Prospective registration

Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of HZ-V055 in Participants with RAS-Mutated Advanced Solid Tumors

QIANKUN-1

Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of HZ-V055 in Participants with RAS-Mutated Advanced Solid Tumors

Miao Hu 

Yu Xianjun 

Room 804, Building 16, Hexiang Technology Center, Xiasha Subdistrict, Qiantang New Area, Hangzhou City, Zhejiang Province

No. 270 Dong'an Road, Xuhui District, Shanghai

Hangzhou Hezheng Pharmaceutical Co., Ltd.

Fudan University Shanghai Cancer Center

Yes

Shanghai Cancer Center Institutional Review Board SCCIRB

Zhang WeiJing

No. 270 Dong'an Road, Xuhui District, Shanghai

Fudan University Shanghai Cancer Center

No. 270 Dong'an Road, Xuhui District, Shanghai

Hangzhou Hezheng Pharmaceutical Co., Ltd.

RAS-mutated advanced solid tumors

Interventional study

1

Single arm 

To evaluate the safety and tolerability of HZ-V055 in study participants with RAS-mutated advanced solid tumors.To determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), as well as the recommended phase II dose (RP2D) of HZ-V055.To characterize the pharmacokinetic (PK) profiles of HZ-V055 in participants with RAS-mutated advanced solid tumors.To assess the preliminary efficacy of HZ-V055 in participants with RAS-mutated advanced solid tumors.

1. The participant has been fully informed about the study and voluntarily signs the informed consent form (ICF). 2. Male or female participants aged >=18 and <=75 years at the time of signing the ICF. 3. An estimated life expectancy of >=3 months. 4. Eastern Cooperative Oncology Group (ECOG) performance status: (1) 0–1 for the dose-escalation and backfill cohorts; (2) 0–2 for the cohort-expansion phase. 5. Dose-escalation cohort: Participants with histologically or cytologically confirmed locally advanced or metastatic solid tumors harboring a nonsynonymous mutation at KRAS codon 12 (G12), who have experienced disease progression following standard therapy, are unable to tolerate or refuse standard therapy, or for whom no standard therapy is available. 6. Backfill cohorts and cohort-expansion phase: (1) Participants with histologically or cytologically confirmed locally advanced or metastatic solid tumors harboring a nonsynonymous RAS mutation, including KRAS, HRAS, or NRAS mutations at codon 12, 13, or 61 (G12, G13, or Q61). Eligible tumor cohorts include pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), biliary tract cancer (BTC), and other advanced solid tumors. Participants must meet the applicable prior-treatment requirements below: 1) Cohort 1—PDAC: Participants must have previously received gemcitabine-based or fluoropyrimidine-based combination chemotherapy, or may be treatment-na?ve participants who have not received any prior systemic therapy, the latter being permitted only in the cohort-expansion phase; 2) Cohort 2—NSCLC: Participants must have previously received anti-PD-(L)1 therapy and/or standard platinum-based chemotherapy; 3) Cohort 3—CRC: Participants must have previously received irinotecan-based or oxaliplatin-based combination chemotherapy; 4) Cohort 4—BTC: Participants must have previously received gemcitabine in combination with a platinum agent, such as cisplatin or carboplatin; 5) Cohort 5—Other advanced solid tumors: Participants must have received the currently available standard therapy. (2) All participants described above must have experienced disease progression following standard therapy, be unable to tolerate or refuse standard therapy, or have no available standard therapy. 7. At least one measurable target lesion according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). For the dose-escalation cohort, participants without a target lesion or with a non-measurable target lesion but with an evaluable non-target lesion may also be considered for enrollment upon approval by the Sponsor. 