DHX33-positive relapsed/refractory advanced malignant tumors

.1 Primary Objectives:  To assess the safety, tolerability, and dose-limiting toxicities (DLTs) of KY386 in patients with relapsed/refractory advanced malignant tumors.  To determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) and recommended doses for expansion (RDEs) in patients with relapsed/refractory advanced malignant tumors.

solution

KY386

084

3.5ml

Safety should be evaluated at follow-up visits and throughout the study. Adverse events
will be assessed for their severity (based on the NCI-CTCAE 5.0 rating), duration, and
association with study treatment.
The following safety indicators will be measured and evaluated at designated intervals
throughout the study. Patient history was taken at baseline to understand underlying
conditions.
3.1 Safety A

1. Participants must be male or female and at least 18 years of age.

2. Participants must be assessed by the trial administrator as meeting the following three criteria: a. They fully understand the study requirements and voluntarily sign a written informed consent form. b. They can comply with the requirements for the medications taken by the participants in the study and all study-related procedures and assessments. c. They are not considered potentially unreliable and/or unable to cooperate.

3. If a participant is participating in a dose escalation trial (Ia), their ECOG (East Coast Cancer Clinical Research Collaboration) assessment scale score must be between 0 and 1. If a participant is participating in a dose expansion trial (Ib), their ECOG score must be between 0 and 2.

4. For participation in Phase Ia, subjects must meet the following criteria: They must have histologically or cytologically confirmed stage III or IV metastatic or unresectable solid tumors, including colon, liver, melanoma, gastric cancer, non-small cell lung cancer, endometrial cancer, and prostate cancer, and have measurable tumors according to RECIST 1.1 (Research Criteria for Efficacy Evaluation in Solid Tumors), and be ineffective or intolerant of existing treatments known to offer clinical benefit. Furthermore, considering that patients with stage III resectable tumors have other effective or survival-prolonging therapies available, this trial will not include this type of patient.

5. For participation in Phase Ib, subjects must meet one of the following criteria: They must have histologically or cytologically confirmed stage III or IV metastatic or unresectable cancers, and these cancers must have measurable tumors according to RECIST 1.1, and be ineffective or intolerant of all existing treatments known to offer clinical benefit. Furthermore, considering that patients with stage III resectable tumors of these cancers have other effective or survival-prolonging therapies available, this trial will not include this type of patient.

(1) Hepatocellular carcinoma (HCC)

(2) Colorectal cancer (including RAS activated carcinoma, but excluding RAS G12C mutation)

(3) HER-2 negative gastric cancer

(4) Endometrial cancer

(5) Prostate cancer

6. Subjects have received chemotherapy or the following treatments:

(1) Prior to receiving at least one treatment for advanced/metastatic tumors;

(2) Prior to receiving up to five treatments for advanced/metastatic tumors.

7. Subjects have recovered from the toxicity of previous treatments (excluding hair loss, fatigue, or peripheral neuropathy), and their physical condition has returned to Level 1 or their pre-treatment baseline level according to the National Cancer Institute Common Terminology for Adverse Events (NCI-CTCAE V5.0).

8. If subjects are participating in Phase Ib, they must be willing to provide tissue samples confirmed by genetic testing to be DHX33 positive.

9. Subjects should avoid blood transfusions or injections of white blood cell growth hormone (G-CSF) for 14 days prior to the blood test for screening assessment to meet inclusion criteria. In addition, the subjects' blood test results should meet the following criteria:

(1) Heme ≥ 90 g/L

(2) Platelet count ≥ 100 × 10⁹/L

(3) Neutrophil count (ANC) ≥ 1.5 × 10⁹/L

(4) Total bilirubin ≤ 1.5 times the upper limit of normal

(5) Liver function indices [aspartate transaminase (AST) and alanine transaminase (ALT)] ≤ 3.0 times the upper limit of normal; for patients with liver cancer, ≤ 5.0 times the upper limit of normal

(6) Renal clearance calculated according to the Cockcroft-Gault equation must be greater than 50 mL/min.

10. Subjects must have no history of alcohol abuse within the past year. 11. Subjects must have adequate coagulation function during screening: activated partial thromboplastin time (APTT) and international normalized ratio (INR) must be less than or equal to 1.5 times the upper limit of normal (values ​​should fall within the target range if the subject is receiving anticoagulation therapy).

