A Phase I Study on Evaluating the Safety, Tolerability, Pharmacokinetic Characteristics and Preliminary Efficacy of SXRN Plasmid DNA Technique in Patients With Advanced Solid Tumors

Обзор

The purpose of this clinical trial is to evaluate the safety and tolerability of SXRN Plasmid DNA Technique in patients with advanced solid tumors.

Подробное описание

This is a Phase I, open-label, dose-escalation study to investigate the safety, tolerability, pharmacokinetics and preliminary efficacy of SXRN Plasmid DNA Technique in patients with advanced solid tumors. Three dose levels are initially formulated, namely 2mg, 4mg, and 10mg of SXRN, adopting an accelerated titration followed by the traditional "3+3" design. SXRN will be administered daily x 5 with 2 days off (total of 21 days) for 3 weeks followed by a no-treatment observation period.

Add a continuous dosing exploration cohort: based on the Phase I dose-escalation study, a randomized, double-blind, placebo-controlled continuous dosing exploration cohort (utilizing an operationally seamless design) will be added to further evaluate the efficacy and safety of continuous administration of Shuxinrui Na Injection in patients with cancer anorexia-cachexia.

Вмешательства

• Препарат SXRN
  SXRN is a naked plasmid DNA drug targeting miRNA.
• Препарат Placebo
  Matching placebo, same dosing regimen (IV infusion once daily for 14 days)

Первичные конечные точки

• Maximum Tolerated Dose (MTD) and Recommended Dose for Expansion (RDE) of SXRN [Срок оценки: 12 months]
• Effect for SXRN on Appetite compared to placebo [Срок оценки: Baseline, weekly up to Day 28]
• Effect of SXRN on physical function compared to placebo [Срок оценки: Baseline, Weekly up to Day 28]

Вторичные конечные точки (9)

• Pharmacokinetic parameters of SXRN [Срок оценки: 12 months]
• Preliminary anti-tumor efficacy of SXRN [Срок оценки: 12 months]
• Weight improvement of SXRN in patients with advanced solid tumors [Срок оценки: 12 months]
• Appetite improvement of SXRN in patients with advanced solid tumors [Срок оценки: 12 months]
• Pain alleviating efficacy of SXRN in patients with advanced solid tumors [Срок оценки: 12 months]
• Effect for SXRN on body weight/fat-free mass compared to placebo [Срок оценки: Baseline, Weekly up to Day 28]
• Effect for SXRN on QoL compared to placebo [Срок оценки: Baseline, Weekly up to Day 28]
• Effect for SXRN on dietary intake compared to placebo [Срок оценки: Baseline, up to Day 28]
• Safety and tolerability of SXRN [Срок оценки: Up to 28 days after first dose]

Критерии участия

For Dose-Escalation Phase:

• Inclusion Criteria:
• male or female, aged 18\~75 at the time of signing the ICF;
• patient with advanced solid tumors who have failed/cannot tolerate previous standard therapies or lack conventional effective therapies;
• at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1);
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;
• expected survival time ≥12 weeks;
• lab results and organ function tested within 7 days before the initial infusion meet the criteria below:
• Blood routine: 1)Absolute Neutrophil Count (ANC) ≥1.5×10\^9/L;2)Platlets (PLT) Count≥90×10\^9/L; 3)Hemoglobins (Hb) ≥90 g/L.

Note: the criteria above shall still be maintained within 14 days before the initial infusion, either without the need of blood transfusion, or using supportive treatment including granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), interleukin-11 (IL-11), and erythropoietin (EPO), and etc.

• Blood biochemistry: 1)Total bilirubin (TBIL) ≤3.0 × upper limit of normal (ULN); 2)Serum creatinine (SCr) ≤1.5 × ULN or creatinine clearance (CrCl) by Cockroft Gault formula ≥50 mL/min; 3)Aspartate Amino Transferase (AST), Alanine Aminotransferase (ALT) ≤2.5×ULN; for participants with liver metastasis, AST, ALT≤5.0×ULN, and ALP≤6.0×ULN; d)Albumin (ALB) ≥30g/L.
• Urine protein ≤2+ (if >2+, urine protein shall be collected for 24 hours; total protein ≤1g is acceptable for inclusion).
• International Normalized Ratio (INR), Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) ≤1.5×ULN.

