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Trial registered on ANZCTR


Registration number
ACTRN12623001219673
Ethics application status
Approved
Date submitted
22/08/2023
Date registered
27/11/2023
Date last updated
27/11/2023
Date data sharing statement initially provided
27/11/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
Phase I-II study on the safety and effectiveness of gel for external application of DRIPs inhibitors in the treatment of non-melanoma skin cancer
Scientific title
A phase I-II clinical trial to evaluate the tolerability, safety, pharmacokinetics and preliminary efficacy of EN002-gel in patients with non-melanoma skin cancer and precancerous lesions
Secondary ID [1] 310419 0
EN002-CN-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Basal cell carcinoma 331185 0
Bowen’s disease 331186 0
Actinic keratosis 331355 0
Squamous cell carcinoma of the skin 331356 0
Condition category
Condition code
Cancer 327960 327960 0 0
Non melanoma skin cancer
Skin 327961 327961 0 0
Dermatological conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a non-randomized, single arm, global multicenter clinical trial, with all participants assigned to the treatment group. No control group is included in this study.
Investigational drug code: EN002
Active Ingredient: DNA replication initiation proteins (DRIPs) inhibitors
Dosage form: Topical gel
Specification: 40 mg:10 g and 20 mg:10 g
Route of administration: Topical application
Method of administration: Spread the EN002 gel evenly on the lesion, avoiding flushing and rubbing, cover with gauze and fix with non-irritating adhesive tape. Ensure that the drug is in contact with the skin for 4±0.5 h per dose. Clean and wipe the administration site with normal saline at room temperature to remove the drug. The administration of the IP will be carried out either by the investigators or by designated site personnel.

Treatment cycle and dosing frequency:
Phase I: The phase I trial is a single dose incremental trial with a total of 5 dose groups. Based on non-clinical study data, the initial dose was set at 0.008 mg EN002/cm^2, while the remaining dose groups were 0.016, 0.027, 0.04, and 0.06 mg EN002/cm^2. During the single administration phase, observe for 2 days after the first administration; During the multiple administration stage, the drug should be administered once every other day for 21 consecutive days; Lasting for a total of 24 days. Participants will undergo all treatments at the study sites. The amount of gel for each dosage will be measured using positive-displacement pipettes.

Phase II:
The dose administered: The maximum tolerated dose (MTD) is determined by isotonic regression at the end of Phase I study. Once the maximum tolerated dose (MTD) or maximum administered dose (MAD) is achieved in the Phase I study, comprehensive evaluation will be performed to finally select the appropriate dose for the Phase II study.
The duration of administration: once every other day for 21 days. Actual dosing frequency and treatment cycle can be modified based on the tolerability, safety, Pharmacokinetics (PK) parameters and efficacy data of the study drug from the Phase I study.
The mode of administration: Topical administration.

Separate cohorts will be enrolled for Phase I and Phase II. However, the same participants can be enrolled to both Phase I and Phase II if they meet the study inclusion and exclusion criteria during the screening periods for each phase.
Intervention code [1] 326819 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 336218 0
Safety will be evaluated by closely monitoring the occurrence of adverse events, which will include an assessment of organ or system functioning. This evaluation will entail a comprehensive physical examination, covering various aspects such as height, weight (using a digital weigh scale), head, eyes, ears, nose, throat, neck, heart (including a 12-lead ECG test), chest (including lungs), abdomen, limbs, skin, lymph nodes, nervous system and the overall condition of the participants. Furthermore, vital signs, including body temperature (using a digital thermometer), blood pressure (systolic and diastolic), heart rate (using a digital sphygmomanometer), respiration, will be assessed. Vital signs will be measured while the participants are in supine or sitting position after they have rested in that position for at least 5 minutes. The physical fitness status will also be evaluated in accordance with the ECOG Physical Fitness Status Scale. An adverse event (AE) refers any untoward medical occurrence in a subject administered the investigational drug which may manifest as signs, symptoms, or diseases. Collection of AEs will begin from the time the subject signs the Informed Consent Form until 28 days after the last dose. AEs that are ongoing at the end of study treatment, whether or not related to study treatment, will be followed up until resolution or return to baseline, the subject’s death, or starting of other anti-tumor therapy, or until they can be reasonably explained. Any adverse event will be graded using the Common Terminology Criteria for Adverse Events (CTCAE 5.0).
Timepoint [1] 336218 0
Physical examination:
Phase I: Screening period, D24, 28 days after last dose (or within 14 days after drug withdrawal for early termination cases). Height and weight must be measured and recorded at screening. Height measurement is not required at subsequent visits, but weight should be measured and recorded.
Phase II: Screening period, D24, 28 days after last dose (or within 21 days after drug withdrawal for early termination cases). Height and weight must be measured and recorded at screening. Height measurement is not required at subsequent visits, but weight should be measured and recorded.

