Safety of the Herbal Medicine SH003 in Patients With Solid Cancer: A Multi-Center, Single-Arm, Open-Label, Dose-Escalation Phase I Study
Cancer, a group of diseases characterized by the uncontrolled growth and spread of abnormal cells, is a leading cause of death globally, accounting for nearly 10 million deaths in 2020. By 2040, the global cancer burden is projected to reach 28.4 million cases, marking a 47% increase from 2020. Despite extensive efforts and substantial resources devoted to cancer research and treatment, cancer continues to be a pressing health issue worldwide. As the cancer treatment market expands due to rising global prevalence and medical advancements, a corresponding increase in interest toward natural products has emerged. These products, rich in bioactive compounds, are increasingly explored not only as potential sources of novel anticancer agents but also for their roles in alleviating symptoms associated with cancer and its treatment. , Despite significant advancements in cancer therapies, the overall rate remains high, underscoring the necessity for innovative approaches. Herbal medicine and natural products are increasingly explored for their potential to offer new therapeutic options in cancer treatment. , SH003, a new herbal medicine, combines Huang-Qi ( Astragalus membranaceus ), Dang-Gui ( Angelica gigas ), and Gua-Lou-Gen ( Trichosanthes kirilowii ). All of which have historical usage in traditional medicine and have shown anticancer properties in various preclinical studies, both in vitro and in vivo. - Studies into the efficacy and mechanism of SH003 on cancer reveal its multiple therapeutic effects. It suppresses breast cancer growth and metastasis by inducing autophagy and obstructing STAT3-IL-6 signaling, and it represses tumor angiogenesis by inhibiting VEGF-induced VEGFR2 activation. - Additionally, SH003 triggers apoptotic cell death in prostate cancer cells by inhibiting ERK2-mediated signaling, and it also restrains HeLa cervical cancer cell growth via G1 phase cell cycle arrest. , In vivo experiments have demonstrated potent anticancer effects of SH003 across various models. SH003 not only suppresses tumor growth and metastasis in MDA-MB-231 breast cancer cells but also, when combined with doxorubicin, exhibits a synergistic effect that significantly enhances therapeutic efficacy in triple-negative breast cancer models. , , Furthermore, SH003 effectively represses tumor angiogenesis in pancreatic cancer. In studies focusing on lung cancer, the combination of SH003 with docetaxel leads to synergistic antitumor activity, and it further enhances the anticancer effect of dabrafenib, showcasing broad efficacy in lung cancer treatment. , Recent studies highlight that Astragalus polysaccharide, a key component derived from Huang-Qi, inhibits tumor growth and enhances apoptosis, showing therapeutic potential in various cancers including prostate, liver, and non-small-cell lung cancer. Decursin, a bioactive compound from Dang-Gui, has been shown to effectively inhibit both tumor progression and autophagy in cancer cells, reducing CXCR7 expression to curtail cell proliferation, migration, and invasion, while also blocking cathepsin C-mediated autophagic flux, thereby demonstrating significant therapeutic potential. , Trichosanthin, an active component of Gua-Lou-Gen, has demonstrated significant anticancer efficacy in inhibiting the proliferation of cancer cells by inducing autophagy, a process dependent on the generation of reactive oxygen species and the activation of the NF-κB/p53 pathway. In our investigation into SH003, a blend of Huang-Qi, Dang-Gui, Gua-Lou-Gen, we observed that individual extracts influenced cell viability, but their combination at a 1:1:1 ratio appeared to enhance the inhibition of cell proliferation and induce apoptosis in cancer cells more effectively. Preliminary mechanistic studies suggest that this synergy could be effective in modulating critical signaling pathways; the SH003 combination seemed to reduce the phosphorylation of EGFR, SRC, and STAT3—pathways crucial for cancer cell survival and proliferation—more effectively than any single component alone. These findings indicate that the 1:1:1 ratio may not only amplify the anticancer properties of the individual components but also potentially plays a key role in selectively blocking STAT3 phosphorylation, warranting further investigation. Previous research has established the safety of SH003 at doses up to 4800 mg per day in a Phase I clinical trial. The previous Phase I trial administered SH003 up to a dosage of 4800 mg per day. This dosage was the highest tested that did not reach a conventional maximum tolerated dose (MTD), defined as the dose immediately below that at which dose-limiting toxicities (DLTs) of grade 3 or higher are observed in more than one participant. Given the absence of such DLTs at and below this dosage in the earlier study, our current trial aimed to explore higher dosage to rigorously establish the MTD of SH003, seeking to ascertain if higher dosage could be tolerated without exceeding these toxicity thresholds. Building on this foundation, the present study is designed to evaluate the safety of even higher doses of SH003, up to 9600 mg per day. The goal is to expand the permissible dosage range for SH003 in future efficacy trials.   