8. The KRAS, NRAS, or HRAS mutation must be confirmed by histological or cytological testing. The test result must be issued by a qualified testing laboratory or a Grade III Class A hospital, and the testing method must be acceptable to the Sponsor. Enrollment may proceed after discussion and confirmation with the Sponsor. 9. Adequate organ function prior to the first dose of study drug, as defined below: (1) Hematologic function, without the use of hematopoietic growth factors: 1) For short-acting growth factors, none may have been used within 7 days before the screening laboratory tests; 2) For long-acting growth factors with a half-life >48 hours, such as pegfilgrastim, none may have been used within 14 days before the screening laboratory tests; 3) Absolute neutrophil count (ANC) >=1.5 × 10^9/L; 4) Platelet count >=90 × 10^9/L, without platelet transfusion within 7 days before screening; 5) Hemoglobin >=9 g/dL, without red blood cell transfusion within 14 days before screening. (2) Hepatic function: 1) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5 × the upper limit of normal (ULN), or <=5 × ULN in participants with liver metastases; 2) Total bilirubin (TBIL) <=1.5 × ULN, or <=3.0 × ULN for participants with Gilbert syndrome or in whom an elevated indirect bilirubin (IBIL) level indicates that the TBIL elevation is attributable to an extrahepatic cause; 3) For participants with obstructive jaundice, TBIL must be reduced to <=1.5 × ULN following drainage; 4) Serum albumin >=2.5 g/dL. (3) Renal function: Creatinine clearance (CrCl) >=50 mL/min, calculated using the Cockcroft–Gault formula or measured by 24-hour urine collection. (4) Coagulation function: International normalized ratio (INR) or prothrombin time (PT), and activated partial thromboplastin time (APTT), <=1.5 × ULN. (5) Cardiac function: 1) Left ventricular ejection fraction (LVEF) >=50%; 2) QT interval corrected using Fridericia's formula (QTcF) <=470 ms, calculated as QTcF = QT/(RR^0.33), where RR is the normalized heart rate interval and RR = 60/heart rate. 10. Any non-hematologic toxicity related to prior treatment must have recovered to Grade 1 or lower according to National Cancer Institute Common Terminology Criteria for Adverse Events version 6.0 (NCI CTCAE v6.0) before the first dose of study drug, except for: (1) Alopecia; (2) Other toxicities of Grade 2 or lower without clinically significant symptoms; such participants may be permitted to enroll after discussion with the Sponsor's medical monitor; (3) Hypothyroidism, provided that the participant has received a stable dose of thyroid hormone replacement therapy for at least 30 days before enrollment. 11. Female and male participants of reproductive potential must have no plans to conceive or father a child with their partners during the study and for 3 months after discontinuation of study treatment. Throughout the study and for 3 months after treatment discontinuation, participants must use at least one of the following effective contraceptive methods: (1) Abstinence; (2) Physical or barrier contraception, such as sterilization or condoms; (3) Hormonal contraception initiated at least 3 months before the first dose of study drug. (4) Male participants must not donate sperm from the start of treatment until 3 months after treatment discontinuation. (5) Women of childbearing potential include premenopausal women and women within 2 years after the onset of menopause. All women of childbearing potential must have a confirmed negative pregnancy test within 7 days before the first dose of study drug. 12. In the investigator's judgment, the participant is able to communicate adequately, attend scheduled follow-up visits, and comply with the requirements of the protocol.