12-lead ECG test:
Phase I: Screening period, D-1 (baseline), D1, D2, D3, D4, D6, D8, D16, D24, 28 days after last dose (or within 14 days after drug withdrawal)
Phase II: Screening period, D-1 (baseline), D1, D7, D14, D24, 28 days after last dose (or within 21 days after drug withdrawal for early termination cases).

Vital signs:
Phase I: Screening period, D-1 (baseline), D1, D2, D3, D4, D6, D8, D16, D24, 28 days after last dose (or within 14 days after drug withdrawal for early termination cases)
Phase II: Screening period, D-1 (baseline), D1, D7, D14, D24, 28 days after last dose (or within 21 days after drug withdrawal for early termination cases).

Physical fitness status:
Phase I: Screening period, D24, 28 days after last dose (or within 14 days after drug withdrawal for early termination cases).
Phase II: Screening period, D14, D24, 28 days after last dose (or within 21 days after drug withdrawal for early termination cases).
Primary outcome [2] 336219 0
Toxicity will be evaluated through laboratory tests, including an assessment of hematologic toxicity using hematology test, blood chemistry test, and coagulation test, and an assessment of non-hematologic toxicity (except skin toxicity) using urinalysis test, stool routine test, and occult blood test. Any adverse event will be graded using the Common Terminology Criteria for Adverse Events (CTCAE 5.0).
Timepoint [2] 336219 0
Phase I: Screening period, D-1 (baseline), D3, D16, D24, 28 days after last dose (or within 14 days after drug withdrawal for early termination cases).
Phase II: Screening period, D-1 (baseline), D14, D24, 28 days after last dose (or within 21 days after drug withdrawal for early termination cases).
Primary outcome [3] 336220 0
The efficacy of the investigational product will be determined through the assessment of tumor lesions in accordance with the Response Evaluation Criteria in solid tumour (RECIST v1.1), which will entail a skin examination (potentially including dermoscopic examination), and measure the sizes of lesions using a vernier caliper and recording them through photography.
Efficacy parameters for subjects with basal cell carcinoma and squamous cell carcinoma of the skin only:
1) Objective response rate (ORR): Refers to the proportion of subjects with CR or PR (based on the best response during treatment) in the analysis set;
2) Disease control rate (DCR): Refers to the proportion of subjects with CR, PR or SD (based on the best response during treatment) in the analysis set;
3) Duration of response (DOR): Refers to the period from the time when CR or PR is first determined to PD or death from any cause;
4) Time to progression (TTP): Refers to the period from the subject’s first dose to definite disease progression;
5) Progression-free survival (PFS): Refers to the period from the subject’s first dose to definite disease progression or death from any cause;
All the five parameters above will be assessed together as a composite primary outcome.
Timepoint [3] 336220 0
Phase I: Screening period (baseline), Multiple Dose Phase Weeks 2 (± 2 days), 3 (± 2 days), 28 days after last dose (or within 14 days after drug withdrawal for early termination cases).