Study Design This multi-center, single-arm, open-label, dose-escalation phase I study was conducted at Gachon University Gil Medical Center in Incheon and Ajou University Hospital in Suwon, Republic of Korea from October 2020 to December 2022. This study was approved by the institutional review board (IRB) of the Gachon University Gil Medical Center (reference GFIRB2020-385) and the Ajou University Hospital (reference AJIRB-MED-CT1-20-264). All participants voluntarily signed an informed consent form before enrollment in the clinical trial and the study followed the guidelines of the Declaration of Helsinki and Tokyo for humans. Participants Inclusion criteria were as follows: age 19 years and older; histologically or cytologically confirmed solid cancers for which standard curative measures do not exist or are no longer effective; previous treatment should have been terminated at least 4 weeks ago and no residual toxicity related to previous treatment has been appeared; Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2; estimated life expectancy of at least 12 weeks; participants who can swallow tablets; those whose organ function test results are as follows: hemoglobin at ≥8 g/dL, absolute neutrophil count ≥1500/μL, platelet count ≥75 000/μL, which is above the threshold for clinically significant chemotherapy-induced thrombocytopenia, bilirubin ≤ 2.5 times the upper limit of normal, AST/ALT ≤ 2.5 times the upper limit of normal, and serum creatinine ≤ 1.5 times the upper limit of normal or calculated CCr (Cockroft) ≥ 60 mL/min; female participants must not be capable of becoming pregnant (women who are 60 years or older and have not had a menstrual period for at least a year or who have undergone a hysterectomy or bilateral oophorectomy), if there was any chance of pregnancy, it had to be ruled out by conducting a pregnancy test prior to study participation; both male and female participants of childbearing potential were required to adhere to effective contraception methods throughout the of investigational product administration period and for at least 8 weeks thereafter; participants had to be able to understand the study and be willing to sign a written informed consent document. Exclusion criteria were as follows: patients who were undergoing systemic drug therapy or any local anticancer therapy, including radiation therapy, for the treatment of cancer; participants with known or suspected hypersensitivity reactions or serious adverse reactions to the study materials or materials of the same class, namely A. membranaceus, A. gigas and T. Kirilowii; participants presenting with evidence of active infection such as HBV, HCV, HIV, TB, etc., requiring treatment; patients with a known history of a positive test for HIV infection; patients with uncontrolled cardiovascular disease, including symptomatic unstable angina, heart failure, myocardial infarction, or uncontrolled hypertension, defined as blood pressure higher than 140/90 despite medication; patients with active CMV disease or infection within the last 4 weeks; patients with cerebrovascular disease, including acute coronary syndrome or stroke, or who had major surgery necessitating mechanical ventilation within the last year; pregnant or breastfeeding individuals; patients with symptomatic metastatic brain lesions, including dural metastases (those asymptomatic following previous surgery or radiotherapy, with no recent evidence of progression, were allowed); individuals who had participated in blood donation or other drug and medical device clinical trials within 1 month prior to study entry; organ transplant patients, including recipients of allogeneic stem cell transplants; substance abusers, or individuals with neurological, medical, psychiatric, or social illnesses that may interfere with study participation or the interpretation of study results; patients with a recent (within 1 year) serious medical condition that, in the opinion of the investigator, may increase the risk associated with the receipt of the investigational product or study participation, or may interfere with the interpretation of the study results, and patients deemed incapable of providing consent due to comorbidities such as dementia. Interventions Each SH003 tablet contains 800 mg of total material, consisting of 400 mg of blended solid extract from 3 herbs— A. membranaceus , A. gigas , and T. kirilowii —in a 1:1:1 ratio, obtained through a 30% ethanol extraction process, and 400 mg of excipients. The production of SH003 was undertaken by the pharmaceutical company Hanpoong Pharm and Foods Co. Ltd. (Jeonju, Republic of Korea,), in accordance with Korea Good Manufacturing Practice (KGMP) standards. The chemical constituents of SH003 are diverse. A. membranaceus contributes compounds including Astragaloside I, II, IV, isomucronulatol 7-O-glucoside, calycosin-7-O-β-D-glucoside, pinitol, daucosterol 6’-palmitate, β-sitosterol, sucrose, formononetin. A. gigas offers decursin, decursinol, decursinol angelate, demethylsuberosine, isoimperatorin, umbelliferone, nodakenin. Finally, T. kirilowii contributes trichosanthin, α-hydroxymethylserine, aspartic acid, threonine, serine, glutamic acid, citrulline, glycine, valine, tyrosine, glucose, galactose. Among