A Study of CSCJC3456 in Patients with Advanced Malignant Tumors

This study is a multicenter, open phase I clinical study of dose escalation, cohort expansion study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of CSCJC3456 in patients with advanced malignant solid tumors.

CSCJC3456 is a multi-target tyrosine kinase inhibitor, and this is the first-in-human trial of CSCJC3456. This study adopts an open-label, non-randomized, single-arm, dose-escalation, and cohort expansion research design, and is divided into two parts, Phase Ia and Phase Ib.

Phase Ia is a single and multiple dose escalation trial with an open-label design, aiming to evaluate the safety, tolerability, PK, and PD characteristics of CSCJC3456 tablets, preliminarily assess the anti-tumor efficacy, and recommend the dose for Phase Ib study.

Phase Ib is a single-arm cohort expansion study conducted in participants with four target solid tumors, based on the recommended dosage and dosing cycle from the Phase Ia study. The actual tumor types for the Phase Ib study will be adjusted according to the safety and efficacy data from the Phase Ia study.

Eligibility Criteria:
Inclusion Criteria:

1. Voluntarily sign the informed consent and follow protocol requirements;
2. Aged 18 to 75 (including both ends), male or female, regardless of race;
3. Expected survival period ≥ 12 weeks;
4. ECOG score ≤1 (see Appendix 6);
5. Phase Ia study:

   ● Participants with advanced malignant solid tumors confirmed by pathology or cytology, who have experienced disease progression despite standard treatment, are intolerant to standard treatment, or lack effective standard treatment; and who possess at least one measurable lesion in accordance with RECIST v1.1 criteria;

   Phase Ib study:
   * Cohort A (hepatocellular carcinoma, including at least 2 participants with FGFR4 positivity), Cohort B (colorectal cancer, including at least 2 participants with FGFR1 or FGFR2 positivity), Cohort C (gastric cancer (including adenocarcinoma at the gastroesophageal junction), including at least 2 participants with FGFR1 or FGFR2 positivity), Cohort D (recurrent/metastatic endometrial cancer, including at least 2 participants with FGFR2 or FGFR3 positivity), or other sensitive tumor types identified in phase Ia trial, confirmed by histology or cytology, who have failed or are intolerant to standard treatment. Investigators may adjust participant selection based on their response to treatment in the trial and communication with the sponsor.
   * Each cohort of participants had at least one measurable lesion that met the criteria of RECIST v1.1.
6. Before the first dose, the participant has recovered from the toxic effects of the previous last treatment (CTCAE grade ≤ 1, except for special conditions such as "hair loss" and "pigmentation"), and in addition, the investigator judges that the corresponding AE did not pose a safety risk;
7. Systolic blood pressure ≤150 mmHg, diastolic blood pressure ≤90 mmHg, and no changes in antihypertensive medication and dosage within 7 days prior to the first administration.
8. Adequate Organ and bone marrow function.
9. Female participants of childbearing age must undergo a serum pregnancy test 7 days before starting the study medication, and the result must be negative. They must also be willing to adopt a medically approved highly effective contraceptive measure (e.g., an intrauterine device, contraceptive pills, or condoms) during the study period and for 3 months after the last administration of study medication. Male participants whose partners are female of childbearing age should agree to adopt an effective contraceptive method during the study period and for 3 months after the last administration of study medication. Breastfeeding women should agree to cease breastfeeding during the study period and for 3 months after the last administration of study medication.
10. Have the gene sequencing results of the current tumor, or are willing to provide tumor tissue specimens (paraffin-embedded tissue blocks, or serial sections).

    * Specimens are preferably derived from recently collected and usable tumor tissues. For relevant instructions, please refer to the Central Laboratory Manual.
    * In cases where there is insufficient tumor tissue (e.g., insufficient number of available slides, including situations where no tissue specimens are available) and the investigator believes that another tumor tissue biopsy is unsafe, intolerable, infeasible, or the patient refuses, the patient can be enrolled in the study after discussion with the sponsor.

