Evaluate the Safety and Clinical Activity of HH2853

Advanced Solid Tumor Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04390737
• Other study ID #: HH2853-G101
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: September 8, 2020
• Est. completion date: December 31, 2025

Study information

• Verified date: May 2024
• Source: Haihe Biopharma Co., Ltd.
• Contact: Haiyue Chen
• Phone: +86 21 20568888
• Email: haiyue.chen[@]haihepharma.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 254
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

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

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Epithelioid Sarcoma
• Lymphoma
• Lymphoma, T-Cell, Peripheral
• Peripheral T Cell Lymphoma
• Sarcoma

Intervention

Drug:
• HH2853 Tablets
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.

Locations

Country	Name	City	State
China	Beijing Cancer Hospital	Beijing	Beijing
China	Beijing Cancer Hospital	Beijing	Beijing
China	Beijing Cancer Hospital	Beijing
China	Beijing Jishuitan Hospital	Beijing	Beijing
China	Hunan Cancer Hospital	Changsha	Hunan
China	West China Hospital of Sichuan University	Chengdu	Sichuan
China	Sun Yat-Sen University Cancer Hospital	Guangzhou
China	Sun Yat-Sen University Cancer Hospital	Guangzhou	Guangdong
China	Zhejiang Cancer Hospital	Hangzhou	Zhejiang
China	The First Affiliated Hospital of Anhui Medical University	Hefei	Anhui
China	Linyi Tumor Hospital	Linyi	Shandong
China	Affiliated Drum Tower Hospital, Medical School of Nanjing University	Nanjing	Jiangsu
China	Affiliated Tumor Hospital of Guangxi Medical University	Nanning	Guangxi
China	Shanghai Sixth People's Hospital	Shanghai	Shanghai
China	Zhongshan Hospital Fudan University	Shanghai	Shanghai
China	Liaoning Cancer Hospital&Institute	Shenyang	Liaoning
China	Shengjing Hospital Of China Medical University	Shenyang	Liaoning
China	Shanxi Cancer Hospital	Taiyuan	Shanxi
China	Tianjin Cancer Hospital	Tianjin	Tianjin
China	Union Hospital, Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei
China	Henan Cancer Hospital	Zhengzhou	Henan
United States	Mayo Clinic	Jacksonville	Florida
United States	Mayo Clinic	Phoenix	Arizona
United States	Mayo Clinic	Rochester	Minnesota
United States	NEXT Oncology	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Haihe Biopharma Co., Ltd.

Countries where clinical trial is conducted

United States,  China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Overall survival (ORR)	Assess the preliminary efficacy of HH2853	28-day treatment cycles
Other	Change in tri-methylation of Histone H3K27 (H3K27me3)	Assss the pharmacodynamic response	14-day treatment
Other	Biomarker Status	Explore the relationship between the alteration status of biomarker and treatment efficacy	28-day treatment cycles
Other	Overall survival (OS)	Assess the preliminary efficacy of HH2853	28-day treatment cycles
Primary	Maximum tolerated Dose (MTD)	Determine MTD of HH2853	28-day treatment cycles
Primary	Recommended phase II dose (RP2D)	Determine RP2D of HH2853	28-day treatment cycles
Primary	Adverse events assessed according to NCI-CTCAE V5.0	Evaluate the safety of HH2853	28-day treatment cycles
Primary	Dose limiting toxicities (DLT)	Evaluate the tolerability of HH2853	28-day treatment cycles
Primary	Objective response rate (ORR)	Assess the preliminary efficacy of HH2853	28-day treatment cycles
Secondary	AUClast	Characterize the pharmacokinetic profile of HH2853	28-day treatment cycles
Secondary	AUCinf	Characterize the pharmacokinetic profile of HH2853	28-day treatment cycles
Secondary	Cmax	Characterize the pharmacokinetic profile of HH2853	28-day treatment cycles
Secondary	Tmax	Characterize the pharmacokinetic profile of HH2853	28-day treatment cycles
Secondary	CL/F	Characterize the pharmacokinetic profile of HH2853	28-day treatment cycles
Secondary	Vz/F	Characterize the pharmacokinetic profile of HH2853	28-day treatment cycles
Secondary	Terminal half-life (T1/2)	Characterize the pharmacokinetic profile of HH2853	28-day treatment cycles
Secondary	Duration of response (DoR)	Assess the preliminary efficacy of HH2853	28-day treatment cycles
Secondary	Progression-free survival (PFS)	Assess the preliminary efficacy of HH2853	28-day treatment cycles
Secondary	Disease control rate (DCR)	Assess the preliminary efficacy of HH2853	28-day treatment cycles
Secondary	Time to response (TTR)	Assess the preliminary efficacy of HH2853	28-day treatment cycles
Secondary	Time to progression (TTP)	Assess the preliminary efficacy of HH2853	28-day treatment cycles
Secondary	Clinical Outcome	Explore the association between potential biomarker and the clinical outcome	28-day treatment cycles