the major chemical compounds of SH003, formononetin and astragaloside IV are attributed to A. membranaceus , decursin and nodakenin to A. gigas , and trichosanthin to T. kirilowii . , Of these, decursin and formononetin are designated as the marker compounds based on the Korean Herbal Pharmacopoeia, and the content of these 2 compounds were used to validate the SH003 formulation. We used traditional 3 + 3 design, which follows specific dose-escalation rules. This approach begins by recruiting 3 participants into a single cohort to evaluate toxicity, after which a decision is made on whether to proceed to the next cohort. If dose-limiting toxicities (DLTs) develop in more than 1 of 6 participants at a specific dose, this indicates that the maximum tolerated dose (MTD) has been exceeded. According to the protocol, this necessitates the cessation of further dose escalation. The dose increments were guided by a modified Fibonacci sequence. Upon establishing the safety of the preceding dose, it was elevated by 1.5 times for cohort 2, and by 1.33 times for cohort 3. The study participants were administered SH003 for a duration of 3 weeks. They ingested 4 to 8 tablets orally, 3 times a day post meals, with the dosage tailored according to their dose level. Participants consuming 4800, 7200, or 9600 mg/day were classified into Cohorts 1, 2, and 3, respectively. A previous phase I clinical trial determined the MTD of SH003 to be 4800 mg. Consequently, this dosage was designated as the starting dose in this study. The second and third cohort doses were subsequently escalated to 7200 and 9600 mg per day, respectively. Throughout the study duration, participants were instructed to abstain from any other cancer treatments, which included chemotherapy and radiotherapy. Outcome Measurements This study aimed to establish the MTD by evaluating the occurrence DLTs. The DLTs were defined as Grade 3 or higher adverse events, based on the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0, outlined by the National Cancer Institute (NCI; Bethesda, MD USA). The MTD was identified as the highest dose at which no more than 1 out of 6 participants experienced a DLT. Furthermore, adverse events of all grades were recorded throughout the study period using the CTCAE. For safety assessments, vital signs, physical examination outcomes, hematologic and biochemical profiles, and urine tests were regularly measured. The present study conducted an exploratory evaluation of anticancer efficacy. This efficacy assessment was based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, enabling a standardized and uniform assessment of tumor response across the diverse solid tumors treated with SH003. Outcome Analysis The MTD was defined as the dose just below the level at which more than 1 of the 6 participants exhibited DLTs during the 4-week trial period. In this study, the MTD of SH003 was determined as the highest dose among the 3 dose groups (4800, 7200, or 9,600 mg per day) that resulted in a DLT in one participant or fewer. All data analyses conducted in this study were descriptive, as the research did not involve inferential analysis or generalized hypothesis testing. Continuous variables were presented as medians and range, while categorical variables were presented in terms of absolute and relative frequencies.   This multi-center, single-arm, open-label, dose-escalation phase I study was conducted at Gachon University Gil Medical Center in Incheon and Ajou University Hospital in Suwon, Republic of Korea from October 2020 to December 2022. This study was approved by the institutional review board (IRB) of the Gachon University Gil Medical Center (reference GFIRB2020-385) and the Ajou University Hospital (reference AJIRB-MED-CT1-20-264). All participants voluntarily signed an informed consent form before enrollment in the clinical trial and the study followed the guidelines of the Declaration of Helsinki and Tokyo for humans.   Inclusion criteria were as follows: age 19 years and older; histologically or cytologically confirmed solid cancers for which standard curative measures do not exist or are no longer effective; previous treatment should have been terminated at least 4 weeks ago and no residual toxicity related to previous treatment has been appeared; Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2; estimated life expectancy of at least 12 weeks; participants who can swallow tablets; those whose organ function test results are as follows: hemoglobin at ≥8 g/dL, absolute neutrophil count ≥1500/μL, platelet count ≥75 000/μL, which is above the threshold for clinically significant chemotherapy-induced thrombocytopenia, bilirubin ≤ 2.5 times the upper limit of normal, AST/ALT ≤ 2.5 times the upper limit of normal, and serum creatinine ≤ 1.5 times the upper limit of normal or calculated CCr (Cockroft) ≥ 60 mL/min; female participants must not be capable of becoming pregnant (women who are 60 years or older and have not had a menstrual period for at least a year or who have undergone a hysterectomy or bilateral oophorectomy), if there was any chance of pregnancy, it had to be ruled out by conducting a pregnancy test prior to study participation; both male and female participants of childbearing potential were required to adhere to effective