WO2018157762A1 - Use of sulfated oligosaccharides in the manufacture of a medicament for treating patients with hepatocellular carcinoma after surgical resection - Google Patents

Use of sulfated oligosaccharides in the manufacture of a medicament for treating patients with hepatocellular carcinoma after surgical resection Download PDF

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WO2018157762A1
WO2018157762A1 PCT/CN2018/077105 CN2018077105W WO2018157762A1 WO 2018157762 A1 WO2018157762 A1 WO 2018157762A1 CN 2018077105 W CN2018077105 W CN 2018077105W WO 2018157762 A1 WO2018157762 A1 WO 2018157762A1
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hcc
invasion
medicament
patient
patients
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Stanley Chang
Kuan-Lang Lai
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Medigen Biotechnology Corp
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Medigen Biotechnology Corp
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Priority to KR1020197028654A priority patent/KR102265159B1/ko
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates generally to hepatocellular carcinoma (HCC) , and more specifically to use of muparfostat in the manufacture of a medicament for increasing disease-free survival rate in HCC patients after surgical resection.
  • HCC hepatocellular carcinoma
  • the standard treatment for patients with early-stage HCC is local ablation or surgical resection (including liver transplantation) .
  • surgical resection with curative intent is initially effective, the 5-year disease-free survival (DFS) rate after surgery is as low as 20%–30%because of a high risk of HCC recurrence.
  • DFS 5-year disease-free survival
  • the invention relates to a use of a therapeutically effective amount of muparfostat in the manufacture of a medicament for reducing intrahepatic tumor recurrence and increasing disease-free survival period in a hepatocellular carcinoma (HCC) patient with microvascular invasion after a liver resection.
  • HCC hepatocellular carcinoma
  • a resected liver tumor sample from the HCC patient is examined to identify the presence of microvascular invasion in the sample.
  • a liver tumor sample from the HCC patient is assessed to identify whether the liver tumor sample has microvascular invasion.
  • the patient is examined by subjecting the patient to three monthly scheduled surveillance CT scans.
  • the use of the invention is in combination with use of a therapeutically effective amount of an immune checkpoint inhibitor in the manufacture of a medicament for reducing intrahepatic tumor recurrence and increasing disease-free survival period in the HCC patient with microvascular invasion.
  • the use of the invention is in combination with use of a therapeutically effective amount of an additional anticancer agent in the manufacture of a medicament for reducing intrahepatic tumor recurrence and increasing disease-free survival period in the HCC patient with microvascular invasion.
  • the therapeutically effective amount of muparfostat is the only anticancer agent of the medicament.
  • the HCC patient with microvascular invasion has one and no more than one single tumor prior to the liver resection.
  • the HCC patient with microvascular invasion has a postoperative Child–Pugh total score of lower than 8.
  • the HCC patient with microvascular invasion has a hepatic tumor with a size of smaller or no greater than 10 cm prior to the liver resection.
  • the HCC patient with microvascular invasion has a well differentiated, or moderately differentiated, or poorly differentiated tumor prior to the liver resection according to a four-tier scale of neoplastic grading.
  • the HCC patient with microvascular invasion has hepatitis B virus (HBV) -related HCC or hepatitis C virus (HCV) -related HCC.
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • the HCC patient with microvascular invasion is non-responsive to anti-hepatitis B virus drug treatment.
  • the HCC patient with microvascular invasion has a body mass index (BMI) of 18.5–35 kg/m 2 .
  • the medicament for reducing intrahepatic tumor recurrence and increasing disease-free survival period excludes those HCC patients with microvascular invasion who have an anaplasia hepatic tumor prior to the liver resection.
  • the medicament is for a dosage regimen of at least 4 consecutive days per week for 3 weeks out of every 4 weeks. In one embodiment, the medicament is for a dosage regimen of at least 52 weeks. In one embodiment, the patient with microvascular invasion is at least 5.2 weeks after the liver resection.
  • the invention relates to a use of a therapeutically effective amount of muparfostat in the manufacture of a medicament for treating a hepatocellular carcinoma (HCC) patient after a liver resection, wherein the HCC patient has below characteristics: (a) a sign of microvascular invasion; and (b) at least one of the following features: (i) no more than one single tumor prior to the liver resection; (ii) having a postoperative Child–Pugh total score of lower than 8; (iii) having a hepatic tumor with a size of smaller than or no greater than 10 cm prior to the liver resection; and (iv) having a well differentiated, or moderately differentiated, or poorly differentiated tumor prior to the liver resection according to a four-tier scale of neoplastic grading.
  • HCC hepatocellular carcinoma
  • the invention relates to a use of a therapeutically effective amount of muparfostat in the manufacture of a medicament for treating a hepatocellular carcinoma (HCC) patient with microvascular invasion after a liver resection, wherein the medicament excludes treating HCC patients with no vascular invasion and HCC patients with macrovascular invasion.
  • HCC hepatocellular carcinoma
  • the immune checkpoint is selected from the group consisting of PD1, PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFR beta, CEACAM-1, CEACAM-3, and CEACAM-5.
  • the immune checkpoint inhibitor may be selected from the group consisting of Pembrolizumab, Nivolumab, Atezolizumab, Avelumab, Durvalumab, and Ipilimumab.
  • FIG. 1 is a flow diagram of the trial protocol.
  • FIGs. 2A-B are graphs showing Kaplan–Meier estimates of disease-free survival curves in the intention-to-treat analysis based on (FIG. 2A) independent central imaging assessments and (FIG. 2B) local imaging assessments at each study site, respectively.
  • FIGs. 3A-D are graphs showing Kaplan–Meier estimates of disease-free survival curves for (FIG. 3A) all patients and patients with (FIG. 3B) macrovascular invasion, (FIG. 3C) microvascular invasion, and (FIG. 3D) no vascular invasion in the per-protocol analysis based on independent central imaging assessments.
  • FIGs. 4A-C are graphs showing Kaplan–Meier estimates of disease-free survival curves for “preferable” patients with (FIG. 4A) microvascular invasion, (FIG. 4B) no vascular invasion, and (FIG. 4C) a combination of microvascular invasion and no vascular invasion in the per-protocol analysis based on independent central imaging assessments (overlap of FIGs. 4A and 4B) .
  • the “preferable” patients were those with one single tumor (no more than one tumor) ; postoperative Child–Pugh total score lower than 8; maximum tumor size ⁇ 10 cm; well, moderately, or poorly differentiated tumor differentiation; BMI of 18.5–35 kg/m 2 ; time from curative resection to first treatment ⁇ 5.2 weeks; and recurrence after 24 weeks from the first treatment.
  • FIG. 5 is a graph showing strong protective effect of muparfostat (PI-88) in a subgroup of patients with microvascular invasion after the study drug had been administered for a period of 52 weeks.
  • FIG. 6 (6-1 to 6-3) is a table (Table 1-1 to 1-3) showing a comparison of baseline demographic and clinical characteristics between the placebo and muparfostat (PI-88) groups in the intention-to-treat analysis.
  • FIG. 7 (7-1 to 7-3) is a table (Table 2-1 to 2-3) showing a comparison of baseline demographic and clinical characteristics between the placebo and muparfostat (PI-88) groups in the per-protocol analysis.
  • FIG. 8 is a table (Table 3) showing multivariate analysis to identify the predictors of disease-free survival by fitting the Cox’s model with time-dependent covariates in patients receiving the placebo or muparfostat (PI-88) in the per-protocol analysis.
  • FIG. 9 (9-1 to 9-2) is a table (Table 4-1 to 4-2) showing a comparison of treatment-related adverse events (AEs) by the System Organ Class (SOC) and preferred terms between the placebo and muparfostat (PI-88) groups.
  • SOC System Organ Class
  • PI-88 muparfostat
  • FIG. 10 is a graph showing delayed protective effect of anti-HBV drug in a subgroup of patients without vascular invasion after the drug had been administered for a period of 60 weeks.
  • around shall generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term “around” , “about” or “approximately” can be inferred if not expressly stated.
  • subject refers to a human or a non-human animal.
  • treating refers to administration of an effective amount of a therapeutic agent to a subject in need thereof, who has cancer or infection, or a symptom or predisposition toward such a disease, with the purpose of cure, alleviate, relieve, remedy, ameliorate, or prevent the disease, the symptoms of it, or the predisposition towards it.
  • a subject can be identified by a health care professional based on results from any suitable diagnostic method.
  • an effective amount refers to the amount of an active compound that is required to confer a therapeutic effect on the treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on rout of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment.
  • baseline event rate refers to the statistical assumption for the primary endpoint (the DFS) to the treatment and placebo group.
  • Relative risk ratio refers to the ratio of the probability of an event occurring in a treatment group to the probability of the event occurring in a comparison, placebo group.
  • Relative risk includes two important features: (i) a comparison of risk between two "exposures”puts risks in context, and (ii) "exposure”is ensured by having proper denominators for each group representing the exposure.
  • censoring refers to a statistics term. Censoring is a condition in which the value of a measurement or observation is only partially known. Such a situation could occur if the individual withdrew from the study before endpoints achieved.
  • the problem of censored data, in which the observed value of some variable is partially known, is related to the problem of missing data, where the observed value of some variable is unknown.
  • PI-88 and “muparfostat” are interchangeable.
  • OS refers to overall survival, the percentage of patients alive at a defined time after initiation of the treatment.
  • DFS refers to the disease free survival, length of time after treatment that a patient survives with no sign of disease.
  • the most frequent use of DFS as trial endpoint is in the adjuvant setting after definitive surgery.
  • overall survival is a conventional endpoint for most adjuvant settings, DFS can be an important endpoint in situations where survival may be prolonged, making a survival endpoint impractical.
  • DFS has been the primary basis of approval for adjuvant therapies.
  • DFS can be a surrogate for clinical benefit or it can provide direct evidence of clinical benefit. This determination is based on the magnitude of the effect, its risk-benefit relationship, and the disease setting.
  • Child–Pugh score also known as Child–Turcotte–Pugh score or Child Criteria
  • Child Criteria is used to assess the prognosis of chronic liver disease, mainly cirrhosis. It is used to determine the prognosis, as well as the required strength of treatment and the necessity of liver transplantation.
  • the score employs five clinical measures of liver disease. Each measure is scored 1–3, with 3 indicating most severe derangement. See table A below for the score assessment.
  • the neoplastic grading is a measure of cell anaplasia (reversion of differentiation) in the sampled tumor and is based on the resemblance of the tumor to the tissue of origin.
  • the grade score (numerical: G1 up to G4) increases with the lack of cellular differentiation -it reflects how much the tumor cells differ from the cells of the normal tissue they have originated from.
  • Tumors may be graded on four-tier, three-tier, or two-tier scales, depending on the institution and the tumor type. In the present invention, the HCC patients were graded by the following four-tier scale: well differentiated (G1) , moderately differentiated (G2) , poorly differentiated (G3) , and anaplasia (G4) .
  • the Kaplan-Meier (KM) survival curve is defined as the probability of surviving in a given length of time while considering time in many small intervals. To estimate the KM, two pieces of data are required for each subject: the “status” at last observation (event/censoring) and the “time” (time to event or time to censoring) . The “arm” assigned to the subject will also be required if comparison is to be proceed. The “status” for a subject can only be either event or censoring. Take overall survival as illustration, death is defined as “event” and all the others not dead are “censored” .
  • the x-axis is “time” , from zero (when observations began) to the last observed time point; the y-axis is the proportion of subjects surviving. At time zero, 100%of the subjects are alive without an event. Each vertical drop indicates an event.
  • the primary efficacy endpoint was DFS period and an event means either tumor occurrence or death.
  • the larger separation between the curves the greater difference between the arms is demonstrated.
  • PI-88 (muparfostat) is a novel adjuvant therapy for patients with HCC post resection.
  • phase II trial PI-88 was well tolerated, with favorable safety profiles at 160 mg/day, and demonstrated a promising time-to-recurrence prolongation for patients with HCC after surgical resection, especially in those with hepatitis virus-related HCC. Therefore, in the present phase III, multicenter, randomized clinical trial (RCT) , the effect of muparfostat (PI-88) , a heparanase inhibitor, on tumor recurrence or death in patients with HBV-or HCV-related HCC after surgical resection was investigated.
  • RCT randomized clinical trial
  • HCC hepatocellular carcinoma
  • DFS disease-free survival
  • ITT intention-to-treat
  • PP per-protocol
  • AE adverse event
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • RCT randomized controlled trial
  • HIT heparin-induced thrombocytopenia
  • OS overall survival
  • SD standard deviation
  • HR hazard ratio
  • SAE serious adverse event
  • ICI immune checkpoint inhibitor.
  • the exclusion criteria were as follows: (1) diameter of single HCC ⁇ 2 cm obtained from the most recent hepatectomy; (2) history of immune-mediated thrombocytopenia, other platelet abnormalities, or other hereditary or acquired coagulopathies; laboratory evidence of antiheparin antibodies; or any previous history of having tested positive for antiheparin antibodies; (3) HCC metastasis or prior or coexisting malignant disease; (4) clinically significant nonmalignant diseases (5) history of receiving prior HCC therapy, including chemotherapy and radiotherapy; molecular targeting agents, such as antiangiogenic antibodies or kinase inhibitors; vaccines; transarterial embolization; transarterial chemoembolization; liver transplantation; or surgical resection prior to the most recent hepatectomy; and (6) history of inflammatory bowel disease or any other abnormal bleeding tendency or being at a risk of bleeding due to open wounds or planned surgery.
  • Eligible patients were stratified by tumor size ( ⁇ 5 cm vs. ⁇ 5 cm) and vascular invasion (no vs. yes) and then randomized at a ratio of 1: 1 within strata to receive PI-88 (160 mg/day) or a placebo by using a centralized interactive web response system (Cenduit Interactive Response Technology; Cenduit, Durham, North Carolina, USA) .
  • PI-88 was supplied to pharmacies as a sterile lyophilized powder in a glass vial (Par Pharmaceutical, Rochester, Michigan, USA) to deliver 160 mg after reconstitution.
  • the placebo was supplied as a sterile, lyophilized powder in a glass vial of identical specifications and appearance to that used for the investigational drug.
  • the principal constituent of the placebo was lactose as a sterile lyophilized powder.
  • the powders and solutions of PI-88 and placebo were identical in appearance to ensure treatment blindness.
  • PI-88 or placebo was administered in a single subcutaneous injection each day for four consecutive days per week for 3 weeks out of every 4 weeks (a cycle with 4-weeks) .
  • the days of injection were the same in every administration week.
  • participants self-administered the study drug at home. Participants received treatment for up to 52 weeks and were followed until 96 weeks.
  • the primary efficacy endpoint of this RCT was the DFS period, which was defined as the time from randomization to tumor recurrence or death from any cause. Secondary efficacy endpoints were time to tumor recurrence, tumor recurrence rate, and overall survival (OS) .
  • Tumor recurrence was diagnosed according to a radiological algorithm based on three monthly scheduled surveillance CT scans. The radiological algorithm emphasizes a “typical vascular pattern” on CT or MRI. This pattern consists of arterial hypervascularity and early-or late-phase portal/venous “washout. ” These findings may be demonstrated on a triphasic spiral CT scan or a gadolinium-enhanced MRI scan. Tumor recurrences on CT/MRI scans were assessed independently by a centralized facility according to the radiological algorithm. Liver biopsy was performed to confirm tumor recurrence in case of equivocal findings any time during the diagnostic algorithm.
  • the data were analyzed using the R 3.3.2 software (R Foundation for Statistical Computing, Vienna, Austria) .
  • the distributional properties of continuous variables are expressed as mean ⁇ standard deviation, categorical variables are presented as frequency and percentage (%) , and the survival curves of the DFS period were estimated using the Kaplan–Meier method.
  • Baseline demographic and clinical characteristics were compared between the PI-88 and placebo groups.
  • the safety profiles of PI-88 and the placebo were examined in all randomized patients who received at least one dose of the assigned drug. Efficacy analysis was conducted for the primary endpoint (the DFS period) and secondary endpoints (time to tumor recurrence and OS) . Both intention-to-treat (ITT) and per-protocol (PP) analyses were performed.
  • the drugs included in this type were: (a) any of the seven anti-hepatitis B virus (HBV) drugs (adefovir, adefovir dipivoxil, entecavir, lamivudine, telbivudine, tenofovir, and tenofovir disoproxil fumarate) ; (b) any of the five anti-hepatitis C virus (HCV) drugs (ribavirin, peginterferon, peginterferon alfa-2A, peginterferon alfa-2B, and pegylated interferon alfa-2A) ; and (c) PI-88.
  • HBV anti-hepatitis B virus
  • HCV anti-hepatitis C virus
  • the GOF measures, concordance, and adjusted generalized R 2 were examined to assess the GOF of the fitted Cox’s model.
  • the concordance which is a value between 0 and 1, of the Cox’s model is equivalent to the c statistic of the logistic regression model; thus, its value of ⁇ 0.7 suggests an acceptable discriminative power.
  • the values of the adjusted generalized R 2 (0 ⁇ R 2 ⁇ 1) proposed by Nagelkerke (1991) , are usually low for the Cox’s model; in our experience, adjusted generalized R 2 ⁇ 0.15 indicates an acceptable fit for the Cox’s model.
  • the anti-HBV drug is selected from the group consisting of Adefovir, Adefovir Dipivoxil, Entecavir, Lamivudine, Telbivudine, Tenofovir, and Tenofovir Disoproxil Fumarate.
  • the anti-HCV drug is selected from the group consisting of Ribavirin, Peginterferon, Peginterferon alfa-2A, Peginterferon alfa-2B, and Pegylated Interferon alfa-2A, Paritaprevir, Simepravir, Grazoprevir, Ladispavir, Ombitasvir, Elbasavir, Sofosbuvir, Edipasvir, Viekira Pak, Ritonavir and Daclatasvir.
  • FIG. 4A illustrates the DFS curves of the patients with microvascular invasion whose time to tumor recurrence or death was >24 weeks adjusted for number of tumors, pathological differentiation, Child–Pugh score, macrovascular invasion, tumor size, and anti-HBV or anti-HCV drug use after randomization.
  • the status event is defined as tumor recurrence or death due to any cause; the time is defined from randomization to tumor recurrence or death due to any cause during the study period in weeks; and the arm is either PI-88 or placebo.
  • FIG. 4B demonstrates a similar Kaplan–Meier curve for the patients without vascular invasion who received PI-88.
  • FIG. 4C FIGs. 4A and 4B are superimposed in the same X and Y scales for easy comparison.
  • FIG. 5 shows strong protective effect of muparfostat (PI-88) in a subgroup of patients with microvascular invasion after the study drug had been administered for a period of 52 weeks.
  • the unit of X axis is time in weeks.
  • the number on the X axis stands for the “accumulative time (in weeks) since the end of last cycle of Muparfostat in patients with microvascular invasion. ”
  • P is the probability of tumor recurrence or death
  • Logit (P) log [P/ (1 -P) ] .
  • the number of observations was 16536, which was reconstructed from the original PP data using counting process style of input.
  • 346 patients completed the treatment at the last cycle (i.e., Cycle 13) .
  • More patients in the placebo group (187/260, 71.9%) completed the study treatment at Cycle 13 than those the PI-88 group (159/258, 61.6%) .
  • the treatment-related AE with the highest overall incidence was alopecia, which was reported in 58 (22.5%) patients in the PI-88 group and 4 (1.5%) patients in the placebo group, followed by a decreased platelet count, which was reported in 36 (14.0%) patients in the PI-88 group and 10 (3.8%) patients in the placebo group, and injection site hematoma, which was observed in 33 (12.8%) patients in the PI-88 group and 7 (2.7%) patients in the placebo group.
  • PI-88 provides clinical benefits by modulating the tumor microenvironment to a stable state and that intrahepatic tumor recurrence can be substantially reduced if the drug is administered for a long period.
  • FIG. 10 shows delayed protective effect of anti-HBV drug in a subgroup of patients without vascular invasion after the drug had been administered for a period of 60 weeks.
  • the unit of X axis is time in weeks.
  • the number on the X axis stands for the “accumulated weeks of anti-HBV drug treatment after randomization minus 28 days prior to each event time” , which is defined as accumulative drug days in weeks since the first day of taking the drug after randomization up to each unique event time of DFS, but ignoring the drug usage within the pre-specified time lag of 28 days as the “latency period” or “incubation period” of anti-HBV drug prior to each unique event time of DFS.
  • P is the probability of tumor recurrence or death
  • Logit (P) log [P/ (1 -P) ] .
  • the number of observations was 16536, which was reconstructed from the original PP data using counting process style of input.
  • the probability of tumor recurrence or death was lower than the probability without tumor recurrence or death.
  • the ratio of probability of tumor recurrence or death to the probability without tumor recurrence or death declines with time (accumulated weeks of anti-HBV drug treatment after randomization minus 28 days prior to each event time) .
  • anti-HBV drugs have a protective effect on tumor recurrence if used for a long period (e.g., >60 weeks) ; however, anti-HBV drugs primarily exerts effects on patients without vascular invasion.
  • anti-HBV treatment particularly nucleotide analogs, can reduce the risk of tumor recurrence after curative treatment in patients with HBV-related HCC.
  • the results of this study indicated that the protective effect was exerted on only a specific subgroup of the patients without vascular invasion, and the protective power of anti-HBV drugs is lower than that of PI-88.
  • PI-88 possesses an undefined biochemical or immunological mode of action other than the already known heparanase inhibition and antiangiogenesis effects.
  • PI-88 exerts unexpected modulatory effects on tumor microenvironment, which are likely to play an enhancing role along with immune checkpoint inhibitor (ICI) effects for various cancer treatments.
  • ICI immune checkpoint inhibitor
  • PI-88 in combination with immune checkpoint inhibitor (ICI) may have promising potential in cancer therapies.
  • PI-88 is an agent that has a cytostatic, but not cytotoxic, mechanism of action, and it is unreasonable to expect that small cancer foci already existing in the liver, which are invisible in imaging or undetectable by biochemistry tests, can be unanimously eradicated by PI-88 if they are left over in the liver tissue after surgery.
  • HCC residuals may become the foci of secondary growth soon after surgery because partial hepatectomy per se may play a crucial role in accelerating the carcinogenesis of HCC.
  • the inability to suppress the growth of remaining cancer foci within the liver post surgery is probably one of the reasons why PI-88 failed to demonstrate a benefit in DFS in this study.
  • the overall 1-, 2-, and 3-year DFS rates were 73%, 66%, and 58%, respectively, which are comparable to survival outcomes reported in most other HCC meta-analyses to date.
  • microenviroment-modifying agents such as PI-88
  • PI-88 might only work for minimal residual tumors after surgery; thus, careful selection of patients to better suit this criterion is critical.
  • PI-88 could significantly prolong the DFS period in the subgroup of patients with microvascular invasion in the histology of resected samples (accounted for nearly 40%of the treated population) .
  • the tumor recurrence protecting effect became significant.
  • the DFS period in the subgroup of patients without vascular invasion in the histology of resected samples could be prolonged by administering an anti-HBV drug for a time period (e.g., >60 weeks) .
  • the present invention also indicated the potential of PI-88 as a single therapy or in combination with other anticancer agents for future HCC trials.

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PCT/CN2018/077105 2017-03-01 2018-02-24 Use of sulfated oligosaccharides in the manufacture of a medicament for treating patients with hepatocellular carcinoma after surgical resection Ceased WO2018157762A1 (en)

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CN201880014397.6A CN110381953A (zh) 2017-03-01 2018-02-24 硫化寡糖在制备治疗手术后肝细胞癌病患的药物的用途
JP2019547371A JP6948080B2 (ja) 2017-03-01 2018-02-24 手術後の肝細胞癌患者を治療するための薬剤の製造における硫酸化オリゴ糖の使用
KR1020197028654A KR102265159B1 (ko) 2017-03-01 2018-02-24 수술적 절제 후 간세포암종 환자를 치료하기 위한 약제의 제조에서 황산화된 올리고당류의 용도

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