Cisplatin Adverse Reaction, Cisplatin Nephrotoxicity
Conditions
Keywords
Cisplatin, GMDTC, Mild renal dysfunction, Solid tumor, Investigational drugs
Brief summary
This trial is a multicenter, combined hydration, multiple-dose, dose-escalation phase Ib clinical study, designed to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic characteristics of the injection product GMDTC in participants with solid tumors and cisplatin-induced mild renal impairment.
Detailed description
The primary objective of this study is to evaluate the safety and tolerability of GMDTC in a single-dose, dose-escalation study in participants with mild renal impairment who are scheduled to receive cisplatin-based chemotherapy for solid tumors, and to determine the recommended phase II dose (RP2D) for this drug. The secondary objective is to evaluate the pharmacokinetic (PK) characteristics, pharmacodynamic (PD) characteristics, and renal function improvement after single-dose multiple administration of GMDTC following cisplatin chemotherapy in this group of participants.
Interventions
DRUGGMDTC 1 mg/ml
Cohort 1: Participants will receive high-dose cisplatin chemotherapy (75mg/m2) on D1 each cycle. Subsequently, they received GMDTC at a concentration of 1 mg/ml via intravenous infusion, once daily for 5 days, over 2 cycles, and then underwent a 2-week follow-up after the last administration.
DRUGGMDTC 2mg/ml
Cohort 2: Participants will receive high-dose cisplatin chemotherapy (75mg/m2) on D1 each cycle. Subsequently, they received GMDTC at a concentration of 2 mg/ml via intravenous infusion, once daily for 5 days, over 2 cycles, and then underwent a 2-week follow-up after the last administration.
DRUGGMDTC 3mg/ml
Cohort 3: Participants will receive high-dose cisplatin chemotherapy (75mg/m2) on D1 each cycle. Subsequently, they received GMDTC at a concentration of 3 mg/ml via intravenous infusion, once daily for 5 days, over 2 cycles, and then underwent a 2-week follow-up after the last administration.
Sponsors
Guangdong Jianersheng Pharmaceutical Technology Co., Ltd.
Sun Yat-Sen University Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The subject is able to understand and voluntarily sign a written Informed Consent Form (ICF), agreeing to comply with the study protocol. 2. When signing the ICF, the participant must be at least 18 years of age, regardless of gender. 3. The expected survival period of the subjects is ≥ 6 months. 4. The subjects have an ECOG performance status score of 0 or 1. 5. Malignant solid tumors (excluding renal cell carcinoma) diagnosed by histological or cytological examination must simultaneously meet the following criteria: Participants who have previously received cisplatin-based chemotherapy and developed mild cisplatin-induced renal insufficiency, and who are still scheduled to undergo cisplatin-based chemotherapy; Mild renal insufficiency is defined as: during the screening phase, estimated glomerular filtration rate (eGFR) ≥ 60 and \< 90 mL/min/1.73 m² (calculated using the CKD-EPI formula). 6. Within 7 days prior to the first administration, participants shall be assessed for adequate bone marrow function, as well as normal cardiac, pulmonary, hepatic, and coagulation function, based on the following laboratory tests (transfusion or administration of other growth factor-based supportive therapy is prohibited within 14 days prior to the first dose of the investigational product): Bone marrow function: Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L, platelet count ≥ 100 × 10\^9/L, and hemoglobin ≥ 90 g/L; Liver function: Total bilirubin (TBIL) ≤ 1.5 × ULN, or total bilirubin (TBIL) ≤ 3 × ULN (in cases of Gilbert syndrome); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.0 × ULN (≤ 5 × ULN if hepatic metastases are present); Serum albumin (ALB) ≥ 30 g/L; Coagulation function (in patients not receiving anticoagulant therapy): Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; Prothrombin time (PT) or International Normalized Ratio (INR) ≤ 1.5 × ULN. Patients receiving long-term anticoagulant therapy may participate in the study provided they have been on a stable anticoagulant dose for at least one month prior to the first administration of the investigational product. Unless the anticoagulant is a factor Xa inhibitor, a stable dose must be maintained for at least one week. 7. Women of childbearing potential must agree to take reliable contraceptive measures or abstain from sexual activity from the moment they sign the informed consent form until 6 months after the last administration of the investigational drug. Women of childbearing age must have a negative serum pregnancy test within 7 days before the first dose. 8. Male participants must agree to take reliable contraceptive measures or abstain from sexual activity from the moment they signed the informed consent form until six months after the last administration of the investigational drug. Additionally, male participants must agree not to donate sperm during this period.