contraception methods throughout the of investigational product administration period and for at least 8 weeks thereafter; participants had to be able to understand the study and be willing to sign a written informed consent document. Exclusion criteria were as follows: patients who were undergoing systemic drug therapy or any local anticancer therapy, including radiation therapy, for the treatment of cancer; participants with known or suspected hypersensitivity reactions or serious adverse reactions to the study materials or materials of the same class, namely A. membranaceus, A. gigas and T. Kirilowii; participants presenting with evidence of active infection such as HBV, HCV, HIV, TB, etc., requiring treatment; patients with a known history of a positive test for HIV infection; patients with uncontrolled cardiovascular disease, including symptomatic unstable angina, heart failure, myocardial infarction, or uncontrolled hypertension, defined as blood pressure higher than 140/90 despite medication; patients with active CMV disease or infection within the last 4 weeks; patients with cerebrovascular disease, including acute coronary syndrome or stroke, or who had major surgery necessitating mechanical ventilation within the last year; pregnant or breastfeeding individuals; patients with symptomatic metastatic brain lesions, including dural metastases (those asymptomatic following previous surgery or radiotherapy, with no recent evidence of progression, were allowed); individuals who had participated in blood donation or other drug and medical device clinical trials within 1 month prior to study entry; organ transplant patients, including recipients of allogeneic stem cell transplants; substance abusers, or individuals with neurological, medical, psychiatric, or social illnesses that may interfere with study participation or the interpretation of study results; patients with a recent (within 1 year) serious medical condition that, in the opinion of the investigator, may increase the risk associated with the receipt of the investigational product or study participation, or may interfere with the interpretation of the study results, and patients deemed incapable of providing consent due to comorbidities such as dementia.   Each SH003 tablet contains 800 mg of total material, consisting of 400 mg of blended solid extract from 3 herbs— A. membranaceus , A. gigas , and T. kirilowii —in a 1:1:1 ratio, obtained through a 30% ethanol extraction process, and 400 mg of excipients. The production of SH003 was undertaken by the pharmaceutical company Hanpoong Pharm and Foods Co. Ltd. (Jeonju, Republic of Korea,), in accordance with Korea Good Manufacturing Practice (KGMP) standards. The chemical constituents of SH003 are diverse. A. membranaceus contributes compounds including Astragaloside I, II, IV, isomucronulatol 7-O-glucoside, calycosin-7-O-β-D-glucoside, pinitol, daucosterol 6’-palmitate, β-sitosterol, sucrose, formononetin. A. gigas offers decursin, decursinol, decursinol angelate, demethylsuberosine, isoimperatorin, umbelliferone, nodakenin. Finally, T. kirilowii contributes trichosanthin, α-hydroxymethylserine, aspartic acid, threonine, serine, glutamic acid, citrulline, glycine, valine, tyrosine, glucose, galactose. Among the major chemical compounds of SH003, formononetin and astragaloside IV are attributed to A. membranaceus , decursin and nodakenin to A. gigas , and trichosanthin to T. kirilowii . , Of these, decursin and formononetin are designated as the marker compounds based on the Korean Herbal Pharmacopoeia, and the content of these 2 compounds were used to validate the SH003 formulation. We used traditional 3 + 3 design, which follows specific dose-escalation rules. This approach begins by recruiting 3 participants into a single cohort to evaluate toxicity, after which a decision is made on whether to proceed to the next cohort. If dose-limiting toxicities (DLTs) develop in more than 1 of 6 participants at a specific dose, this indicates that the maximum tolerated dose (MTD) has been exceeded. According to the protocol, this necessitates the cessation of further dose escalation. The dose increments were guided by a modified Fibonacci sequence. Upon establishing the safety of the preceding dose, it was elevated by 1.5 times for cohort 2, and by 1.33 times for cohort 3. The study participants were administered SH003 for a duration of 3 weeks. They ingested 4 to 8 tablets orally, 3 times a day post meals, with the dosage tailored according to their dose level. Participants consuming 4800, 7200, or 9600 mg/day were classified into Cohorts 1, 2, and 3, respectively. A previous phase I clinical trial determined the MTD of SH003 to be 4800 mg. Consequently, this dosage was designated as the starting dose in this study. The second and third cohort doses were subsequently escalated to 7200 and 9600 mg per day, respectively. Throughout the study duration, participants were instructed to abstain from any other cancer treatments, which included chemotherapy and radiotherapy.   