Note: for subjects receiving precautious anti-coagulation treatment, the investigator shall determine whether INR and APTT remains in a safe and effective range for treatment.

• Left Ventricular Ejection Fraction (LVEF) ≥50%.
• can understand and voluntarily sign the Informed Consent Form (ICF); must be voluntary and able to finish the study program and follow-up tests.

Критерии исключения

• Subjects who meet any of the criteria below must not be included:
• has received any of the anti-tumor treatments below:a) received cytotoxic chemotherapy, tumor immunotherapy, anti-tumor biologics or other trail agents within 4 weeks or 5 half-times (whichever is shorter) before the initial infusion.b)received an oral small-molecule targeted anti-tumor agent within 2 weeks before the first infusion or for five half-lives(whichever was shorter).c) received anti-tumor Chinese patent medicine approved by NMPA within 2 weeks before the initial infusion.d) received more than 30% bone marrow radiotherapy or large area radiotherapy within 2 weeks before initial infusion (palliative radiotherapy at the bone or superficial lesions is acceptable).
• participated in and received an investigational drug or device clinical trial within 4 weeks before initial infusion.
• Patients who had undergone or planned to undergo major surgery or interventional therapy (excluding tumor biopsy, puncture, etc.) within 4 weeks before initial infusion.
• unrecovered from the toxic reaction caused by previous anti-tumor treatment (not recovered to ≤ grade 1 or baseline; not including toxic reactions with no safety risk as determined by the investigator, such as alopecia, asymptomatic hypothyroidism caused by immune checkpoint inhibitors that can be treated with only thyroid hormone and remains stable, and etc.).
• with clinically uncontrollable serous effusion (pleural effusion, ascites and pericardio effusion). Conditions may include: moderate or above sized effusion, received within 2 weeks before the selection or plans to receive local treatments (including drainage, peritoneal shunt, and cell-free concentrated ascites reinfusion, and etc.), or effusion obviously increased within 2 weeks after the local treatment and thus needs long-term catherterization. Candidates who meet any of the conditions above, or determined by the investigator as unsuitable, shall not be included.
• with central nervous system metastasis and show relating symptoms.
• with a history of other malignant tumors, except for those that have received radical surgery and not relapsed 5 years thereafter, such as carcinoma in situ of cervix, skin basal cell carcinoma, and etc.
• with a history of immune deficiency diseases, including acquired or congenital immunodeficiency disorders; or a history of organ transplantation, heterogeneous bone marrow transplantation, or autologous hematopoietic stem cell transplantation.
• had (non-infectious) lung inflammation / interstitial lung disease that required steroid treatment within 4 weeks before the initial infusion.
• with a history of severe cardiovascular and cerebrovascular diseases, including but not limited to:

• severe abnormalty in cardiac rhythm or conduction, such as ventricular arrhythmia requiring clinical intervention, atrioventricular block of II\~III grade, and etc.;
• cardiac insufficiency of III\~IV grade as defined by New York Heart Association(NYHA);
• acute coronary syndrome, congestive cardiac failure, aortic dissection, cerebral stroke or other grade 3 or above cardio-cerebral vascular events within 6 months before the initial infusion.
• with uncontrollable high blood pressure (systolic pressure ≥160 mmHg and/or diastolic pressure ≥100 mmHg) after treatment with anti-hypertensive drugs of stable doses.
• with active chronic hepatitis B (such as, HbsAg or HbcAb positive and HBV DNA ≥ lower limit of detection, active hepatisis C (such as, HCV antibody positive and HCV RNA≥ lower limit of detection), or HIV infection.
• with active infections within 2 weeks before the initial infusion that require systematic treatment.
• with a history of active tuberculosis infection within 1 year before the initial infusion.
• had or has uncontrollable or serious diseases that may interfere with the participation or evaluation in the study, as considered by the investigator;
• known to be allergic or taking drugs contradictionary to the study drug (Suplussirna) or its excipients.
• premenopause female candidates (postmenopausal female patients can only be considered infertilewhen they have been postmenopausal for at least 12 months) with positive results in serum pregnancy test; candidates of reproductive age (also including female spouse of reproductive age of male candidates), during the study or within 6 months after the last infusion, who will probably bear children, breastfeed, or are unwilling to cake effective contraceptives, as considered by the investigator.
• other conditions that are determined by the investigator as unsitable for entering this trial.