12. Subjects must have a life expectancy longer than 12 weeks.

13. If the subject is a woman of fertility, a serum pregnancy test must be performed within 7 days prior to the first infusion of the investigational drug and confirmed to be negative. Both male and female subjects of fertility must agree to use effective contraception during screening, the trial, and for three months after the last treatment. A patient is considered fertile if, according to the trial administrator's assessment, they are biologically capable of reproduction and have engaged in sexual activity.

1. Participants must be male or female and at least 18 years of age.

2. Participants must be assessed by the trial administrator as meeting the following three criteria: a. They fully understand the study requirements and voluntarily sign a written informed consent form. b. They can comply with the requirements for the medications taken by the participants in the study and all study-related procedures and assessments. c. They are not considered potentially unreliable and/or unable to cooperate.

3. If a participant is participating in a dose escalation trial (Ia), their ECOG (East Coast Cancer Clinical Research Collaboration) assessment scale score must be between 0 and 1. If a participant is participating in a dose expansion trial (Ib), their ECOG score must be between 0 and 2.

4. For participation in Phase Ia, subjects must meet the following criteria: They must have histologically or cytologically confirmed stage III or IV metastatic or unresectable solid tumors, including colon, liver, melanoma, gastric cancer, non-small cell lung cancer, endometrial cancer, and prostate cancer, and have measurable tumors according to RECIST 1.1 (Research Criteria for Efficacy Evaluation in Solid Tumors), and be ineffective or intolerant of existing treatments known to offer clinical benefit. Furthermore, considering that patients with stage III resectable tumors have other effective or survival-prolonging therapies available, this trial will not include this type of patient.

5. For participation in Phase Ib, subjects must meet one of the following criteria: They must have histologically or cytologically confirmed stage III or IV metastatic or unresectable cancers, and these cancers must have measurable tumors according to RECIST 1.1, and be ineffective or intolerant of all existing treatments known to offer clinical benefit. Furthermore, considering that patients with stage III resectable tumors of these cancers have other effective or survival-prolonging therapies available, this trial will not include this type of patient.

(1) Hepatocellular carcinoma (HCC)

(2) Colorectal cancer (including RAS activated carcinoma, but excluding RAS G12C mutation)

(3) HER-2 negative gastric cancer

(4) Endometrial cancer

(5) Prostate cancer

6. Subjects have received chemotherapy or the following treatments:

(1) Prior to receiving at least one treatment for advanced/metastatic tumors;

(2) Prior to receiving up to five treatments for advanced/metastatic tumors.

7. Subjects have recovered from the toxicity of previous treatments (excluding hair loss, fatigue, or peripheral neuropathy), and their physical condition has returned to Level 1 or their pre-treatment baseline level according to the National Cancer Institute Common Terminology for Adverse Events (NCI-CTCAE V5.0).

8. If subjects are participating in Phase Ib, they must be willing to provide tissue samples confirmed by genetic testing to be DHX33 positive.

9. Subjects should avoid blood transfusions or injections of white blood cell growth hormone (G-CSF) for 14 days prior to the blood test for screening assessment to meet inclusion criteria. In addition, the subjects' blood test results should meet the following criteria:

(1) Heme ≥ 90 g/L

(2) Platelet count ≥ 100 × 10⁹/L

(3) Neutrophil count (ANC) ≥ 1.5 × 10⁹/L

(4) Total bilirubin ≤ 1.5 times the upper limit of normal

(5) Liver function indices [aspartate transaminase (AST) and alanine transaminase (ALT)] ≤ 3.0 times the upper limit of normal; for patients with liver cancer, ≤ 5.0 times the upper limit of normal

(6) Renal clearance calculated according to the Cockcroft-Gault equation must be greater than 50 mL/min.

10. Subjects must have no history of alcohol abuse within the past year. 11. Subjects must have adequate coagulation function during screening: activated partial thromboplastin time (APTT) and international normalized ratio (INR) must be less than or equal to 1.5 times the upper limit of normal (values ​​should fall within the target range if the subject is receiving anticoagulation therapy).

12. Subjects must have a life expectancy longer than 12 weeks.

13. If the subject is a woman of fertility, a serum pregnancy test must be performed within 7 days prior to the first infusion of the investigational drug and confirmed to be negative. Both male and female subjects of fertility must agree to use effective contraception during screening, the trial, and for three months after the last treatment. A patient is considered fertile if, according to the trial administrator's assessment, they are biologically capable of reproduction and have engaged in sexual activity.