Overview

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.

Eligibility

Inclusion criteria:

1. Provided signed written informed consent prior to initiation of any study-related procedures;
2. Males and females ≥ 18years of age at the time of consent are obtained (or meet the country's regulatory defined adult legal age);
3. Tumor type criteria:

        The specific requirements for specific subtypes of recurrent/refractory non Hodgkin's
        lymphoma (NHL) confirmed by histology are as follows:
        Histologically confirmed follicular lymphoma (FL) that has been treated with at least two
        lines of systemic therapy (at least one regimen based on anti-CD20 monoclonal antibodies)
        according to GELF criteria or as determined by researchers (Grade 1-3a);
        Relapsed/refractory diffuse large B-cell lymphoma - non-specific (DLBCL NOS, 2016 World
        Health Organization Lymphoma Classification) that has received at least two treatment
        regimens in the past (at least one with CD20 monoclonal antibody as the main treatment,
        with a maximum number of treatment lines<5), and is not a candidate for salvage treatment
        or autologous/allogeneic stem cell transplantation.
        Relapsed/refractory clinicopathologically documented PTCL with at least 1 line of prior
        systemic treatment (maximum <5 lines). Solid tumors that meet the following criteria:
          1. Histologically or cytologically documented advanced recurrent or metastatic solid
             tumor.
          2. 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.)
          3. 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.
        For epithelioid sarcoma in Phase I and Phase II cohort 2:
          1. Confirmed by local histology or cytology
          2. Patients with unresectable locally delayed or metastatic epithelioid sarcoma who have
             undergone treatment (including those who have failed treatment and developed
             intolerable toxicity).
        For solid tumors in Phase I and Phase II queue 3:
          1. Confirmed by local pathology as advanced recurrent or metastatic solid tumor.
          2. Patients must have disease not amenable to surgery, radiation, or combined modality
             therapy with curative intent 4. Eastern Cooperative Oncology Group (ECOG) performance
             status ≤1; 5. Availability of archival tissue within three years 6.
             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 7. Predicted life expectancy
             of ≥ 3 months; 8. Patient must meet the following laboratory values: 1.Serum total
             Bilirubin ≤ 1.5 x ULN or ≤ 3.0 mg/dL for patients with Gilbert's syndrome 2.AST/SGOT
             and ALT/SGPT ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases are present 3.24-hour
             creatinine clearance (calculated or measured value*)≥ 50 mL/min 4.Platelets ≥ 1 x
             LLN (no Platelet transfusion for 7 days prior to screening) 5.Hemoglobin (Hgb) ≥ 9
             g/dL 6.Absolute Neutrophil Count (ANC) ≥ 1.0 x 10^9/L 7.Adequate coagulation function:
             International normalized ratio (INR) <1.3 (or <3.0 on anticoagulants) 9. Measurable
             lesion
        Exclusion Criteria:
          1. 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.
          2. Symptomatic CNS metastases that are neurologically unstable or requiring increasing
             doses of steroids to control CNS disease.
          3. Patients with prior transplant are excluded;
          4. Major surgery within 4 weeks prior to first dose;
          5. A prohibited medication or expected to require any of these medications during
             treatment with study drug within 2 weeks of first dose;
          6. 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).
          7. Concomitant malignancies or previous malignancies
          8. 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.
          9. Any toxicities from prior treatment that have not recovered to ≤ CTCAE Grade 1
         10. There were ≥ 3 lesions with punctate bleeding, any active bleeding, intratumoral
             bleeding, known bleeding tendencies, or treatment with antiplatelet/antithrombotic
             drugs.
         11. Gastrointestinal condition which could impair absorption of study medication;
         12. Psychological, familial, sociological or geographical conditions that do not permit
             compliance with the protocol;
         13. 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