Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001339741
Ethics application status
Approved
Date submitted
16/09/2022
Date registered
18/10/2022
Date last updated
20/02/2024
Date data sharing statement initially provided
18/10/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A First-in-Human Study to Evaluate the Safety and Tolerability of HH3806 in Patients With Advanced Tumors
Scientific title
A Phase I, Open-label, Multicenter, First in Human Study to Evaluate the Safety and Tolerability of HH3806 in Patients with Advanced Malignancies
Secondary ID [1] 307823 0
HH3806-A101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid Tumors 327617 0
relapsed/refractory Non-Hodgkin’s lymphomas (NHL) 327618 0
Condition category
Condition code
Cancer 324706 324706 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
HH3806 is a novel highly potent and selective inhibitor against the BD2 of bromo- and extra-terminal domain (BET ) proteins family (BET-BD2). BET family proteins is known to play important roles in human cancers, associated with tumour cell growth. HH3806 has exhibited strong anti-tumor effects in pre-clinical and animal studies.
In this First-In Human study, HH3806 is being studied for the treatment of advanced non-Hodgkin’s lymphomas (NHL), solid tumours and will evaluate the safety and tolerability of HH3806.
Approximately 36 participants with either relapsed/ refractory NHL or solid tumours will be enrolled in this study.
HH3806 capsule will be administered as an oral capsule once daily for the duration of each 28-day treatment cycle without any study treatment interruption between each cycle. The starting dose level of HH3806 is 10 mg once daily and the decision to dose escalate to the next dose level will be made based on the emerging safety data. Dosing schedule and cycle may be adjusted during the study on the basis of this data. The provisional dose in the dose escalation planned for this study is 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 75mg, 90mg, 110mg, 135mg and 165mg once daily.
The dose level for individual participants will vary depending on the dose level enrolling participants at the time of study entry.
HH3806 will be administered at the clinic on days 1, 8, 15 and 22 of cycle 1 & days 1 and 15 of cycle 2. It is to be taken at home on the others days. HH3806 will also be administered at clinic on approx. 3 days before cycle 1 if you are first participant in first 3 dose levels. The participants will complete a dosing diary to record time when HH3806 capsules are taken each day.
Intra-patient dose escalation is not permitted at any time within the first four cycles of treatment. After the first four cycles are completed and the participant must have not experienced CTCAE v5.0 grade greater than or equal to 2 HH3806 related toxicity over at least four cycles of therapy at the lower dose, the participant may be considered for treatment at a higher dose of HH3806, which can be only the last cleared dose level of the study drug.
The participant who develops any non-DLT during DLT observation period, treatment may be interrupted depending on the grade of AE, but dose modification is not allowed in first cycle. In principle, each participant is only allowed 2 dose reductions. If participant need to modify dose for the third time, the investigator must contact the sponsor to evaluate patient’s benefit and interest, then make the decision together.
HH3806 dispensing and administration will also be documented as per study guidelines which will be monitored, and accountability assessed by Sponsor representatives.
Study treatment could be continued until disease progression, unacceptable toxicity, death or withdrawal of consent until the date of the last data collection (1 year post-treatment commencement), whichever occurs first.
After the completion of the study, if a patient still requires administration of HH3806 which has been assessed as beneficial per the study doctor, the sponsor and the study doctor will discuss the post-study provisions for the patient’s access to HH3806.
Intervention code [1] 324417 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332524 0
To determine the Maximum Tolerated Dose (MTD) and/or to establish the Recommended Phase 2 Dose (RP2D, dose for the following study of HH3806) by evaluating the incidence rate of Dose-limiting toxicity (DLT). A DLT could be neutropenia (low count of neutrophils, a type of white blood cells), anaemia (low red blood cells), thrombocytopenia (low platelet level), increase in level of enzymes in the liver, nausea, vomiting, diarrhoea, fatigue, cardiac disorders (myocarditis (inflammation in the heart wall)).
1.Blood tests are used to assess full blood count and liver function, including neutropenia, anaemia, thrombocytopenia and increase in level of enzymes in the liver.
2.The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5) is used to assess the incidence, severity and relationship of treatment-emergent adverse events including nausea, vomiting, diarrhoea, fatigue.
3.Echocardiography is used to assess for cardiac disorders.
Timepoint [1] 332524 0
Assessment will be performed throughout Day 1 to Day 28 (cycle 1: the first treatment cycle) of each dose level. All patients will be closely monitored and will be seen at the clinic, specifically:
1.Blood tests will be performed on Day 1, Day 8, Day 15 and Day 22 of Cycle 1.
2.Daily from the screening, the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5) is used to assess the incidence, severity and relationship of treatment-emergent adverse events including nausea, vomiting, diarrhoea, fatigue upon the AE occurs.
