Phase I Study of HSK42360 in Solid Tumors With BRAF V600 Mutation

A Phase I, Open-label, Dose-escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic of HSK42360 in Patients With BRAF V600 Mutation Locally Advanced or Metastatic Solid Tumors

This is a phase I, open-label, dose-escalation and expansion study to evaluate the safety, tolerability, PK and PD of HSK42360 when given orally in patients with active BRAF V600 mutation locally advanced or metastatic Solid Tumors.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: HSK42360

Detailed Description

The study will contain two phases: Phase Ia is dose escalation phase and Phase Ib is dose expansion phase.

Phase Ia will contain two part: Dose Escalation Part (Part A) and Extension Part (Part B). Part A based on the "3+3" design for dose escalation and safety evaluation requirements. Patient cohorts at selected doses may be extended to further investigate the tolerability, PK and PD of HSK42360. The number of patients to be enrolled will be up to 10 subjects in each Part B cohort. Approximately 30-70 subjects will be enrolled in Phase Ia.

Phase Ib no less than 10-50 subjects will be enrolled in each expansion cohort.

• Study Type: Interventional
• Enrollment (Estimated): 316
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100142
      • Recruiting
      • Beijing Cancer Hospital
      • Contact: Lin Shen; Phone Number: 0086-10-88196561; Email: doctorshenlin@sina.cn
    • Beijing, Beijing, China, 100034
      • Recruiting
      • Peking University First Hospital
      • Contact: ShiKai Wu; Phone Number: 15810037307; Email: Skywu4923@sina.com
    • Beijing, Beijing, China, 100070
      • Recruiting
      • Beijing Tiantan Hospital,Capital Medical University
      • Contact: WenBin Li; Phone Number: 15301377998; Email: neure55@126.com
  • Fujian
    • Fuzhou, Fujian, China, 350005
      • Recruiting
      • The First Affiliated Hospital Of Fujian Medical University
      • Contact: Dezhi Kang; Phone Number: 15759413951; Email: kdz99988@sina.com
  • Guangdong
    • Guangzhou, Guangdong, China, 510145
      • Recruiting
      • Sun yat-sen University Cancer Center
      • Contact: XiaoShi Zhang; Phone Number: 15915733209; Email: zhangxsh@sysucc.org.cn
  • Guangxi
    • Nanning, Guangxi, China, 530012
      • Recruiting
      • Guangxi Medical University Cancer Hospital
      • Contact: ZhenChao Yuan; Phone Number: 18677102309; Email: yzhenchao11@163.com
      • Contact: Wei Jiang; Phone Number: 13557710254; Email: 775022385@qq.com
  • Henan
    • Zhengzhou, Henan, China, 450099
      • Recruiting
      • The Third People's Hospital of Zhengzhou
      • Contact: WeiZhen Zhang; Phone Number: 13937130192; Email: zwzgcp@163.com
  • Hunan
    • Changsha, Hunan, China, 410000
      • Recruiting
      • Hunan Cancer Hospital
      • Contact: XianAn Li; Phone Number: 18874933879; Email: lixianan2001@163.com
      • Contact: YongChang Zhang; Phone Number: 13873123436; Email: zhangyongchang@hnca.org.cn
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Recruiting
      • Nanjing Drum Tower Hospital
      • Contact: RuTian Li; Phone Number: 13813863961; Email: li_rutian@163.com
  • Shanghai
    • Shanghai, Shanghai, China, 201321
      • Recruiting
      • Fudan University Shanghai Cancer Center
      • Contact: Jian Zhang; Phone Number: 18017312991; Email: syner2000@163.com
      • Contact: Yu Xu; Phone Number: 18017312784; Email: xuyudaniel@hotmail.com
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310006
      • Recruiting
      • Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University
      • Contact: Ying Wang; Phone Number: 18367124548; Email: nancywangying@163.com
      • Contact: Bing Xia; Phone Number: 18857110928; Email: bingxia_hzch@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years，Male and female patients, at time of signing informed consent form (ICF).
2. ECOG performance status 0-1, or KPS (Karnofsky Performance Status) Score>60.
3. Life expectancy ≥ 3 months.
4. Patients with locally advanced or metastatic solid tumors confirmed by histology or cytology, who have failed standard treatment (disease progression after treatment or intolerable treatment); patients who have previously received BRAF and/or MEK inhibitor therapy are allowed to be included in this study.
5. Positive BRAF V600 mutation result confirmed prior to the administration of HSK42360.
6. Patients will provide blood or tumor sample according to their own willingness.
7. Measurable or non-measurable disease by RECIST 1.1 or RANO criteria.
8. Brain metastasis patients with inactive CNS lesions; Original intracranial tumor patient with inactive CNS lesions, or patients treated with ≤4mg/day corticosteroid and without convulsion for ≥2 weeks.
9. Adequate hematologic, hepatic, and renal function.
10. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days after the last dose.