Phase II: Screening period (baseline), D14, D24, 28 days after last dose (or within 21 days after drug withdrawal for early termination cases).
Secondary outcome [1] 427389 0
The efficacy of the investigational product will be determined through the assessment of tumor lesions in accordance with the Response Evaluation Criteria in solid tumour (RECIST v1.1), which will entail a skin examination (potentially including dermoscopic examination), and measure the sizes of lesions using a vernier caliper and recording them through photography.
Efficacy evaluation parameters for subjects with Bowen's disease and actinic keratosis (AK) only:
1) Complete clearance ratio: Refers to the proportion of subjects with 100% clearance of the lesion;
2) Partial (75%) clearance ratio: Refers to the proportion of subjects with at least 75% clearance of the lesion;
3) Partial (50%) clearance ratio: Refers to the proportion of subjects with at least 50% clearance of the lesion;
4) Lesion-specific clearance ratio: Refers to the proportion of subjects with a decrease trend in the number of cleared lesions from baseline to the time of evaluation.
All the four parameters above will be assessed together as a composite primary outcome.
Timepoint [1] 427389 0
Phase I: Screening period (baseline), Multiple Dose Phase Weeks 2 (± 2 days), 3 (± 2 days), 28 days after last dose (or within 14 days after drug withdrawal for early termination cases).
Phase II: Screening period (baseline), D14, D24, 28 days after last dose (or within 21 days after drug withdrawal for early termination cases).
Secondary outcome [2] 427390 0
The pharmacokinetics of investigational product will be evaluated by a high performance liquid chromatography-mass spectrometry/mass spectrometry method. The following parameters will be examined in participants' plasma during the study: pharmacokinetics concentrations, the primary pharmacokinetics parameters, including single dose: Tmax, Cmax, AUC0-t, AUC0-8, Vz/F, Kel, t1/2, MRT, CL/F, and multiple dose: Tmax, Css_min, Css_max, Css_av, t1/2, CL/F, AUCss, and DF, etc.
Timepoint [2] 427390 0
Single Dose Phase: D1 (predose, 1h, 2h, 3h, 4h (before erasure), 5h, 6h, 8h, 10h, and 24h post-dose)
Multiple Dose Phase: D4 (predose), D6 (predose), D8 (predose), D24 (1h, 2h, 3h, 4h (before erasure), 5h, 6h, 8h, 10h, and 24h post-dose)
Secondary outcome [3] 428831 0
The quality of life will be evaluated using the SF-36 health survey scale. The SF-36 is a brief health questionnaire developed by the Boston Institute of Health and is widely used in the fields of quality of life measurement, clinical study effect evaluation, and health policy assessment in the general population. As a brief health questionnaire, the SF-36 comprehensively summarizes the quality of life of the respondents from eight aspects: physical function, physical function, physical pain, general health status, energy, social function, emotional function, and mental health.
Timepoint [3] 428831 0
Screening period (baseline), D24 after treatment.