Exclusion criteria
1. Those who have participated in any other clinical trials within 4 weeks before the first administration of the investigational drug or within 5 half-lives (whichever is shorter); 2. Those who are known or suspected to be allergic to any active ingredient or excipient of this product, or who have a specific history of allergic reactions as determined by the investigator to be unsuitable for treatment with the investigational drug; 3. Those who are known or suspected to be allergic to any active ingredient or excipient of cisplatin or any other platinum-based drugs; 4. The researchers identified those participants who would require a dose adjustment of cisplatin upon their first administration after being included in the study. 5. Previous administration and toxicity recovery status: Before the first administration of the investigational drug, all adverse events (AEs) experienced by the participants during previous anti-tumor administration had not returned to baseline levels or were ≤ grade 1 (based on NCI CTCAE V6.0). Participants with the following conditions are allowed to be included: alopecia (any grade), participants with renal insufficiency (estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73 m2); participants with other AEs (≤ grade 2), and their inclusion is determined by the investigator; 6. Those who have taken any drugs or health supplements (such as SGLT2 inhibitors like dapagliflozin, canagliflozin, empagliflozin, englestat, canagliflozin, hexagliflozin, igliflozin, rugliflozin, togliflozin, and natural compounds like aesculin; GLUT2 inhibitors such as cytochalasin B, aesculin, Huoxiang Zhengqi San, luteolin and isofraxidin) that may have interactions with the investigational drug within 4 weeks before the first administration of the investigational drug or 5 half-lives (whichever is longer) are excluded from the study. 7. Those who have taken any drugs or health supplements (such as colchicine, probenecid, antihistamines, phenothiazine drugs, aminoglycoside antibiotics, amphotericin B, cephalothin, chloramphenicol or its furan benzenic acid or furoxan sodium, penicillamine or other chelating agents) that may have interactions with cisplatin within 4 weeks before the last cisplatin administration or 5 half-lives (whichever is longer) will be excluded from the screening. 8. Participants with a history of peripheral neuropathy caused by cisplatin. 9. Participants with chickenpox or shingles, except those who have been cured in the past. 10. Participants with gout and hyperuricemia. 11. Participants with a history of type 1 diabetes or type 2 diabetes accompanied by kidney disease. 12. Patients with severe hepatobiliary disorders, decompensated liver cirrhosis (Child-Pugh class B or C), portal hypertension-related complications (ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy), or any form of cholestatic liver disease. 13. Patients who have previously undergone liver transplantation or are scheduled for liver transplantation. 14. Participants with meningeal metastasis. 15. Uncontrolled CNS metastases are excluded.However, Participants with symptomatic CNS metastases may be eligible if the metastases are limited to the supratentorial and/or cerebellar region (i.e., without metastasis to the midbrain, pons, medulla oblongata, or spinal cord), local treatment has been received, neurological symptoms have been stable for at least 2 weeks before the first dose, and the participant does not require hormone therapy or is receiving ≤ 10 mg/day prednisone (or equivalent). 16. Within 5 years prior to the first administration of the investigational drug, the subject had other malignant tumors (excluding the solid tumor diseases treated with cisplatin as part of this study, and excluding skin basal cell carcinoma, superficial bladder cancer, in situ cervical cancer, etc., which were considered eligible for inclusion by the investigators and had not recurred within the previous 5 years). 17. There is a history of previous administration of allogeneic organ transplantation or allogeneic peripheral blood stem cell (PBSC)/immune cell/marrow transplantation. 18. The subject had undergone major surgical procedures within 4 weeks prior to the first administration of the investigational drug, or had not yet fully recovered from any previous invasive procedures. 