This study aimed to establish the MTD by evaluating the occurrence DLTs. The DLTs were defined as Grade 3 or higher adverse events, based on the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0, outlined by the National Cancer Institute (NCI; Bethesda, MD USA). The MTD was identified as the highest dose at which no more than 1 out of 6 participants experienced a DLT. Furthermore, adverse events of all grades were recorded throughout the study period using the CTCAE. For safety assessments, vital signs, physical examination outcomes, hematologic and biochemical profiles, and urine tests were regularly measured. The present study conducted an exploratory evaluation of anticancer efficacy. This efficacy assessment was based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, enabling a standardized and uniform assessment of tumor response across the diverse solid tumors treated with SH003.   The MTD was defined as the dose just below the level at which more than 1 of the 6 participants exhibited DLTs during the 4-week trial period. In this study, the MTD of SH003 was determined as the highest dose among the 3 dose groups (4800, 7200, or 9,600 mg per day) that resulted in a DLT in one participant or fewer. All data analyses conducted in this study were descriptive, as the research did not involve inferential analysis or generalized hypothesis testing. Continuous variables were presented as medians and range, while categorical variables were presented in terms of absolute and relative frequencies.   In our phase I trial using the traditional 3 + 3 design, we closely monitored for any DLTs to determine the MTD. Initially, 3 participants were administered SH003 at 4800 mg/day in Cohort 1. A DLT was observed in one of these initial participants, prompting the enrollment of an additional 3 participants to ensure a robust assessment of this dose level. Ultimately, the cohort expanded to 6 participants, and with only one DLT occurrence, the trial was able to proceed. The dosage was then escalated to 7200 mg/day for the 3 participants in Cohort 2, and eventually to 9600 mg/day for the 4 participants in Cohort 3, following the predefined escalation rules without further DLTs. presents a flow chart of the study, illustrating the participant enrollment process, dose escalation steps, and overall study design. The participant characteristics are detailed in . The median age of participants was 62 years, with a predominance of male participants (9 males and 4 females). The most common cancer types among the participants were colon cancer (6 patients), followed by gastric (2 patients), and pancreatic cancer (2 patients). All participants had an ECOG PS of 2. Laboratory parameters, including WBC, RBC, Hemoglobin, Hematocrit, Platelets, AST, ALT, Creatinine, and BUN were within normal ranges or, if outside normal ranges, deviations were clinically non-significant. The occurrence of adverse events during the study is summarized in . A total of 12 kinds of adverse events were observed, totaling 15 occurrences across all cohorts. Cohort 1 reported 5 adverse events, Cohort 2 had 3, and Cohort 3 experienced 5. Dizziness was the most common adverse event with 3 cases, followed by nausea with 2 cases. All other adverse events were reported only once. In Cohort I, a DLT was observed as the GGT increased corresponded to a Grade 3. Cohorts II and III experienced Grade 2 or lower adverse events, with no Grade 3 or higher toxicities reported. In Cohort I, initially 3 participants were enrolled, but due to the occurrence of a DLT in one participant, the protocol necessitated the recruitment of an additional 3 participants, maintaining the same dosage of 4800 mg/day. For Cohort III, one of the initially recruited participants was excluded due to low medication compliance. As per the protocol, this participant was replaced by enrolling an additional participant, resulting in a total of 4 participants in this cohort receiving 9600 mg/day.   We conducted a clinical trial to evaluate the safety of SH003 at doses up to 9600 mg per day. Previously, the safety of SH003 had been established for doses up to 4800 mg per day. This study successfully extended the safety profile of SH003, confirming its tolerability at a dose level of 9600 mg per day. This outcome enables us to explore higher dosages in future clinical trials investigating the efficacy of SH003. With the established safety profile up to 9600 mg per day, it opens new possibilities for upcoming research in various combination treatment settings. In addition to safety assessments, tumor response rates in this study, as well as in a previous study assessing the safety of SH003, were evaluated using RECIST 1.1. This standardized approach was selected due to its broad acceptance for assessing tumor size changes across diverse types of solid tumors. In the current study, one participant in the 4800 mg/day cohort and one in the 9600 mg/day cohort showed stable disease. For the remaining participants in both studies, the response was classified as progressive disease. In our study, stable disease was observed in participants with gallbladder and colon cancer. However, due to the diverse range of solid tumors included and the limited sample size, it remains premature to draw definitive conclusions about the tumor-specific efficacy of SH003. Continued research in larger, more focused trials is essential to determine the therapeutic potential of SH003 across different cancer subtypes. In the Republic of Korea, there exists a regulatory provision that allows the