3.Echocardiography will be performed on Day 1, Day 8, Day 15 and Day 22 of Cycle 1 and as needed.
Primary outcome [2] 332525 0
To evaluate the Safety and tolerability of HH3806, which will be measured by a composite of:
1. Incidence and severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 [NCI CTCAE v5.0]) of treatment-emergent AEs (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to discontinuation from study treatment
2. Clinical laboratory analyses including Aspartate aminotransferase, Alanine aminotransferase, creatinine, Platelets, total bilirubin, hemoglobin, activated partial prothrombin time (APTT) and international normalized ratio (INR) and Cardiac enzymes (troponin T/I), all assessed by blood test.
3. Left ventricular ejection fraction (LVEF) assessed by echocardiogram
4. Vital signs-heart rate by pulse oximeter, blood pressure by sphygmomanometer and temperature by thermometer.
5. Eastern Cooperative Oncology Group (ECOG) performance status,
6. Physical examination finding - weight assessed using digital standing scales.
Timepoint [2] 332525 0
1. AE- Daily from first treatment dose until 28 days after the last treatment dose
2. Clinical laboratory - at screening, Day 1, Day 8, Day 15 and Day 22 of Cycle 1, Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 3 and Subsequent cycles, End of treatment visit (within 7 days after the last treatment dose), safety follow up visit (28 days after the last dose)
3. LVEF is examined with echocardiography every 12 weeks for the duration of treatment and if clinically indicated.
4. Vital signs- At screening, Day 1, Day 8, Day 15 and Day 22 of Cycle 1, Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 3 and Subsequent cycles, End of treatment visit (within 7 days after the last treatment dose), safety follow up visit (28 days after the last dose)
5. ECOG-at Screening, Day 1 of Cycle 1, Cycle 2, Cycle 3 and Subsequent cycles, end of treatment visit (within 7 days after the last treatment dose) and safety follow up visit (28 days after the last dose)
6. Physical examination (weight) - at Screening, Day 1 of Cycle 1, Cycle 2, Cycle 3 and Subsequent cycles, end of treatment visit (within 7 days after the last treatment dose) and safety follow up visit (28 days after the last dose)
Secondary outcome [1] 413817 0
To characterize the pharmacokinetic (PK) of HH3806 by evaluating the HH3806 and metabolites plasma concentration-time profiles and PK parameters, including Cmax, Tmax, AUC0-24h, AUCinf. Other PK parameters such as CL/F, Vz/F and the terminal half-life (T1/2), Accumulation Ratio (Rac_AUC /Rac_Cmax). These parameters will be calculated from serum concentration of HH3806 using blood samples collected at various time points.
Timepoint [1] 413817 0
Blood samples for the PK analysis will be collected at the following timepoints:
Cycle 1 Day 1 pre-dose, Cycle 1 Day 15 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose, pre-dose on Cycle 1 Day 8, Cycle 1 Day 22 and pre-dose on Day 1 of cycles 2, 3, 4, 5 and the day of End of Treatment visit (within 7 days of the last dose of study drug or within 7 days of the decision to discontinue study treatment).
Secondary outcome [2] 413818 0
To assess the preliminary efficacy of HH3806 in patients with advanced malignancies by calculating the Objective response rate (ORR) defined as the proportion of patients with a second confirmed completed response (CR) or partial response (PR) as evaluated according to RECIST v1.1 by CT scans for solid tumor and according to the Lugano Classification for NHL by CT/MRI and PET-CT scans.
Timepoint [2] 413818 0
The tumor assessment will be performed every 6 weeks (±7 days) after the first dose of HH3806 from Cycle 1 Day 1 (C1D1) until 1 year post-treatment commencement, followed by every 12 weeks (±7 days) until disease progression, intolerability or withdrawal of consent.
Secondary outcome [3] 414282 0
To assess the preliminary efficacy of HH3806 in patients with advanced malignancies by calculating the Disease control rate (DCR) defined as the proportion of patients with confirmed CR, PR and Stable disease (SD) as evaluated according to RECIST v1.1 by CT scans for solid tumor and according to the Lugano Classification for NHL by CT/MRI and PET-CT scans lasting for greater than or equal to 4 weeks.
Timepoint [3] 414282 0
The tumor assessment will be performed every 6 weeks (±7 days) after the first dose of HH3806 from Cycle 1 Day 1 (C1D1) until 1 year post-treatment commencement, followed by every 12 weeks (±7 days) until disease progression, intolerability or withdrawal of consent.