Exclusion Criteria:

1. Previous or current diagnosis of other types of malignancy, except for the following:

   1. Radically cured basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, cervical carcinoma in situ, or breast cancer in situ;
   2. Second primary cancer that has been cured with no recurrence within 5 years;
2. Patients who are allergic to any component of the study drug or have a history of severe allergies;
3. Having received any of the following treatments or medications before the first study treatment:

   1. Major surgery or major trauma occurred within 4 weeks before the first study drug, but diagnostic tissue biopsies are allowed. Severe trauma refers to unhealed wounds, ulcers, or fractures;
   2. Received treatment with traditional Chinese patent medicines and simple preparations with anti-tumor indications within 2 weeks before the first study drug treatment;
   3. Received anti-tumor treatment (including chemotherapy, radiotherapy, immunotherapy, targeted therapy, biotherapy, or tumor embolization) within 4 weeks before the first administration. For oral fluoropyrimidine drugs and endocrine therapy, drug withdrawal ≤2 weeks; nitrosourea, mitomycin, or monoclonal antibody therapy, drug withdrawal ≤6 weeks. If the elution time is insufficient due to schedule or drug PK characteristics, it is necessary to discuss with the sponsor;
   4. Have received a potent CYP2C8 or CYP3A4 inducer within 2 weeks before the first dose; Or have received potent CYP2C8 or CYP3A4 inhibitors with less than 5 half-lives before the first dose;
   5. Have received medications known to significantly prolong the QT interval (e.g., class Ia and class III antiarrhythmic drugs) within 1 week before the first dose;
   6. Previously received treatment with FGFR inhibitors (e.g., pemetrexed, erdafilone, infigranib, forodesine, ponatinib, dovitinib, nintedanib, AZD4547, NVP-BGJ398, LY2784455, BAY1163877, etc.);
4. Patients with a history of central nervous system metastasis or spinal cord compression. Those who meet the following criteria can be enrolled:

   1. Patients who have clearly received treatment and have been clinically stable for 4 weeks after discontinuing anticonvulsants and steroids prior to the first administration of the study drug (definition of clinical stability: no clinical accompanying symptoms such as intracranial hypertension or neurological symptoms within 4 weeks, and imaging findings indicating stable lesions within 4 weeks prior to the first administration of the drug);
   2. For patients with brain metastases, ≥21 days from whole brain radiation therapy (WBRT) to the first study treatment administration, ≥7 days from stereotactic radiosurgery (SRS) to the first study treatment administration, or ≥28 days from surgical resection to the first study treatment administration;
5. Advanced patients who have symptoms, spread to viscera, and are at risk of life-threatening complications in a short period of time, patients who have undergone at least two paracentesis and drainage within 4 weeks before the first dose, or patients who have undergone one paracentesis and drainage but have unstable pleural effusion, peritoneal effusion, or pericardial effusion;
6. Within the 6 months prior to screening, having a cardiovascular disease.
7. Uncontrolled systemic diseases, such as diabetes, hypertension, etc.;
8. Currently suffering from sudden pulmonary disease, interstitial lung disease or pneumonia, pulmonary fibrosis, acute pulmonary disease, etc., except for local interstitial pneumonia induced by radiotherapy;
9. Patients with a clear tendency towards gastrointestinal bleeding, including the following conditions: those with a history of black stool or hematemesis within 2 months; those whom investigators believe may have a high risk of major gastrointestinal bleeding;
10. Patients with previous or current grade ≥3 gastrointestinal perforation or visceral fistula;
11. Grade ≥3 diarrhea during the screening period;
12. Evidence of active infection.
13. Positive for human immunodeficiency virus (HIV RNA) or treponema pallidum antibodies;
14. Have multiple factors that affect oral medication (e.g., inability to swallow, chronic diarrhea, intestinal obstruction, etc.) or a condition that the investigator has judged to severely affect gastrointestinal absorption;
15. Having a clear history of neurological or psychiatric disorders, including epilepsy or dementia;
16. Having received any investigational drug within 4 weeks before the first administration, or participating in another clinical study at the same time (excluding the following situations: the patient is participating in an observational, non-interventional clinical study, or is in the follow-up period of an interventional clinical study; or the last study drug has been taken for more than 5 half-lives);
17. Patients deemed unsuitable for inclusion in this study by the investigators.