Exclusion Criteria:

1. malignant tumor within 2 years, with the exception of cutaneous squamous cell carcinoma, cervical carcinoma in situ, papillary thyroid carcinoma, or other tumors with low malignancy.
2. Uncontrollable pleural effusion, ascites, or pericardial effusion per protocol.

3. Treatment with any of the following:

   Prior treatment with anti-tumor drug within 4 weeks or approximately 5 × t1/2 prior to the first dose of HSK42360, whichever is shorter; Prior treatment with nitrosourea or mitomycin C within 6 weeks prior to the first dose of HSK42360; Prior treatment with palliative radiotherapy or anti-tumor herbs within 2 weeks prior to the first dose of HSK42360; Prior treatment with radiotherapy, electric field therapy, or other anti-tumor therapies within 4 weeks prior to the first dose of HSK42360.

4. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment, with the exception of alopecia, dermal toxicity, and other toxicity considering no safety risks by investigator.
5. Any disease which would preclude drug absorption, metabolism or pharmacokinetics, e.g. active peptic ulcer or chronic gastroesophageal reflux disease.
6. Patients who have clinically significant or uncontrolled cardiac disease, include: QTc interval ≥ 450(male)/470(female) msec; any clinically significant arrhythmia; left ventricular ejection fraction < 50%; myocardial infarction, unstable angina, or class III/IV cardiac failure by the NYHA that occurred within 6 months prior to the first dose of HSK42360.
7. Any thromboembolic events within 6 months prior to the first dose of HSK42360; any familial or acquired thrombophilia.
8. Uncontrolled hypertension (systolic pressure≥160mmHg, or diastolic pressure≥100mmHg), diabetes (fasting blood-glucose≥10mmol/L), seizures, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, pulmonary interstitial fibrosis, Parkinson's disease, active bleeding, or systemic active infection.
9. Any unstable systemic disease, e.g. severe metabolic disease: liver cirrhosis, renal failure, or uremia.
10. Treatment with inhibitors/inducers for CYP3A4, or substrates of CYP3A4, CYP2C9, CYP2C8, OATP1B1, OATP1B3, OAT1, OAT3, P-gp or BCRP within 14 days or approximately 5 × t1/2 prior to the first dose of HSK42360, whichever is shorter.
11. Patient with cognitive dysfunction, or history of mental illness, other uncontrolled comorbidities, alcohol dependence, hormone dependence or drug abuse.
12. Autologous transplantation surgery within 3 months prior to the first dose of HSK42360; Allogeneic transplantation, or stem-cell Transplant surgery within 6 months prior to the first dose of HSK42360; Major surgery or significant traumatic injury occurring within 4 weeks prior to the first dose of HSK42360.
13. Patient with a history of immunodeficiency, including HIV positive, or other acquired/congenital immunodeficiency diseases.
14. Any disease of the eyes > CTCAE v5.0 Grade 1.
15. Patient with active hepatitis B or hepatitis C.
16. Patient with active syphilis infection.
17. Allergic to any HSK42360 active constituent or ingredients.
18. Participate in other clinical trials within 4 weeks prior to the first dose of HSK42360.
19. Positive pregnancy test, or breastfeeding.
20. Any other circumstances that would, in the investigator's judgment, prevent the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase Ia (Part A): HSK42360 as monotherapy; Phase 1a (Part A): dose escalation of HSK42360 as monotherapy at various dose levels	Drug: HSK42360; Oral administration, QD