Eligibility
Key inclusion criteria
All enrolled subjects should meet the following criteria:
(1) Able to sign the informed consent form freely and voluntarily, finish the follow-ups and complete the study assignments;
(2) Aged greater than or equal to 18 years old;
(3) Study subjects should be (one or more of the following):
diagnosed with AK by histopathological examination or non-invasive diagnosis (dermoscopy, skin CT, etc.);
diagnosed with Bowen's disease by histopathological examination;
diagnosed with primary basal cell carcinoma of the skin (including nodular, superficial, micronodular and other histopathological types with low risk of recurrence) by histopathological examination;
diagnosed with primary squamous cell carcinoma of the skin by histopathological examination;
(4) The total lesion area of the whole body is not more than 25 cm²;
(5) Not suitable for surgical or radiotherapy treatment at the affected area, or unwilling to accept surgical or radiotherapy treatment;
(6) Major organs’ functions meet the following criteria:
·Hematology: neutrophil greater than or equal to 1.5×109 /L, platelets greater than or equal to 50×109 /L, hemoglobin greater than or equal to 9.0 g/dL;
·Liver function: total bilirubin less than or equal to 1.5 x ULN, except for those with Gilbert syndrome; ALT/AST less than or equal to 2.5 x ULN in the absence of liver metastases;
·Coagulation: international normalized ratio (INR) less than or equal to 1.5 x ULN and activated partial thromboplastin time (APTT) less than or equal to 1.5 x ULN (INR and APTT are within the safe and effective therapeutic range as judged by the investigator for those on anticoagulation);
·Renal function: serum creatinine less than or equal to 1.5 x ULN, or creatinine clearance greater than or equal to 60 mL/min/1.73 m2 (for those with creatinine > ULN); urine protein less than or equal to 1+ (if greater than or equal to 2+, 24 h urine protein test is required; if 24 h urine protein < 1 g, enrollment is allowed);
·Cardiac function: Left ventricular ejection fraction (LVEF) > 50% by echocardiography (ECHO) or multi-gated acquisition (MUGA);
(7) Men and women of childbearing potential must agree to take effective contraception measures from the time they sign the informed consent form until 3 months after the last dose of the investigational drug; women of childbearing potential must have a negative clinical pregnancy test result within 7 d prior to the first dose of the investigational drug; and postmenopausal women must be amenorrheic for at least 12 months before they are considered infertile.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Subjects have any of the following conditions should not be enrolled:
(1) Subjects with known serious hypersensitivity or serious adverse reactions to the investigational drug, or with an allergic constitution;
(2) Life expectancy is estimated to be less than 12 weeks;
(3) Subjects who have used other topical treatments (e.g., fluorouracil ointment, Imiquimod cream, photodynamic therapy) within 7 d prior to the first dose;
(4) Subjects who have received targeted therapy, chemotherapy, immunotherapy and other systemic anticancer therapy within 4 weeks prior to enrollment;
(5) Subjects with ulcerate/damaged skin within 5 cm of the target lesion;
(6) Subjects with lymph node metastasis or important organ metastasis of tumors by imaging examination;
(7) Subjects with neurological/psychiatric, respiratory, cardiovascular, digestive, hematological and lymphatic, endocrine, skeletal-muscular, or any other disorders or physiological conditions that may impair the results of the study;
(8) Subjects with positive antibodies to human immunodeficiency virus (HIV); positive hepatitis B surface antigen (HBsAg) and HBV-DNA greater than or equal to the lower limit of quantification; positive antibodies to hepatitis C virus (HCV) and HCV-RNA greater than or equal to the lower limit of quantitation; or positive treponema pallidum antibodies;
(9) Pregnant or lactating women, or subjects with a planned pregnancy within 3 months;
(10) Subjects who have participated in any other clinical trial within 3 months prior to this study;
(11) Other conditions judged by the investigator to be ineligible for the study.

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
22/08/2022
Date of last participant enrolment
Anticipated
3/02/2025
Actual
Date of last data collection
Anticipated
30/09/2025
Actual
Sample size
Target
95
Accrual to date
15
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 25413 0
Novatrials - Kotara
Recruitment hospital [2] 25414 0
Veracity Clinical Research - Woolloongabba
Recruitment postcode(s) [1] 41155 0
2289 - Kotara
Recruitment postcode(s) [2] 41156 0
4102 - Woolloongabba
Recruitment outside Australia
Country [1] 25721 0
China
State/province [1] 25721 0

Funding & Sponsors
Funding source category [1] 314774 0
Commercial sector/Industry
Name [1] 314774 0
EnKang Pharmaceuticals (Guangzhou) Ltd.
Country [1] 314774 0
China
Primary sponsor type
Commercial sector/Industry
Name
EnKang Pharmaceuticals (Australia) Pty Ltd.
Address
Suite 1103, 109 Pitt Street, Sydney, NSW 2000, Australia
Country
Australia
Secondary sponsor category [1] 316588 0
Commercial sector/Industry
Name [1] 316588 0
EnKang Pharmaceuticals (Guangzhou) Ltd
Address [1] 316588 0
5th Floor, Building 4C, Unit 2, Luoxuan 4th Road, Guangzhou International Bio-Island, Guangzhou, Guangdong province, China,Postcode 510145
Country [1] 316588 0
China