exemption of Phase I safety evaluations for new drug development using natural substances, based on traditional usage experience. This enables the commencement of clinical trials directly from Phase 2. Consequently, there have been very few Phase I clinical trials conducted in Korea on natural substances. SH003 represents the first Phase I clinical trial in Korea focused on a natural substance. In this trial, we have additionally confirmed the safety of SH003 at higher dosages. While many studies on natural products in cancer research have focused on symptom relief in cancer patients, our study with SH003 is distinctly aimed at developing it as a therapeutic anticancer agent. The current phase I trial is crucial for establishing a safe dosing regimen, which lays the groundwork for future rigorous evaluation of its potential anticancer efficacy. Historically, the use of natural products in oncology has been largely limited to supportive care, aiming to alleviate the side effects of conventional cancer treatments or improve the quality of life for patients. However, with SH003, we are exploring the direct antitumor effects of an herbal medicine. We highlighted the diverse therapeutic effects of SH003, such as its capacity for inducing autophagy, obstructing key signaling pathways, , and arresting cell cycle progression in various cancer cells. The diverse range of actions of SH003, attributed to its multi-component nature, marks a departure from traditional single-target cancer therapies. This multi-targeted approach, utilizing the synergy of various bioactive compounds, is designed to concurrently address different aspects of tumor biology. Such an approach aligns with the growing interest in multi-component natural compounds for cancer treatment, as evidenced by recent researches. , The results of our study suggest that SH003 is safe up to a dosage of 9600 mg/day, as significant adverse reactions were not frequently observed. Among the adverse events, dizziness, occurring in 3 instances, was the most common, followed by nausea, reported in 2 instances. Although these were not considered major concerns, the absence of a control group in this study limits our ability to make definitive comparison. Nevertheless, given the common occurrence of such symptoms in patients with advanced cancer, , coupled with clinical judgment of the attending physician, it is considered unlikely that these symptoms are directly related to SH003. Furthermore, in Cohort 1, a case of Grade 3 GGT increase was observed. This event is particularly noteworthy as it occurred in a patient with advanced-stage cancer and liver metastases, conditions often associated with elevated GGT levels. - These factors suggest that the increase in GGT may not be directly attributable to SH003, but rather could be a consequence of the underlying advanced cancer condition of the patient, especially the liver involvement. The evaluating physician supported this view, indicating a likely association of the increased GGT level with the advanced disease state of the patient, rather than with SH003 administration. We plan to keep a close watch on such symptoms in future clinical trials to further investigate their association with SH003. The absence of frequently occurring or severe adverse reactions, even at the highest dosage tested, is a promising indicator of the safety profile of SH003. This finding is particularly significant in cancer treatment, where the utmost importance is placed on patient tolerance and safety, especially considering the often compromised health of many patients. The potential for lower associated risks with SH003 may provide a safer alternative or adjunct to existing treatments, which are often accompanied by substantial side-effect burdens. This study, a single-arm trial involving a small cohort of patients with various solid cancers, represents an early phase in the development of the potential new drug SH003. Despite the safety profile demonstrated in this phase I trial, the limitations posed by the small sample size and the diversity of cancer types must be acknowledged. The limited number of participants and heterogeneity of cancer types studied restrict the generalizability of the findings and the statistical power required for definitive efficacy conclusions. As an initial step in drug development, this study aimed to establish a safety baseline and identify the maximum tolerated dose of SH003. These constraints underscore the need for more focused research to ascertain the effectiveness of the drug across specific cancer subtypes. Future studies are planned to include larger patient cohorts and concentrate on particular types of cancer, enhancing statistical robustness and enabling more precise evaluations of efficacy. Such an approach will provide stronger evidence for the therapeutic potential of SH003 and allow for a more accurate assessment of its clinical relevance to specific cancer subtypes. By increasing both sample size and study population homogeneity, these studies aim to deliver a more definitive understanding of the efficacy and safety profile of SH003, thereby meeting the rigorous requirements for statistical and clinical validation in subsequent clinical trials. Furthermore, the predominant involvement of end-stage cancer