19. Clinically significant cardiovascular diseases include: 1. Within 6 months prior to the first administration of the investigational drug, there was a myocardial infarction, unstable angina pectoris, viral myocarditis or other uncontrolled heart disease; 2. Left ventricular ejection fraction (LVEF) \< 50%, congestive heart failure with NYHA cardiac function classification of II-IV; 3. Symptomatic orthostatic hypotension occurred within 6 months prior to the first administration of the investigational drug; 4. Uncontrolled hypertension \[after standard medication, systolic blood pressure (SBP) ≥ 160 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg or a history of hypertension crisis or hypertensive encephalopathy\]; 5. QTc \> 470 ms (female), QTc \> 450 ms (male), or a known family history of long QT syndrome; 6. History of cardiac surgery such as angioplasty or coronary artery bypass grafting within 6 months prior to the first administration of the investigational drug; 20. Uncontrolled seizures despite appropriate medical treatment. 21. Within 6 months prior to the first administration of the investigational drug, the subject had experienced cerebral infarction, cerebral hemorrhage or transient ischemic attack. 22. Those with interstitial pneumonia or interstitial lung disease, or those who have a history of interstitial pneumonia or interstitial lung disease that affects self-care daily activities or is accompanied by life-threatening respiratory disorders; or those with a history of pulmonary fibrosis, persistent pneumonia, pneumonia caused by drugs or radiotherapy, congenital pneumonia, or any evidence of active pneumonia found on chest CT scan. Or those with severe pulmonary diseases, including but not limited to pulmonary embolism that occurred within 3 months before the first administration, severe asthma, chronic obstructive pulmonary disease (COPD), restrictive lung disease, or active pneumonia, or those whose pulmonary function test indicates severe impairment of lung function. 23. Those with a history of acute or chronic renal disease due to causes other than cisplatin treatment, or with a history of kidney transplantation, or currently undergoing renal replacement therapy (such as dialysis), or having persistent hematuria for unknown reasons, etc. 24. Clinically uncontrolled serous cavity effusion (including pleural, pericardial, or peritoneal effusion), as determined by the investigator, is defined as requiring a drainage tube or drainage more than once weekly, and shall be excluded. 25. Participants who have received a live attenuated vaccine within 4 weeks prior to the first administration of the investigational drug, or who are expected to require such vaccination during the study, are excluded. 26. According to the researchers' assessment, there is a history or current condition of autoimmune diseases (such as myasthenia gravis or periodic hypokalemia), severe or uncontrolled systemic diseases, active bleeding disorders or active infections; 27. Participants with active hepatitis B (HBsAg positive and HBV-DNA ≥ 1000 copies/mL or 500 IU/mL or the lower limit of the center's detection), or active hepatitis C (HCV antibody positive and HCV-RNA above the upper limit of the normal value), or positive screening result for human immunodeficiency virus (HIV) antibody, or active syphilis infection, or active tuberculosis infection will be excluded during the screening process. 28. Female participants who are pregnant or breastfeeding; 29. Those who have a clear history of neurological or mental disorders, such as dementia, and have poor compliance. 30. Other serious diseases, or any other circumstances that the researcher deems may increase the risks for the participants or interfere with the test results, and any other condition that, in the investigator's judgment, makes the participant unsuitable for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events | Up to 90 days | Adverse events will be evaluated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, V6.0), which includes spontaneously reported adverse events as well as clinically significant changes in vital signs, physical examination, laboratory tests, electrocardiogram, and other examinations conducted during the trial. |