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313649 0
Hospital of Dermatology, Chinese Academy of Medical Sciences
Ethics committee address [1] 313649 0
Jiangwangmiao Street 12, Xuanwu District, Nanjing, Jiangsu province, postcode 210042
Ethics committee country [1] 313649 0
China
Date submitted for ethics approval [1] 313649 0
Approval date [1] 313649 0
16/03/2022
Ethics approval number [1] 313649 0
Ethics committee name [2] 313925 0
Bellberry Human Research Ethics Committee
Ethics committee address [2] 313925 0
123 Glen Osmond Road, Eastwood, SA, 5063, Australia
Ethics committee country [2] 313925 0
Australia
Date submitted for ethics approval [2] 313925 0
23/08/2023
Approval date [2] 313925 0
02/11/2023
Ethics approval number [2] 313925 0

Summary
Brief summary
The purpose of this study is to assess the acceptability, safety, how your body interacts and the effectiveness of the EN002-gel in patients with non-melanoma skin cancer and precancerous lesions, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Actinic keratosis (AK), and Bowen's disease (BD).

Who is it for?
You may be eligible for this trial if you are aged between 18 years or older, have been diagnosed with basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Actinic keratosis (AK), or Bowen's disease (BD).

Study details
This study comprises two phases. Currently, Phase I clinical trials are underway in China and Australia. In Phase 1, participants will be grouped into small cohorts, with each group receiving topical administration of EN002-gel on affected skin once every 2 days for a duration of 3 weeks. We will test five different dose levels (0.008, 0.016, 0.027, 0.04, and 0.06 mg EN002 per cm^2) to assess the safety, tolerability, and EN002 gel concentration in the blood of patients with non-melanotic skin cancer.

How many people will participate in this clinical trial?
We anticipate enrolling approximately 25 participants from both Australia and China for the Phase I study. In Australia, two sites will participate, with a planned total of 8 participants. Australian subjects will be allocated to receive either 0.04 mg/cm^2 or 0.06 mg/cm^2 of EN002 based on when they participate in the study.

The Phase II study comprises four cohorts, each representing different tumor or precancerous lesion types, including 35 cases of AK, 12 cases of SCC, 12 cases of BCC, and 11 cases of BD. This sums up to a total of 70 required participants for the Phase II study in China and Australia.

The purpose and prospects of this clinical trial
It is hoped that this clinical trial can help to evaluate the safety, tolerance and efficacy of EN002 gel in the treatment of non-melanoma skin cancer and other diseases, and provide a basis for the dosage and administration scheme of the subsequent phase of the trial.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128874 0
Dr Juliana Junger
Address 128874 0
Level 1, OTP House, 10 Bradford Close, Kotara, NSW2289
Country 128874 0
Australia
Phone 128874 0
+61 2 40893746
Fax 128874 0
Email 128874 0
[email protected]
Contact person for public queries
Name 128875 0
Juliana Junger
Address 128875 0
Level 1, OTP House, 10 Bradford Close, Kotara, NSW2289
Country 128875 0
Australia
Phone 128875 0
+61 2 40893746
Fax 128875 0
Email 128875 0
[email protected]
Contact person for scientific queries
Name 128876 0
Donna Lai
Address 128876 0
ENKANG PHARMACEUTICALS (AUSTRALIA) PTY LTD, Suite 1103, 109 Pitt Street, Sydney, NSW 2000, Australia
Country 128876 0
Australia
Phone 128876 0
+61 403151568
Fax 128876 0
Email 128876 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No plan for publication so far.


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.