Secondary outcome [4] 414283 0
To assess the preliminary efficacy of HH3806 in patients with advanced malignancies by calculating the Duration of Response (DOR) defined as the time from first confirmed CR or PR as evaluated according to RECIST v1.1 by CT scans for solid tumor and according to the Lugano Classification for NHL by CT/MRI and PET-CT scans to tumor progression or death due to any reason, whichever comes first. If no tumor progression or death is observed, censoring will be made at the date of the last tumor imaging.
Timepoint [4] 414283 0
The tumor assessment will be performed every 6 weeks (±7 days) after the first dose of HH3806 from Cycle 1 Day 1 (C1D1) until 1 year post-treatment commencement, followed by every 12 weeks (±7 days) until disease progression, intolerability or withdrawal of consent.
Secondary outcome [5] 414284 0
To assess the preliminary efficacy of HH3806 in patients with advanced malignancies by calculating the Time to Response (TTR) defined as the time from the first dose of study treatment to confirmed CR or PR as evaluated according to RECIST v1.1 by CT scans for solid tumor and according to the Lugano Classification for NHL by CT/MRI and PET-CT scans
Timepoint [5] 414284 0
The tumor assessment will be performed every 6 weeks (±7 days) after the first dose of HH3806 from Cycle 1 Day 1 (C1D1) until 1 year post-treatment commencement, followed by every 12 weeks (±7 days) until disease progression, intolerability or withdrawal of consent.

Eligibility
Key inclusion criteria
1. Male and female patients 18years of age or older .
2. Provide informed consent voluntarily prior to initiation of any study-related procedures.
3. Tumor type criteria: Histologically or cytologically confirmed diagnosis of one of the following advanced malignancy:
a) Solid tumors that meet the following criteria:
- Measurable disease by RECIST v1.1 in at least 1 site with the exception of Castration-Resistant Prostate Cancer (CRPC), who may be enrolled with objective evidence of disease as per certain criteria; disease progression with the last line of therapy and at least one prior standard of care regimens, or for which there is no approved therapy, or for which standard therapy is unsuitable or refused. Patients must have disease not amenable to surgery, radiation, or combined modality therapy with curative intent. Patients without treatment options available known to provide clinical benefit are also eligible
b) Relapsed/refractory NHL must have received at least 2 prior systemic therapies and there is no standard salvage regimen available.
4. Life expectancy greater than or equal to 3 months.
5. ECOG performance status less than or equal to 1.
6. Patient must have adequate organ function measured within 28 days of screening.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients are ineligible for this study if they meet any of the following criteria:
1. Anticancer therapy (including chemotherapy, targeted therapy, biotherapy, hormone therapy, traditional Chinese medication with cancer indication or other investigational agents) within 4 weeks or 5 times of half-lives (whichever is shorter) prior to the first dose of the study drug.
2. Patients who had prior treatment with any BET inhibitor.
3. Radical radiation therapy within 4 weeks prior to the first dose of the investigational product or received local palliative radiation therapy for bone metastases within 2 weeks.
4. Any toxicities from prior treatment that have not recovered to baseline or less than or equal to NCI-CTCAE v5.0 Grade 1 before the start of study treatment, except for Adverse Events not considered a likely safety risk.
5. Patients who have been treated with any hematopoietic colony-stimulating growth factors 2 weeks prior to starting study drug.
6. Patients who have symptomatic CNS metastasis which is neurologically unstable or those who have CNS disease requiring increase in the dose of steroid. (Note: Patients with controlled CNS metastasis can participate in the trial. Before entering the study, patients should have finished radiotherapy, or have received operation for CNS tumor metastasis at least two weeks before. Patients’ neurological function must be in a stable state; no new neurological deficit is found during clinical examination and no new abnormality is found during CNS imaging examinations. If patients need to use steroids to treat CNS metastasis, the therapeutic dose of steroid should be stable for 3 months at least two weeks prior to entering the study with treatment dose no more than dexamethasone 4 mg daily or an equivalent dose of steroids).
7. Major surgery or had significant traumatic injury within 28 days prior to the first dose of the investigational product or has not recovered from major side effects.
8. Patients with prior immunodeficiency, or organ transplantation or patients after allogeneic stem cell transplantation if they are less than 100 days has elapsed from the day of transplantation, they are on any treatment for graft-versus-host disease, or they have not been off calcineurin inhibitors for at least 4 weeks are excluded.
9. Patients diagnosed with cataract who have not undergone surgery and do not meet either of the following conditions: best corrected visual acuity greater than or equal to 0.6, Postmydriatic LOCS III lens opacity classification criteria: posterior subcapsular (P) = 0, cortex (C) less than or equal to 2, nuclear (N) less than or equal to 2.
10. Known HIV.
11. Active hepatitis B and hepatitis C.
12. Patients with clinically significant cardiovascular disease.
13. Any active malignancy 2 years before the first dose of study drugs, except for the specific cancer under investigation and any locally recurring cancer that has been treated with curative intent.