| DLT | 21 days after the participant completes the first dose in the dose-escalation phase. | DLT is defined as any TEAE (including those definitely related, likely related, and possibly related) to GMDTC that occurs during the DLT observation period (the severity of adverse events \[Adverse events, AE\] is evaluated according to NCI CTCAE V6.0) or any clinically significant abnormal laboratory test results. |
| RP2D | From first participant enrollment to the completion of the entire study, approximately 1 year. | RP2D is defined as the Recommended Phase 2 dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic parameters,Tmax | Cycle 1 Days 1-5 | Peak time, reflecting the absorption, distribution, metabolism and excretion characteristics of drugs in the body. |
| Pharmacokinetic parameters, Cmax | Cycle 1 Days 1-5 | Peak concentrations, reflecting the absorption, distribution, metabolism and excretion characteristics of drugs in the body. |
| Pharmacokinetic parameters, λz | Cycle 1 Days 1-5 | The apparent terminal elimination rate constant, estimated by log-linear regression of the terminal portion of the concentration-time curve, reflecting the absorption, distribution, metabolism and excretion characteristics of drugs in the body. |
| Pharmacokinetic parameters, t1/2 | Cycle 1 Days 1-5 | The apparent terminal elimination half-life, calculated according to the following equation:t1/2= Ln(2)/ λz,reflecting the absorption, distribution, metabolism and excretion characteristics of drugs in the body. |
| Pharmacodynamic parameters, urine platinum | Baseline (the day before first dose) and Day1 to Day5 of each cycle. | Urine platinum level before and after drug administration (μmol/mol creatinine) |
| Pharmacodynamic parameters, amount of platinum excreted in urine over 24 hours | Baseline (the day before first dose) and Day1 to Day5 of each cycle. | 24-hour urine platinum excretion before and after drug administration |
| Renal function indicators： creatinine clearance | Baseline(Within 3 days before Cycle 1 treatment),D6 after the last cisplatin treatment prior to enrollment,D15 after the last cisplatin treatment prior to enrollment,Day 6 of each Cycle ,Day 15 of each Cycle,Day 20 of each Cycle | creatinine clearance before and after administration. |
| Pharmacodynamic parameters,Urine platinum excretion rate | Baseline (the day before first dose) and Day1 to Day5 of each cycle. | Cumulative urinary platinum excretion on Days 1 to 5 of each cycle as a percentage of the administered cisplatin dose. |
| Renal function indicators：serum creatinine | Baseline(Within 3 days before Cycle 1 treatment),D6 after the last cisplatin treatment prior to enrollment,D15 after the last cisplatin treatment prior to enrollment,Day 6 of each Cycle ,Day 15 of each Cycle,Day 20 of each Cycle | serum creatinine before and after drug administration. |
| Renal function indicators：urea nitrogen/urea, | Baseline(Within 3 days before Cycle 1 treatment),D6 after the last cisplatin treatment prior to enrollment,D15 after the last cisplatin treatment prior to enrollment,Day 6 of each Cycle ,Day 15 of each Cycle,Day 20 of each Cycle | Urea nitrogen/urea before and after drug administration |
| Renal function indicators：estimated glomerular filtration rate (eGFR) | Baseline(Within 3 days before Cycle 1 treatment),D6 after the last cisplatin treatment prior to enrollment,D15 after the last cisplatin treatment prior to enrollment,Day 6 of each Cycle ,Day 15 of each Cycle,Day 20 of each Cycle | estimated glomerular filtration rate (eGFR) before and after drug administration. |
| Renal function indicators：cystatin C | Baseline(Within 3 days before Cycle 1 treatment),D6 after the last cisplatin treatment prior to enrollment,D15 after the last cisplatin treatment prior to enrollment,Day 6 of each Cycle ,Day 15 of each Cycle,Day 20 of each Cycle | Cystatin C before and after drug administration |
| Renal function indicators：24-hour urine protein quantification | Baseline (the day before first dose) ,Day 1of each Cycle | 24-hour urine protein quantification before and after drug administration. |
Countries
China
Contacts
CONTACTLi Zhang, Doctor of Medicine
Outcome results
None listed