Clinical trial NCT04390737: Evaluate the Safety and Clinical Activity of HH2853
Official title: A Phase I/II Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Clinical Activity of HH2853 in Patients with Relapsed/Refractory Non-Hodgkin's Lymphomas or Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: FL Lymphoma
Epithelioid Sarcoma
Peripheral T Cell Lymphoma
Advanced Solid Tumor
Keywords: Phase I/II
HH2853
PRC2
EZH 1/2 inhibitor
Lead sponsor: Haihe Biopharma Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2020-05-15
Enrollment: 254
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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)

Eligibility criteria: 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

Primary outcomes:
measure: Maximum tolerated Dose (MTD)
timeFrame: 28-day treatment cycles
measure: Recommended phase II dose (RP2D)
timeFrame: 28-day treatment cycles
measure: Adverse events assessed according to NCI-CTCAE V5.0
timeFrame: 28-day treatment cycles
measure: Dose limiting toxicities (DLT)
timeFrame: 28-day treatment cycles
measure: Objective response rate (ORR）
timeFrame: 28-day treatment cycles
Secondary outcomes:
measure: AUClast
timeFrame: 28-day treatment cycles
measure: AUCinf
timeFrame: 28-day treatment cycles
measure: Cmax
timeFrame: 28-day treatment cycles
measure: Tmax
timeFrame: 28-day treatment cycles
measure: CL/F
timeFrame: 28-day treatment cycles
measure: Vz/F
timeFrame: 28-day treatment cycles
measure: Terminal half-life (T1/2)
timeFrame: 28-day treatment cycles
measure: Duration of response (DoR)
timeFrame: 28-day treatment cycles
measure: Progression-free survival (PFS)
timeFrame: 28-day treatment cycles
measure: Disease control rate (DCR)
timeFrame: 28-day treatment cycles
measure: Time to response (TTR)
timeFrame: 28-day treatment cycles
measure: Time to progression (TTP)
timeFrame: 28-day treatment cycles
measure: Clinical Outcome
timeFrame: 28-day treatment cycles
Other outcomes:
measure: Overall survival (ORR）
timeFrame: 28-day treatment cycles
measure: Change in tri-methylation of Histone H3K27 (H3K27me3)
timeFrame: 14-day treatment
measure: Biomarker Status
timeFrame: 28-day treatment cycles
measure: Overall survival (OS)
timeFrame: 28-day treatment cycles
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: San Antonio
country: United States
facility: NEXT Oncology
state: Texas
city: Hefei
country: China
facility: The First Affiliated Hospital of Anhui Medical University
state: Anhui
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing Jishuitan Hospital
state: Beijing
city: Guangzhou
country: China
facility: Sun Yat-Sen University Cancer Hospital
state: Guangdong
city: Nanning
country: China
facility: Affiliated Tumor Hospital of Guangxi Medical University
state: Guangxi
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Nanjing
country: China
facility: Affiliated Drum Tower Hospital, Medical School of Nanjing University
state: Jiangsu
city: Shenyang
country: China
facility: Liaoning Cancer Hospital&Institute
state: Liaoning
city: Shenyang
country: China
facility: Shengjing Hospital Of China Medical University
state: Liaoning
city: Linyi
country: China
facility: Linyi Tumor Hospital
state: Shandong
city: Shanghai
country: China
facility: Shanghai Sixth People's Hospital
state: Shanghai
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan University
state: Shanghai
city: Taiyuan
country: China
facility: Shanxi Cancer Hospital
state: Shanxi
city: Chengdu
country: China
facility: West China Hospital of Sichuan University
state: Sichuan
city: Tianjin
country: China
facility: Tianjin Cancer Hospital
state: Tianjin
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Guangzhou
country: China
facility: Sun Yat-Sen University Cancer Hospital
Study officials:
affiliation: Haihe Biopharma Co., Ltd.
name: Fugen Li
role: STUDY_DIRECTOR
References: