Herbs and Helpers
Complementary and alternative medicine (CAM) are medical and healthcare practices that are considered outside the realm of conventional mainstream Western medicine.[1,2] Specifically, complementary medicine involves the use of healing practices and products that work together with conventional medicine. In contrast, alternative medicine is used in place of traditional therapies. The National Center for Complementary and Integrative Health (NCCIH; known until 2015 as the National Center for Complementary and Alternative Medicine [NCCAM]) has recognized five main categories of CAM: mind-body medicine; whole medical systems; manipulative and body-based practices; energy medicine; and biologically based practices with a focus on herbal medicines, dietary supplements, vitamins, and nutrition. More recently, the NCCIH has developed the term integrative medicine, which combines conventional medical therapies and CAM therapies in a more highly coordinated and integrated manner based on high-quality evidence of safety and effectiveness. There are many definitions of “integrative” medicine, but all involve bringing conventional and complementary approaches together in a coordinated way. The use of integrative approaches to health and wellness has grown significantly within healthcare settings across the United States.
Over the past 10 to 15 years, there has been steadily increasing use of integrative medicine approaches in conjunction with conventional systemic anticancer therapies.[4-10] It is estimated that 40% to 50% of cancer patients, and perhaps more, have used integrative medicine therapies for symptom relief during the course of their conventional systemic treatments. Acupuncture, for example, has been shown to be an effective mind-body practice in alleviating treatment-associated side effects of fatigue, postoperative pain, and nausea and vomiting.[11-15] An important medicinal agent in cancer care is ginger (Zingiber officinale), a flowering plant whose rhizome is widely used as a folk medicine, and which is available in a variety of formulations. Ginger supplementation may represent an alternative adjuvant treatment for chemotherapy-induced nausea and vomiting. Controlled randomized clinical trials to confirm the clinical benefit of ginger are ongoing.[16,17] Finally, integrative medicine approaches have become especially popular with cancer survivors to manage the adverse effects and consequences of particular treatments—whether they be surgical resection; radiation therapy; or systemic therapy with cytotoxic chemotherapy, targeted therapy, and/or biologic therapy.
Chinese Herbal Medicine and the Herbal Formula PHY906
Traditional Chinese medicine has been practiced for more than 2,000 years. The earliest medical text on traditional Chinese medicine, written around 200 AD, includes the medicinal and toxicological properties of 364 entries, the vast majority describing plants. In the 16th century, the classical Chinese herbal medicine textbook documented the use of nearly 1,900 individual herbs and more than 11,000 formulas to treat human diseases. Traditional Chinese medicine has been used to control disease-associated symptoms and to improve overall quality of life for patients affected by a wide range of medical conditions, including cancer, gastrointestinal disorders, skin disorders, fatigue, stress, liver disease, cardiovascular disease, and allergies and autoimmune diseases.
Our own studies of traditional Chinese medicine began in the early 2000s, when we sought to answer the question of whether there was a Chinese herbal medicine that could prevent and/or reduce the gastrointestinal toxicities associated with irinotecan-based chemotherapy. Around that time, the combination of irinotecan, fluorouracil (5-FU), and leucovorin (IFL) was being developed as a frontline treatment regimen, and it was associated with a 25% to 30% incidence of grade 3 or 4 gastrointestinal toxicity in the form of diarrhea, nausea and vomiting, and abdominal cramps. Two large phase III clinical studies sponsored by the National Cancer Institute revealed an increased early death rate in patients treated with the IFL regimen, which was largely secondary to the treatment-related gastrointestinal toxicities. With this in mind, Professor Yung-Chi Cheng, PhD, and his research team at Yale University reviewed the Chinese literature and identified Huang Qin Tang as a classic formula that has been widely used in China and other Asian countries to treat gastrointestinal disorders, including nausea and vomiting, abdominal cramps, and diarrhea,[19,20] with the latter presumably occurring secondary, but not limited to, infectious etiologies in humans without serious side effects, other than reversible constipation.
PHY906 is a powder containing a spray-dried aqueous extract derived from the Huang Qin Tang formula; it consists of four principal herbs (Figure 1): Glycyrrhiza uralensis Fisch, Paeonia lactiflora Pall, Scutellaria baicalensis Georgi, and Ziziphus jujuba Mill. Of note, up to 65 individual chemicals have been identified, to date, in these four herbs. The identity of each herb was confirmed by trained botanists, and the plants were closely monitored with respect to soil and growth conditions to ensure the highest levels of chemical consistency in the raw herbs. In addition, testing was performed to ensure the absence of contaminants, such as heavy metals, pesticides/insecticides, and various microbial organisms. In contrast to Huang Qin Tang, the PHY906 formulation was prepared according to a proprietary manufacturing protocol that was specifically designed and implemented by Sun Ten Pharmaceutical Company in Taiwan. This protocol employed standard operating procedures involving hot water extraction of the four herbal components in a specific dry weight ratio of 3:2:2:2; this ratio is different from that which is traditionally used in everyday clinical practice in Asia. The hot water extraction was then spray-dried into a granulated powder and packaged in the form of capsules according to stringent manufacturing practices that followed Current Good Manufacturing Practices (CGMP) as determined by the US Food and Drug Administration.
Quality Control in the Production of PHY906
One of the main challenges associated with the development of Chinese herbal medicine relates to the issue of quality control and batch-to-batch variability. Since herbal extracts contain up to hundreds of individual phytochemical components, it is critical to develop robust quality-control metrics. To address this concern, a platform termed PhytomicsQC was developed; this unique and comprehensive set of methodologies integrates chemical analysis, bioresponse analysis, and in vivo animal pharmacology to achieve quality control and batch-to-batch reproducibility in the production of PHY906. For chemical analysis, liquid chromatography/mass spectrometry (LC/MS) was selected (Figure 2), given its broad capability and increased spectral sensitivity. Gene expression profiling, as seen in Figure 3, was used for bioresponse fingerprinting, since it provides a sensitive, comprehensive, and unique pattern in response to exposure to a given herbal formula. Working closely with Professor Hongyu Zhao, PhD, his bioinformatics colleagues at Yale, and PhytoCeutica (the developers of PhytomicsQC), a Phytomics Similarity Index (PSI) was developed for both the chemical analysis and the bioresponse fingerprint analysis. This PSI value is determined by integrating peak patterns, peak ratios, and peak intensities from various batches; it is a quantitative measure of similarity between two compounds, ranging from 0 to 1, with 1 being identical. This work has been critically important both for the clinical development of PHY906 and as a framework for the development of herbal medicines, as it has shown that herbal formulations manufactured under strict CGMP guidance can yield highly consistent batches of high-quality herbal products that can then be used for both preclinical and clinical studies.
Clinical Experience With PHY906 in Metastatic Colorectal Cancer, and Incorporation of Biomarkers
As noted previously, there has been extensive historical experience regarding the safety of PHY906 use in humans at daily doses as high as 4 to 6 g. As previously mentioned, in China and other Asian countries, this herbal medicine is referred to as Huang Qin Tang, and in the large majority of cases, it has been used to treat short-term diarrhea, presumably secondary, but not limited to, infectious etiologies in humans without serious side effects, other than reversible constipation. Preclinical in vivo studies conducted by the Cheng lab using the murine MC38 model documented the ability of PHY906 to reduce the toxicity associated with irinotecan treatment while increasing irinotecan’s antitumor effects. Additional preclinical studies have shown that PHY906 reduces the infiltration of neutrophils/macrophages, reduces tumor necrosis factor alpha expression in mouse intestine, and decreases proinflammatory cytokine levels in circulating plasma.[22-24]
In February 2002, a double-blind, placebo-controlled, crossover phase I study was initiated by the group at Yale in collaboration with PhytoCeutica. The purpose of the trial was to evaluate the safety and tolerability of the CGMP product PHY906 in combination with the irinotecan-based IFL regimen. At the time this first clinical study was designed, the bolus, weekly IFL regimen was considered the standard first-line treatment for patients with metastatic colorectal cancer, and as mentioned earlier, one of the main reasons for developing this study was that the main dose-limiting toxicity of IFL was, in fact, diarrhea and dehydration, which led to death in a small yet significant fraction of patients. In this study, patients served as their own internal controls; they received IFL plus oral PHY906 with the first cycle, and the same IFL chemotherapy plus placebo with the second cycle. This dose-escalation study examined the effect of PHY906 on the severity of irinotecan-induced toxicities and the effect of PHY906 on the pharmacokinetics of irinotecan and 5-FU. The initial dose level of PHY906 used in this study was 1.2 g/day, which is less than 30% of the dose usually used in the everyday setting, and a second cohort of patients received a total daily dose of 2.4 g/day. PHY906 therapy reduced the severity of diarrhea and nausea/vomiting induced by IFL chemotherapy by at least one grade level, and significantly reduced the incidence of grades 3 and 4 diarrhea, nausea/vomiting, and fatigue.[25,26] This first study was important because it clearly documented the ability of PHY906 to significantly reduce the gastrointestinal toxicity associated with IFL chemotherapy.
An extensive series of pharmacokinetic studies were conducted as part of the initial phase I study. They showed that PHY906 did not alter the metabolism of 5-FU and irinotecan, suggesting no unforeseen pharmacokinetic herb-drug interactions. It should be emphasized that the potential for herb-drug interactions must be carefully evaluated when one is investigating any new botanical medicine in combination with a conventional agent. For this first study, no pharmacodynamic biomarker studies were incorporated into the study design, since most of the preclinical studies that would provide the rationale for the inclusion of such translational science were just being initiated.
As a follow-up to this first study with PHY906, a second phase I clinical trial was designed in which PHY906 was combined with irinotecan monotherapy in the second-line treatment of patients with metastatic colorectal cancer. This second study is noteworthy in that it used an entirely new batch of PHY906 that was prepared and formulated under CGMP guidelines and tested using the PhytomicsQC platform to confirm quality control and batch consistency as compared with the original batch prepared 10 years earlier. This study used a traditional 3+3 design and identified irinotecan at 215 mg/m2 and PHY906 at 3.6 g/day to be the recommended phase II doses. Pharmacokinetic studies were performed as part of this phase I study, with LC/MS analysis confirming that the pharmacokinetics and metabolism of irinotecan, SN-38, and their respective glucuronidated metabolites were not altered with increasing doses of PHY906. Pharmacodynamic biomarker assays were also conducted in this study, to begin to correlate the effect of PHY906 on toxicity and/or clinical activity of irinotecan. For these translational studies, we investigated the effect of drug treatment on expression of cytokines, chemokines, and various growth factors; on metabolomic profiling; and on expression of key signaling proteins (total protein and phosphoprotein profiling). In addition, a novel LC/tandem MS (LC/MS/MS) assay was developed to identify the individual chemical components and metabolites in the peripheral blood of patients treated with PHY906.
Earlier in vivo animal experiments revealed a reduced expression of inflammatory markers in the intestine and plasma of mice treated with PHY906 and irinotecan compared with irinotecan alone. RNA microarray data of tumor tissue showed that the combination of PHY906 and irinotecan could enhance various key immune regulatory pathways associated with acute inflammatory processes. It is conceivable, then, that plasma levels of certain immunocytokines, chemokines, and growth factors may be altered as a result of PHY906 treatment and that their expression may be used as surrogate biomarkers that could then be correlated with clinical outcomes. Preliminary results from the phase I study of PHY906 and irinotecan have, indeed, identified different patterns of expression of various cytokines and chemokines.
Based on this second phase I study, a randomized, double-blind, placebo-controlled phase II study was subsequently designed to investigate the effect of PHY906 on the toxicity and clinical efficacy of single-agent irinotecan. Patients who progressed on frontline oxaliplatin-based chemotherapy were randomized to receive irinotecan in combination with either PHY906 or placebo. The primary endpoints of this phase II study were to determine the effect of PHY906 on the safety profile and clinical efficacy of irinotecan monotherapy, and the associated treatment-related quality of life.
In addition to these standard clinical endpoints, an extensive series of translational studies were incorporated into this study. These included profiling of immunocytokines, chemokines, and growth factors; metabolomic profiling; and assessment of tumor mutational load as determined by the presence of mutations of KRAS, BRAF, and/or PI3K/Akt. The approach for cytokine/chemokine profiling utilized a multiplexed cytometric bead array that allows for the simultaneous detection of 30 to 100 plasma proteins with the potential to assay up to 300 proteins.
Metabolomic profiling studies have been performed by Professor Wei Jia, PhD, and his group at the University of Hawaii. Their analysis has employed time-of-flight MS or quadrupole MS/MS coupled to chromatographic separations including gas chromatography (GC) and LC. The use of both LC/MS and GC/MS platforms to analyze each biological sample increases the number of metabolites detected by the two complementary analytical platforms, and the two platforms will also cross-validate results for each other given their mutual identification of metabolites. The combined GC/MS and LC/MS metabolomic profiling is a powerful technique providing a chemical snapshot of specific and dynamic cellular processes that will potentially correlate with tumor response and side effects. To date, 136 identified metabolites (typically with molecular weight [MW] < 1,000 kD) have been identified in plasma samples from patients treated on the phase II clinical trial of PHY906 plus irinotecan. Preliminary analysis of the data has identified four metabolites whose expression in plasma appears to be altered in response to treatment with PHY906. These results need to be confirmed and validated in the phase II randomized study.
For studies on tumor mutational analysis, a quantitative real-time polymerase chain reaction assay employing peptide nucleic acid clamping with a locked nucleic acid substituted primer will be used to detect colon tumor–associated mutated DNA circulating in patients’ plasma. The level of circulating plasma tumor DNA with different mutations will be quantified for analysis and correlated with clinical outcomes. The levels of circulating tumor DNA are anticipated to decrease in the responder group after chemotherapy and increase with tumor progression. Different mutations of the circulating tumor DNA may be detected throughout treatment since dominance of mutations may change in tumors, and this evolution in tumor mutational load may correlate with disease progression.
Further studies will be performed using the novel LC/MS/MS methodology to characterize the chemical profile of PHY906 and metabolites in each blood sample taken from patients. Using this LC/MS/MS protocol, up to 33 chemicals and/or metabolites of PHY906 have been identified in patient blood samples with high reproducibility using only 100 mL of plasma at each time point. Of note, not all chemicals found in the PHY906 herbal formulation are present in the peripheral circulation, and new PHY906 metabolites have been identified in the peripheral blood of patients. Moreover, the formation of some of these herbal metabolites appears to be dose-related. There are also individual differences in the circulating levels of flavones and their metabolites following treatment with PHY906. Finally, the presence of herbal metabolite profiles is being correlated with the biological activity of an individual patient’s plasma sample against several key immunologic regulatory signaling pathways and DNA repair pathways using unique reporter cell lines established by Professor Cheng and colleagues at Yale University.
The goal of these informationally rich translational studies is to begin to identify potential biomarker(s) that can be used to predict the clinical activity of PHY906 when used in combination with irinotecan chemotherapy. Specifically, our hope is to use these biomarkers in determining the potential effect of PHY906 on the toxicity and/or clinical benefit of irinotecan chemotherapy. These translational studies should also serve to support the results of the extensive in vivo preclinical studies, which have already documented the potential effects of PHY906 on various key signaling pathways. Finally, we hope to gain new insights into the underlying biochemical and molecular mechanisms of action of PHY906 and begin to identify the potential active compounds and/or metabolites for each biological activity, so that these can be investigated in further detail in future studies.
Over the past 15 years, we have learned a great deal from the preclinical and clinical studies investigating the Chinese herbal medicine PHY906, and we believe that the insights gained can serve as a model for investigators interested in the clinical development of Chinese herbal medicine and/or other botanical products. First and foremost is the issue of quality control and standardization of processes used both to create the Chinese herbal medicine and to identify the high-quality material that will be used for both the preclinical and clinical studies. It is notable that, at the very start of this journey with PHY906, the PhytomicsQC platform was developed; this platform represents a comprehensive multiplex technology that integrates chemical and biological fingerprints combined with a novel biostatistical methodology to assess and confirm the quality and identity of different batches of PHY906. With high-quality herbal material in hand, in vivo animal studies can then be performed to establish safety, efficacy, and potential dosing schedules. Characterization of the in vivo metabolism of the Chinese herbal medicines is also necessary to identify the presence of active as well as inactive herbal metabolites and to investigate potential herb-drug interactions. Our recent work has shown that the formation of herbal metabolites can differ quite significantly between in vivo model systems and use in patients. Studies to investigate the potential biological mechanisms of action using a systems biology approach are critical in providing the preclinical rationale to move forward with the clinical studies. This preclinical work is of particular relevance as it begins to identify potential biomarkers that can then be incorporated in the clinical studies.
The design of early-phase clinical trials combining Chinese herbal medicine with cytotoxic chemotherapy should follow the same rigorous principles that guide the clinical development of conventional Western medicines and be based on a sound preclinical rationale. The phase I aspect of these studies can follow a traditional 3+3 design as we have done with PHY906, or it can use adaptive designs in cases where the herbal medicine under study has been widely used and its safety profile is well established. The clinical trials must be designed with well-defined endpoints, and well-validated quality-of-life instruments and/or patient-reported outcome questionnaires should be incorporated. Translational pharmacodynamic biomarkers should be incorporated to begin to assess the biological effects of the herbal medicine. For PHY906 and other herbal medicines, these biomarkers can include tumor mutational load, cytokine/chemokine expression, metabolomic profiling, and formation of key herbal metabolites.
As with the development of conventional systemic therapies such as targeted agents, biologic agents, and/or immunotherapies, the tissue source from which these biomarkers are derived needs to be carefully considered. A topic of ongoing debate is whether tumor tissue, peripheral blood, or some other surrogate tissue should be used for these translational studies. While tumor tissue is ideal, there are several important limitations to using tumor tissue for biomarker interrogation. These include the inability to obtain pre- and posttreatment samples, the issue of tumor heterogeneity (leading to variable biomarker measurements), potential harm and inconvenience to the patient during the actual biopsy procedure, and the financial costs associated with tumor biopsies. Given these concerns, peripheral blood has now become an appropriate surrogate tissue for biomarker studies, although it remains to be determined whether peripheral blood adequately reflects what is actually taking place in tumor tissue. Once the translational biomarker data have been generated, sophisticated bioinformatic computational biology approaches must be developed to mine the data and facilitate identification of the biomarkers that can potentially be used to determine which patients will benefit from PHY906 or any other herbal medicine in terms of reduced toxicity from systemic chemotherapy, a better quality of life, and/or enhanced clinical activity in the form of improved overall response and progression-free survival.
Finally, as with the clinical development of any novel therapeutic agent, successful development of a Chinese herbal medicine such as PHY906 requires close and effective collaboration between academic centers, the biopharmaceutical industry, and government. All of the preclinical work with PHY906 was completed at the Yale Cancer Center, with much of the financial support coming from the National Cancer Institute and PhytoCeutica. The clinical studies were conducted at Yale, the University of Pittsburgh Medical Center Hillman Cancer Center (formerly the University of Pittsburgh Cancer Institute) and the University of Pittsburgh, and City of Hope Cancer Center. The translational metabolomic studies were performed at the University of Hawaii Cancer Center. All of these investigations were carried out in close partnership with industry partners, including Sun Ten Pharmaceutical Company, PhytoCeutica, and Yviva, as well as multiple governmental agencies, including the National Cancer Institute and the Office of Cancer Complementary and Alternative Medicine, NCCAM/NCCIH, and the US Food and Drug Administration’s Center for Drug Evaluation and Research Botanical Review Team.
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Source: Cancer Network
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