14. Any condition that required systemic treatment with either corticosteroids or other immunosuppressive medication 14 days before the first dose of study drugs.
15. Unable or unwilling to swallow study medication or gastrointestinal condition which could impair absorption of study medication.
16. Patient has any other concurrent severe and/or uncontrolled medical condition such as active infection, unresolved bowel obstruction, or psychiatric disorders that would, in the investigator’s judgment, contraindicate patient participation in the clinical study.
17. Patients with a history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, noninfectious pneumonitis, or uncontrolled lung diseases, including but not limited to pulmonary fibrosis, acute lung disease, etc.
18. Severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc.
19. Activity gastrointestinal ulcers within 2 months.
20. Was administered a live vaccine 4 weeks before first dose of study drug.
21. Any diseases or medical conditions, at the investigator's discretion, that may be unstable or influence their safety or study compliance, including organ transplantation, abuse of psychotropic medication, alcohol abuse or history of drug abuse.
22. Concurrent participation in another therapeutic clinical study.
23. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug or their excipients.
24. Pregnant or breast-feeding patients. Women of childbearing potential will be enrolled only after a confirmed menstrual period. Breast-feeding women can become eligible for this study if she stops breast-feeding, however, cannot restart the breast-feeding on/after the completion of the study treatment.
25. Male and Female of childbearing potential not using effective contraception during the trial and within 6 months after the end of treatment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
31/01/2023
Actual
13/03/2023
Date of last participant enrolment
Anticipated
28/02/2025
Actual
Date of last data collection
Anticipated
1/03/2026
Actual
Sample size
Target
36
Accrual to date
13
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 23151 0
Peninsula Oncology Centre - Frankston
Recruitment hospital [2] 23786 0
Icon Cancer Care South Brisbane - South Brisbane
Recruitment hospital [3] 24550 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 38509 0
3199 - Frankston
Recruitment postcode(s) [2] 39236 0
4101 - South Brisbane
Recruitment postcode(s) [3] 40144 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 312094 0
Commercial sector/Industry
Name [1] 312094 0
Taizhou Haihe Pharmaceutical Co.,Ltd.
Country [1] 312094 0
China
Primary sponsor type
Commercial sector/Industry
Name
Tigermed Australia Pty Ltd
Address
Level 35, International Tower One, 100 Barangaroo Avenu . Sydney 2000 , Australia
Country
Australia
Secondary sponsor category [1] 313762 0
None
Name [1] 313762 0
Address [1] 313762 0
Country [1] 313762 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311500 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 311500 0
Ethics committee country [1] 311500 0
Australia
Date submitted for ethics approval [1] 311500 0
23/08/2022
Approval date [1] 311500 0
04/11/2022
Ethics approval number [1] 311500 0
Ethics committee name [2] 312215 0
Bellberry Human Research Ethics Committee
Ethics committee address [2] 312215 0
Ethics committee country [2] 312215 0
Australia
Date submitted for ethics approval [2] 312215 0
21/11/2022
Approval date [2] 312215 0
15/12/2022
Ethics approval number [2] 312215 0
Ethics committee name [3] 312834 0
Monash Health Human Research Ethics Committee
Ethics committee address [3] 312834 0
Ethics committee country [3] 312834 0
Australia
Date submitted for ethics approval [3] 312834 0
23/11/2022
Approval date [3] 312834 0
15/03/2023
Ethics approval number [3] 312834 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121318 0
A/Prof Vinod Ganju
Address 121318 0
Peninsula & South Eastern Haematology and Oncology Group, Level 3, Suite 7, North Building, Frankston Private, 5 Susono Way, Frankston, VIC 3199,Australia
Country 121318 0
Australia
Phone 121318 0
+610397815244
Fax 121318 0
Email 121318 0
vg@paso.com.au
Contact person for public queries
Name 121319 0
Yu Zhou
Address 121319 0
Haihe Biopharma Co., Ltd.,No.865 Zuchongzhi Road, Zhangjiang Hi-Tech, Pudong, Shanghai 201203,Chna
Country 121319 0
China
Phone 121319 0
+8602120568888
Fax 121319 0
Email 121319 0
yu.zhou@haihepharma.com
Contact person for scientific queries
Name 121320 0
Ni Song
Address 121320 0
Haihe Biopharma Co., Ltd.,No.865 Zuchongzhi Road, Zhangjiang Hi-Tech, Pudong, Shanghai 201203,China
Country 121320 0
China
Phone 121320 0
+8615989184257
Fax 121320 0
Email 121320 0
ni.song@haihepharma.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Privacy and intellectual property considerations


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.