1. An active malignancy other than the primary tumor within the previous 3 years, except for adequately treated basal cell carcinoma or squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, or papillary thyroid carcinoma. 2. Unstable or progressive central nervous system (CNS) metastases or leptomeningeal carcinomatosis, or other evidence indicating that CNS metastases have not been adequately controlled and, in the investigator's judgment, render the participant unsuitable for enrollment. 3. Prior or current treatment with a Pan-RAS or Pan-KRAS inhibitor. Note: Participants who have previously received or are currently receiving an inhibitor targeting a specific KRAS mutant allele, such as a KRAS G12C or KRAS G12D inhibitor, may be considered for enrollment after adequate assessment and with the Sponsor's approval. 4. Receipt of systemic anticancer treatment, including investigational anticancer drugs or vaccines, within 4 weeks before the first dose of study drug, except as follows: (1) Cytotoxic agents associated with severe delayed toxicity, such as nitrosoureas or mitomycin C, within 6 weeks before the first dose of study drug; (2) Oral fluoropyrimidines, small-molecule targeted therapies, or local anticancer therapies within 2 weeks or 5 drug half-lives before the first dose of study drug, whichever is shorter; (3) Traditional Chinese medicines with an anticancer indication within 2 weeks before the first dose of study drug; (4) Immunotherapy, including immune checkpoint inhibitors, within 4 weeks or 5 drug half-lives before the first dose of study drug, whichever is shorter; (5) Palliative radiotherapy directed at a local lesion and not expected to affect bone marrow hematopoietic function, which must have been completed at least 2 weeks before the first dose of study drug. 5. Major organ surgery or significant trauma within 4 weeks before the first dose of study drug; a non-study-related minor surgical procedure, such as needle biopsy or venous catheter placement, within 7 days before the first dose; or anticipated need for major surgery during the study. 6. Receipt of a live attenuated vaccine within 4 weeks before the first dose of study drug, or planned receipt of a live attenuated vaccine during the study. 7. Clinically significant, symptomatic, and uncontrolled fluid accumulation in a body cavity, such as pericardial effusion, ascites, or pleural effusion that remains uncontrolled despite drainage or other treatment. 8. Any condition that affects the participant's ability to swallow the study drug or that, in the investigator's judgment, may substantially impair study drug absorption, including uncontrolled chronic gastrointestinal disease or a history of gastrointestinal resection or surgery. 9. A definite bleeding tendency, including gastrointestinal bleeding or a bleeding gastric ulcer; a history of melena or hematemesis within 2 months before study drug administration; or a risk of visceral bleeding, as determined by the investigator. 10. A history of clinically significant idiopathic pulmonary fibrosis requiring treatment; any active interstitial lung disease or noninfectious pneumonitis; or receipt of thoracic radiotherapy within 2 months before enrollment. 11. An uncontrolled active infection, whether viral, bacterial, fungal, or otherwise, such as infectious pneumonia, or a requirement for anti-infective therapy administered via a non-enteral route. 12. Active hepatitis B or hepatitis C infection: hepatitis B includes acute hepatitis B, untreated chronic hepatitis B virus infection, or chronic HBV carriage with HBV DNA at or above the lower limit of detection of the local laboratory; hepatitis C includes positive HCV RNA. Participants with active syphilis or tuberculosis, including active or stable tuberculosis, a history of a positive tuberculosis screening result, or suspected tuberculosis, are also excluded. Note: Inactive hepatitis B surface antigen (HBsAg) carriers; participants with active HBV infection who have achieved sustained viral suppression with anti-HBV treatment, with HBV DNA below the lower limit of detection of the local laboratory; participants with cured HCV infection; and participants who are negative for HCV antibodies may be enrolled. 13. A history of immunodeficiency, including a positive HIV test; another acquired or congenital immunodeficiency disorder; or a history of organ transplantation. Participants are also excluded if they have active autoimmune disease or a history of autoimmune disease, such as autoimmune enteritis or systemic lupus erythematosus, or an ongoing immune-related adverse event of any grade caused by an immune checkpoint inhibitor or other immunomodulatory therapy that requires systemic treatment, such as a disease-modifying agent, supraphysiologic corticosteroid doses, or immunosuppressive therapy. Note: Participants with an endocrine disorder caused by an autoimmune disease, immune checkpoint inhibitor, or other immunomodulatory therapy who are receiving hormone replacement therapy may be considered for enrollment following adequate assessment and with the approval of the Sponsor's medical monitor. 14. A history of a CNS disorder within 12 months before screening, including seizure, cerebrovascular ischemia or hemorrhage, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychiatric illness, or any autoimmune disease involving the CNS. 15. A clinically significant severe cardiovascular disease, including any of the following: (1) Congestive heart failure; (2) New York Heart Association (NYHA) Class III or IV heart disease; (3) Unstable angina; (4) Myocardial infarction or another cardiovascular event within 6 months before enrollment; (5) Clinically significant moderate or severe valvular heart disease; (6) Atrial fibrillation with a European Heart Rhythm Association (EHRA) classification of Grade >=2b, or an arrhythmia that is symptomatic or requires treatment during screening, except for supraventricular tachycardia with a controlled heart rate; (7) A history of other risk factors for torsades de pointes, such as heart failure, hypokalemia, or a family history of long QT syndrome; (8) A requirement for concomitant administration of a drug known to prolong the QT/QTc interval; (9) Uncontrolled hypertension, defined as systolic blood pressure >=160 mmHg or diastolic blood pressure >=100 mmHg, which, in the investigator's judgment, renders the participant unsuitable for participation. 16. Another poorly controlled systemic disease or clinically significant clinical or laboratory abnormality that, in the investigator's judgment, may interfere with the safety assessment. 17. A requirement for treatment with systemic cyclosporine A or a cyclosporine A derivative. 18. Within 14 days or 5 drug half-lives before the first dose of study drug, whichever is longer: receipt of a strong or moderate inhibitor or inducer of CYP3A4 or P-glycoprotein (P-gp), except for local or topical treatment; receipt of a drug known to be a sensitive substrate of CYP2C9, P-gp, OATP1B1, or OATP1B3, except for local or topical treatment; or consumption of Seville oranges, grapefruit, or grapefruit-containing products. 19. Female participants who are pregnant or breastfeeding. 20. A severe psychiatric or psychological disorder, a history of drug abuse, or a history of severe alcohol abuse. 21. Any other serious systemic disease, laboratory abnormality, or other condition that, in the investigator's judgment, makes the participant unsuitable for participation in the clinical study. 22. Current participation in another clinical trial involving an investigational drug, vaccine, or medical device; completion of another such clinical trial less than 28 days previously; or current receipt of another investigational drug or vaccine.

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EDC