patients complicates the clear identification of adverse reactions specifically attributable to SH003, due to symptom overlap commonly seen in advanced cancer stages. The decision to include end-stage cancer patients was driven by ethical considerations, as this was the first human study of SH003. Established guidelines in oncology clinical trials recommend reserving experimental treatments for individuals who lack curative options. This approach ensures that patients with potentially curative cancers are not deprived of effective treatments in favor of experimental therapies. As the safety profile of SH003 becomes better established and if partial efficacy is observed, it may become feasible and ethical to consider including earlier-stage cancer patients in future trials. This would be particularly pertinent in combination therapy trials, where SH003 could potentially be evaluated alongside standard treatments. Therefore, it is essential to conduct future studies with larger and more diverse patient cohorts to better understand unique adverse effect profile of SH003 and validate its safety and efficacy across various cancer stages and types. While special attention should continue to be given to the occurrence of dizziness, reported in 3 instances, and nausea in 2 instances, it is also crucial to carefully monitor and analyze other observed adverse events, such as increased levels of GGT. In this study, a notable limitation is the absence of human pharmacokinetic data for SH003. While pharmacokinetic parameters have been evaluated in animal models, these findings are unpublished and cannot be directly extrapolated to human subjects. The primary challenge in conducting human PK studies lies in the low bioavailability of index compounds in SH003, requiring large blood sample volumes for analysis—a procedure not feasible in patients with cancer without compromising ethical standards. As our research progresses, we will consider the possibility of integrating pharmacokinetic studies into the development process of SH003 under appropriate conditions, potentially including trials with healthy volunteers, ensuring ethical standards are met. Another limitation is that no marker compound was set for T. kirilowii due to the low concentration of its components. We plan to establish a standardization method through techniques such as chemical fingerprinting for SH003, to ensure consistent quality across all components. An important consideration for future research is that although we have established the safety of administering up to 9600 mg/day, the current formulation requires the consumption of a considerable number of tablets. This could potentially reduce patient compliance. Moving forward, it will be crucial to explore optimal dosing that balances efficacy with patient adherence and to consider the development of alternative formulations that could reduce the tablet burden. This study provides initial insights for future clinical trials assessing the efficacy of SH003 in cancer treatment. Separately, another clinical trial is currently underway to evaluate the safety of combining SH003 with docetaxel. This separate study reflects the common practice of combination therapy in oncology and is an important step in understanding the broader potential of SH003 when used in conjunction with established treatments. The initial findings regarding SH003 are encouraging, yet they represent just the initial steps toward a deeper understanding of its potential in cancer therapy. The ongoing exploration of SH003, both as an independent treatment and in combination with other drugs such as docetaxel, is anticipated to significantly contribute to the field of oncology. Furthermore, recent reports have highlighted the potential of SH003 in symptom management for cancer patients. Notably, SH003 has been observed to alleviate pain induced by chemotherapy agents like paclitaxel and docetaxel, , and to enhance immune responses. These properties suggest that SH003 could be a valuable adjunct in cancer therapy, not only for its direct anticancer effects but also for improving the quality of life of patients by mitigating treatment-related symptoms. The prospect of combining SH003 with conventional chemotherapy agents is noteworthy, as it may enhance the overall therapeutic efficacy and potentially reduce adverse effects. This research not only has the potential to lead to the development of new, less toxic cancer treatments but also sets a precedent for future studies on other natural products. The progress made in understanding and utilizing SH003 could serve as a valuable foundation for broader research into natural products in cancer therapy, potentially ushering in a new era of innovative and effective treatment options.   In conclusion, this study has established that SH003 is safe for use in cancer patients at doses up to 9600 mg/day, expanding its known safety threshold. This advancement underscores the importance of patient tolerance and safety in cancer treatments, particularly given the often compromised health status in this patient group. While the results are promising, they also highlight the necessity for further, more extensive research to fully determine the efficacy and broader applicability of SH003 in various cancer types and stages.   