Experimental: Phase Ia (Part B): HSK42360 as monotherapy; Phase 1a (Part B): dose extention of HSK42360 as monotherapy at certain dose levels	Drug: HSK42360; Oral administration, QD
Experimental: Phase Ib: HSK42360 as monotherapy; Phase 1b: dose expansion for HSK40118 as monotherapy at a dose determined during Phase 1a (Part B) in patients with BRAF V600 mutation locally advanced or metastatic solid tumors	Drug: HSK42360; Oral administration, QD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MTD	MTD determination: dose limiting toxicity (DLT) rate	Up to approximately 52 months
DLTs	Incidence of dose-limiting toxicities (DLTs) at Cycle 0 and Cycle1	Up to approximately 52 months
AEs	Rate and severity of adverse events of HSK42360 as monotherapy	Up to approximately 52 months
RP2D	RP2D determination: DLT, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary safety and anticancer activity data	Up to approximately 52 months
ECOG Performance Status Scale	Change of the grade as a part of HSK43260 safety data	Up to approximately 52 months
Karnofsky Performance Scale, KPS	Change of the grade as a part of HSK43260 safety data	Up to approximately 52 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease control rate (DCR)	DCR, defined as the proportion of patients who experience a best response of CR, PR, or stable disease (SD) according to RECIST 1.1	Up to approximately 52 months
Duration of response (DOR)	DOR, defined as the time from first documented response of complete response (CR) or partial response (PR) to the date of first documented progressive disease or death due to any cause, whichever occurs first	Up to approximately 52 months
Overall response rate (ORR)	ORR, defined as the proportion of patients who experience a best response of confirmed CR or PR according to RECIST 1.1/RANO	Up to approximately 52 months
Progression free survival (PFS)	PFS, defined as the time frocease or death due to any cause, whichever occurs first	Up to approximately 52 months
Overall survival (OS)	OS, defined as the time from the first dose of HSK42360 until the date of death due to any cause	Up to approximately 52 months
Area under the curve (AUC) of HSK42360		Circle 0 (single-dose circle, 3 days) and circle 1 (multiple-dose circle, 21days)
maximum plasma concentration (Cmax) of HSK42360		Circle 0 (single-dose circle, 3 days) and circle 1 (multiple-dose circle, 21days)
half-life (t1/2) of HSK42360		Circle 0 (single-dose circle, 3 days) and circle 1 (multiple-dose circle, 21days)
Tmax(Time to maximum plasma concentration) of HSK42360		Circle 0 (single-dose circle, 3 days) and circle 1 (multiple-dose circle, 21days)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
circulating tumor DNA (ctDNA)	Assess treatment-induced modulation of MAPK pathway biomarkers	Up to approximately 52 months
phosphorylate ERK (pERK)	Assess the degradation of pERK protein	Up to approximately 52 months

Collaborators and Investigators

• Sponsor: Haisco Pharmaceutical Group Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2024
• Primary Completion (Estimated): August 30, 2026
• Study Completion (Estimated): July 7, 2027

Study Registration Dates

• First Submitted: July 24, 2024
• First Submitted That Met QC Criteria: August 1, 2024
• First Posted (Estimated): August 5, 2024

Study Record Updates

• Last Update Posted (Estimated): August 5, 2024
• Last Update Submitted That Met QC Criteria: August 1, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: HSK42360-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No