitors. 20. Grade 3b FL or evidence of transformation to invasive lymphoma
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description HH2853 administered on a BID schedule in continuous 28-day treatment cycles HH2853 Tablets HH2853 is supplied as tables with dosage strength of 25mg and 200mg. HH2853 Tablet will be administered orally on a continuous twice daily (BID) schedule, on a flat scale of mg and not individually adjusted by weight or body surface area. A treatment cycle is defined as 28 days for the purposes of scheduling procedures and evaluations. All patients will be treated with HH2853 orally on a continuous BID schedule, beginning on Cycle 1 Day 1. But patients in accelerated titration (ATD) part should be administered a single dose on the first day in order to evaluate the PK of a single dose administration. Dosing is twice daily from the second day thereafter.
- Primary Outcome Measures
Name Time Method Recommended phase II dose (RP2D) 28-day treatment cycles Determine RP2D of HH2853
Dose limiting toxicities (DLT) 28-day treatment cycles Evaluate the tolerability of HH2853
Objective response rate (ORR） 28-day treatment cycles Assess the preliminary efficacy of HH2853
Adverse events assessed according to NCI-CTCAE V5.0 28-day treatment cycles Evaluate the safety of HH2853
Maximum tolerated Dose (MTD) 28-day treatment cycles Determine MTD of HH2853
- Secondary Outcome Measures
Name Time Method AUCinf 28-day treatment cycles Characterize the pharmacokinetic profile of HH2853
CL/F 28-day treatment cycles Characterize the pharmacokinetic profile of HH2853
AUClast 28-day treatment cycles Characterize the pharmacokinetic profile of HH2853
Tmax 28-day treatment cycles Characterize the pharmacokinetic profile of HH2853
Progression-free survival (PFS) 28-day treatment cycles Assess the preliminary efficacy of HH2853
Disease control rate (DCR) 28-day treatment cycles Assess the preliminary efficacy of HH2853
Terminal half-life (T1/2) 28-day treatment cycles Characterize the pharmacokinetic profile of HH2853
Time to response (TTR) 28-day treatment cycles Assess the preliminary efficacy of HH2853
Clinical Outcome 28-day treatment cycles Explore the association between potential biomarker and the clinical outcome
Cmax 28-day treatment cycles Characterize the pharmacokinetic profile of HH2853
Vz/F 28-day treatment cycles Characterize the pharmacokinetic profile of HH2853
Duration of response (DoR) 28-day treatment cycles Assess the preliminary efficacy of HH2853
Time to progression (TTP) 28-day treatment cycles Assess the preliminary efficacy of HH2853
Trial Locations
- Locations (20)
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
NEXT Oncology
🇺🇸San Antonio, Texas, United States
The First Affiliated Hospital of Anhui Medical University
🇨🇳Hefei, Anhui, China
Beijing Cancer Hospital
🇨🇳Beijing, China
Beijing Jishuitan Hospital
🇨🇳Beijing, Beijing, China
Sun Yat-Sen University Cancer Hospital
🇨🇳Guangzhou, China
Affiliated Tumor Hospital of Guangxi Medical University
🇨🇳Nanning, Guangxi, China
Henan Cancer Hospital
🇨🇳Zhengzhou, Henan, China
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
🇨🇳Wuhan, Hubei, China
Hunan Cancer Hospital
🇨🇳Changsha, Hunan, China
Affiliated Drum Tower Hospital, Medical School of Nanjing University
🇨🇳Nanjing, Jiangsu, China
Liaoning Cancer Hospital&Institute
🇨🇳Shenyang, Liaoning, China
Shengjing Hospital Of China Medical University
🇨🇳Shenyang, Liaoning, China
Linyi Tumor Hospital
🇨🇳Linyi, Shandong, China
Shanghai Sixth People's Hospital
🇨🇳Shanghai, Shanghai, China
Zhongshan Hospital Fudan University
🇨🇳Shanghai, Shanghai, China
Shanxi Cancer Hospital
🇨🇳Taiyuan, Shanxi, China
West China Hospital of Sichuan University
🇨🇳Chengdu, Sichuan, China
Tianjin Cancer Hospital
🇨🇳Tianjin, Tianjin, China
Zhejiang Cancer Hospital
🇨🇳Hangzhou, Zhejiang, China