Evaluate the Safety and Clinical Activity of HH2853

Study Overview
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Brief Summary
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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
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This first-in-human study of HH2853 will be conducted in patients with non-Hodgkin's lymphomas or patients with advanced solid tumors that have relapsed or are refractory to prior therapies and have a high degree of unmet medical need in terms of available treatment options. The purpose of the study is to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD), the Maximum Tolerated Dose (MTD) and/or the Recommended Phase II dose (RP2D) and preliminary efficacy of HH2853 administered orally on a continuous twice daily (BID) schedule in adult patients with relapsed/refractory Non-Hodgkin's lymphomas or advanced solid tumors. 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. 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, i.e., no more than 29.8% DLT in each dose level. Phase II is planned after the completion of phase I. Up to approximately 108 patients will be enrolled into 3 cohorts to evaluate clinical activities at the RP2D.

Official Title
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A First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Clinical Activity of HH2853, an EZH1/2 Inhibitor, in Patients With Relapsed/Refractory Non-Hodgkin's Lymphomas or Advanced Solid Tumors

Conditions
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Non-Hodgkin's Lymphoma, Relapsed, Non-Hodgkin's Lymphoma Refractory, Advanced Solid Tumor

Intervention / Treatment
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* Drug: HH2853 Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provided signed written informed consent prior to initiation of any study-related procedures; Males and females ≥ 18years of age at the time of consent are obtained (or meet the country's regulatory defined adult legal age); Tumor type criteria: Relapsed/refractory histologically documented non-Hodgkin's lymphoma (NHL) must have received at least 2 prior systemic therapies (maximum <5 lines, patients without treatment options available known to provide clinical benefit are also eligible upon agreement from investigator and sponsor.) The specific requirements for certain tumor types are listed below: Follicular lymphoma (FL) must meet criteria requiring at least two prior systemic treatment per the GELF criteria and there is no salvage regimen available (maximum <5 lines); Diffuse large B-cell lymphoma NOS (2016 WHO classification of lymphoma neoplasms) relapsed or refractory with at least 2 prior regimen (e.g., at least one regimen of anti-CD20 based therapy, maximum <5 lines) and not a candidate for salvage regimens or autologous or allogeneic stem cell transplant. Relapsed/refractory clinicopathologically documented PTCL with at least 1 line of prior systemic treatment (maximum <5 lines). Subtypes include Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS), Angioimmunoblastic T-cell lymphoma (AITL), ALK+ Anaplastic large cell lymphoma, anaplastic lymphoma kinase positive (ALCL), ALK-ALCL, Extranodal natural killer (NK)/T-cell lymphoma-nasal type (ENKL), Enteropathy-associated T-cell lymphoma (EATL), Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), Hepatosplenic T-cell lymphoma (HSTCL), Follicular T-cell lymphoma (FTCL), Nodal peripheral T-cell lymphoma with TFH phenotype (PTCL-TFH) and other invasive T-cell-derived NHL that the investigator considered eligible and approved by the sponsor (Other than highly invasive subtype). The definition of relapse: A relapse after CR or progression after PR with at least one prior systemic therapy. The definition of refractory: Tumor evaluation of PD after 2 cycles of treatment; tumor evaluation of SD after 4 cycles of treatment; no response or treatment progression within 1 month after completion of initial treatment; tumor evaluation of PR but require second-line treatment immediately at the physician's judgment. Solid tumors that meet the following criteria: Histologically or cytologically documented advanced recurrent or metastatic solid tumor. Phase I dose escalation: Measurable or evaluable lesions by RECIST v1.1 in at least 1 site; phase I dose extension and phase II: Measurable target lesions by RECIST v1.1 in at least 1 site. (Lesions that have been treated with radiotherapy or other local treatment are generally considered unmeasurable unless there is definite progression of the lesion.) Patients must have disease not amenable to surgery, radiation, or combined modality therapy with curative intent. One of the following criteria should be met. Patients must experience at least one prior standard therapy. Disease progression occurred on or after last line of therapy, or intolerant to last line of therapy (maximum ≤3 lines, Patients without treatment options available known to provide clinical benefit are also eligible upon agreement from investigator and sponsor) There is no approved therapy, or for which standard therapy is unsuitable or refused by patients after being fully informed. Eastern Cooperative Oncology Group (ECOG) performance status ≤1; Availability of archival tissue within three years, or willingness to undergo fresh biopsy if archival tissue is not available (only for phase I dose extension and phase II) ; Relapsed/Refractory FL, Epithelioid sarcoma, relapsed/refractory PTCL, other relapsed/refractory non-Hodgkin's lymphomas with EZH2 mutation, and advanced solid tumors with specific genetic alterations, including EZH2 mutation, INI1 deficiency, BAP1 deficiency, ARID1A mutation, or/and SMARCA4 mutation tested by local labs will be enrolled in phase I dose extension and phase II. For phase II, patients may be enrolled in one of 3 cohorts upon their tumor types: Relapsed/Refractory FL Epithelioid sarcoma 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. Predicted life expectancy of ≥ 3 months; Patient must meet the following laboratory values: Serum total Bilirubin ≤ 1.5 x ULN or ≤ 3.0 mg/dL for patients with Gilbert's syndrome AST/SGOT and ALT/SGPT ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases are present 24-hour creatinine clearance (calculated* or measured value**)≥ 50 mL/min *For calculated creatinine clearance (Ccr) value, the eligibility should be determined using the Cockcroft-Gault formula: Male Ccr (mL/mim) = body weight (kg) x (140-age)/[72 x creatinine (mg/dL)] Female Ccr (mL/min) = male Ccr x 0.85 ** A measured value Ccr value (i.e. not calculated) should meet this criterion. Platelets ≥ 1 x LLN (no Platelet transfusion for 7 days prior to screening) Hemoglobin (Hgb) ≥ 9 g/dL (no RBC transfusion for 7 days prior to screening) Absolute Neutrophil Count (ANC) ≥ 1.0 x 10^9/L Adequate coagulation function: International normalized ratio (INR) <1.3 (or <3.0 on anticoagulants) Exclusion Criteria: Any cancer-directed therapy (chemotherapy, antibody therapy, radiotherapy, hormonal therapy, biologic or immunotherapy, Chinese medicine/Chinese patent medicine with anti-tumor effect, etc.) within 28 days or five half-lives prior to first dose (whichever is shorter); Small molecule anticancer therapy within 2 weeks or five half-lives (whichever is longer); Local radiotherapy (without radioactive particle implantation) within 14 days of first dose. Symptomatic CNS metastases that are neurologically unstable or requiring increasing doses of steroids to control CNS disease. Note: Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first dose of study drug, or palliative radiotherapy to a single symptomatic lesion within the 2 weeks prior to first dose of study drugs; Patients with prior transplant are excluded; however, patients who have previously received an autologous stem cell transplant are allowed if a minimum of 100 days has elapsed from the time of transplant and the patient has recovered from transplant-associated toxicities prior to the first dose of HH2853. Patients who have previously received an allogeneic stem cell transplant are also allowed if a minimum of 6 months has elapsed prior to the first dose of HH2853; Major surgery within 4 weeks prior to first dose; Current use of a prohibited medication or expected to require any of these medications during treatment with study drug; 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). However, patients that can be controlled with treatment are eligible; Concomitant malignancies or previous malignancies with less than 2 years of 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); 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 before the start of study drug, with exception of hair loss or fatigue; a) Lymphoma patients with ≤ Grade 3 lymphopenia can be enrolled at the discretion of the investigator Packed red blood cell or platelet transfusion within 7 days of screening laboratory tests; 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: 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; Fridericia's corrected QT interval (QTcF) > 450 ms (for male) and > 470 ms (for female) on ECG conducted during screening; Congenital long QT syndrome, or any known history of torsade de pointes (TdP), or family history of unexplained sudden death; History or current evidence of serious uncontrolled ventricular arrhythmias; 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; Left ventricular ejection fraction (LVEF) < 50%; Any evidence of serious active infections requiring antibiotics; Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug or their excipients; Pregnant or breast-feeding female; Contraception: Patients who do not meet the following requirements 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 3 months after the treatment period. Abstinence is not considered as an adequate contraceptive regimen; For men: must be surgically sterile, or compliant with a contraceptive regimen (as above) during and for a minimum of 3 months after the treatment period. Other serious illness or medical conditions at the Investigator's discretion, that may influence study results, including but not limited to cerebrovascular diseases or lung disease.