For Expansion Cohort(Randomized, Double-blind, Placebo-controlled Part):

• Inclusion Criteria:
• Male or female, aged 18 to 75 years at time of signing ICF.
• Histologically or cytologically confirmed solid tumor.
• Patients who have failed standard therapy, lack standard therapy, or are in a treatment holiday period (4 weeks) without need for anti-tumor therapy.
• Diagnosis of cancer anorexia-cachexia according to 2025 CSCO guideline, meeting either (①+②) or (①+③):

• Involuntary weight loss >5% in 6 months; OR weight loss >2% with BMI <18.5 kg/m²; OR weight loss >2% with reduced muscle mass.

• Anorexia (VAS ≤70 or FAACT-A/CS-12 score ≤37).

• CRP >5 mg/L.
• ECOG performance status 0-2.
• Life expectancy ≥12 weeks.
• Adequate organ function and laboratory parameters within 7 days prior to first study drug, meeting the same criteria as listed above for the dose-escalation phase (i.e., ANC, platelets, hemoglobin, liver/kidney function, coagulation, LVEF, etc.).
• Same informed consent requirement as the dose-escalation phase: able to understand and voluntarily sign the ICF, and willing/able to complete study procedures and follow-up.

Критерии исключения

The exclusion criteria are the same as those for the dose-escalation phase above, with the following additional or modified criteria:

• Reversible causes of reduced food intake determined by investigator (e.g., mechanical obstruction preventing eating).
• Use of any medication or therapy for cachexia, anorexia, or weight loss (excluding enteral nutrition support) within 28 days or 5 half-lives (whichever shorter) prior to first study drug, including but not limited to progestins (megestrol acetate, medroxyprogesterone acetate), corticosteroids, anamorelin, cannabinoids, androgens, NSAIDs.
• Currently receiving tube feeding or parenteral nutrition.
• Cachexia clearly due to other causes (e.g., severe COPD, AIDS).
• Hormone therapy judged by investigator to improve cachexia.
• Central nervous system metastases requiring intervention (instead of "symptomatic CNS metastases").
• Known allergy or contraindication to SXRN or its process impurities (e.g., spectinomycin).
• Note: For the expansion cohort, the washout period for other investigational drugs is "4 weeks or 5 half-lives" (same as dose-escalation phase), and all other exclusion criteria (prior anti-tumor treatments, unresolved toxicity, serous effusion, cardiovascular disease, infections, etc.) apply identically as listed above.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Последовательный дизайн

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Cancer Hospital Chinese Academy of Medical Sciences — Пекин

Публикации

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• Wang Q, Liu Y, Wu Y, Wen J, Man C. Immune function of miR-214 and its application prospects as molecular marker. PeerJ. 2021 Feb 16;9:e10924. doi: 10.7717/peerj.10924. eCollection 2021. PMID 33628646
• Zhao L, Liu YW, Yang T, Gan L, Yang N, Dai SS, He F. The mutual regulation between miR-214 and A2AR signaling plays an important role in inflammatory response. Cell Signal. 2015 Oct;27(10):2026-34. doi: 10.1016/j.cellsig.2015.07.007. Epub 2015 Jul 11. PMID 26171727
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• Malik M, Michalak M, Radecka B, Gelej M, Jackowska A, Filipczyk-Cisarz E, Hetman K, Foszczynska-Kloda M, Kania-Zembaczynska B, Manka D, Orlikowska M, Rogowska-Dros H, Bodnar L. Prognostic Value of Sarcopenia in Metastatic Colorectal Cancer Patients Treated with Trifluridine/Tipiracil. J Clin Med. 2021 Oct 30;10(21):5107. doi: 10.3390/jcm10215107. PMID 34768626
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• Loberg RD, Bradley DA, Tomlins SA, Chinnaiyan AM, Pienta KJ. The lethal phenotype of cancer: the molecular basis of death due to malignancy. CA Cancer J Clin. 2007 Jul-Aug;57(4):225-41. doi: 10.3322/canjclin.57.4.225. PMID 17626119

Идентификаторы

NCT: NCT06736275 · AA0101

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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