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: HH2853 administered on a BID schedule in continuous 28-day treatment cycles<br>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. | Drug: HH2853 Tablets<br>* Proposed daily dose (BID): 50mg, 100mg, 200mg, 400mg, 600mg, 800mg, 1000mg. It is possible for additional and/or intermediate dose levels to be added during the course of the study. Cohorts may be added at any dose level below the MTD in order to better understand safety, PK or PD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated Dose (MTD) | Determine MTD of HH2853 | 28-day treatment cycles | 
| Recommended phase II dose (RP2D) | Determine RP2D of HH2853 | 28-day treatment cycles | 
| Adverse events assessed according to NCI-CTCAE V5.0 | Evaluate the safety of HH2853 | 28-day treatment cycles | 
| Dose limiting toxicities (DLT) | Evaluate the tolerability of HH2853 | 28-day treatment cycles | 
| Objective response rate (ORR） | Assess the preliminary efficacy of HH2853 | 28-day treatment cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUClast | Characterize the pharmacokinetic profile of HH2853 | 28-day treatment cycles | 
| AUCinf | Characterize the pharmacokinetic profile of HH2853 | 28-day treatment cycles | 
| Cmax | Characterize the pharmacokinetic profile of HH2853 | 28-day treatment cycles | 
| Tmax | Characterize the pharmacokinetic profile of HH2853 | 28-day treatment cycles | 
| CL/F | Characterize the pharmacokinetic profile of HH2853 | 28-day treatment cycles | 
| Vz/F | Characterize the pharmacokinetic profile of HH2853 | 28-day treatment cycles | 
| Terminal half-life (T1/2) | Characterize the pharmacokinetic profile of HH2853 | 28-day treatment cycles | 
| Duration of response (DoR) | Assess the preliminary efficacy of HH2853 | 28-day treatment cycles | 
| Progression-free survival (PFS) | Assess the preliminary efficacy of HH2853 | 28-day treatment cycles | 
| Disease control rate (DCR) | Assess the preliminary efficacy of HH2853 | 28-day treatment cycles | 
| Time to response (TTR) | Assess the preliminary efficacy of HH2853 | 28-day treatment cycles | 
| Time to progression (TTP) | Assess the preliminary efficacy of HH2853 | 28-day treatment cycles | 
| Clinical Outcome | Explore the association between potential biomarker and the clinical outcome | 28-day treatment cycles | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I/II, HH2853, PRC2, EZH 1/2 inhibitor