Phase Ⅰ of clinical trials is the first stage of clinical pharmacology and body safety evaluation,including body tolerance test and pharmacokinetics test.The aim is providing evidence for dosage regimen and be the co...Phase Ⅰ of clinical trials is the first stage of clinical pharmacology and body safety evaluation,including body tolerance test and pharmacokinetics test.The aim is providing evidence for dosage regimen and be the cornerstone of the preliminary assessment of efficacy and safety of phase Ⅱ of clinical trials.This text discussed the technique and requirement of phase Ⅰ of new drugs' clinical tolerance trials.展开更多
Aim To assess the safety and tolerance of adefovir dipivoxil （ADV） in Chinese healthy volunteers. Methods A total of 52 healthy volunteers, 26 males and 26 females, aged from 19 to 26 were enrolled in the study. For...Aim To assess the safety and tolerance of adefovir dipivoxil （ADV） in Chinese healthy volunteers. Methods A total of 52 healthy volunteers, 26 males and 26 females, aged from 19 to 26 were enrolled in the study. Forty-two subjects were randomized into 5, 10, 20, 40, and 60 mg dose groups （6 - 10 subjects in each） matched by sex and weight for single-dose trial. Ten subjects were orally given 10 mg of ADV tablets once daily for 7 d for multiple-dose trial. Physical examination, vital signs examination, electrocardiography, type-B ultrasonography, chest fluoroscopy, routine blood test, routine urine test, coagulation tests, and blood biochemical test were conducted on schedule and statistically evaluated. Results Asthenia frequently occurred in multiple-dose trial, nausea, abdominal pain, and diarrhea occurred in both single- and multiple-dose trials. ALT, bilirubin, CK, and LDH were slightly elevated. All adverse reactions and laboratory abnormalities were mild, and the frequency and severity were not related to doses. Conclusion ADV is safe and well tolerated in Chinese healthy volunteers at dose of 5 - 60 mg oncedaily or 10 nag once daily for 7 d. The recommended oral dosage regimen is 10 mg once daily. Attention should be paid to renal and liver functions, CK, AMY and LDH, if we take ADV for a long period of time.展开更多
While ovarian cancer （OvCa） responds well to surgery and conventional chemotherapy, a high recurrence rate of advanced OvCa is observed. In this phase Ⅰ/Ⅱ study, 10 OvCa patients with minimal residual disease were...While ovarian cancer （OvCa） responds well to surgery and conventional chemotherapy, a high recurrence rate of advanced OvCa is observed. In this phase Ⅰ/Ⅱ study, 10 OvCa patients with minimal residual disease were treated with autologous dendritic cells （DCs） and IL-2 to evaluate the safety and feasibility of this therapeutic strategy and to characterize the antigen-specific immune alterations induced through this treatment. Approximately 4 months after initial debulking and chemotherapy, patients received two subcutaneous doses of autologous monocyte-derived DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin （KLH） at 4-week intervals. After each DC inoculation, low-dose （200 mlU） IL-2 was introduced for 14 consecutive days as an immune adjuvant. The vaccination was well tolerated. In three out of 10 patients, the inclusion status after the initial therapy showed the maintenance of complete remission （CR） after DC vaccination for 83, 80.9 and 38.2 months without disease relapse. One patient with stable disease （SD） experienced the complete disappearance of tumor after DC vaccination, and this status was maintained for 50.8 months until tumor recurrence. In two patients with partial response （PR） was not responding to DC vaccination and their disease recurred. In the three patients with disease free long-term survival, significant immune alterations were observed, including increased natural killer （NK） activity, IFN-γ-secreting T cells, immune-stimulatory cytokine secretion and reduced immune-suppressive factor secretion after DC vaccination. Thus, in patients with NED status and increased overall survival, DC vaccination induced tumor-related immunity, potentially associated with long-term clinical responses against OvCa.展开更多
Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-E...Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-Esc and D-Ex)trial in patients with advanced solid cancer.Methods:This was a 3+3 phaseⅠD-Esc trial with a 3-level D-Ex at 5 hospitals in China.Eligible patients for DEsc had advanced solid tumors refractory to standard therapies,and D-Ex enrolled patients with ovarian cancer(OC).Fluzoparib was administered orally once or twice daily(bid)at 11 dose levels from 10 to 400 mg/d.Endpoints included dose-finding,safety,pharmacokinetics,and antitumor activity.Results:Seventy-nine patients were enrolled from March,2015 to January,2018[OC(47,59.5%);breast cancer(BC)(16,20.3%);colorectal cancer(8,10.1%),other tumors(8,10.1%)];48 patients were treated in the D-Esc arm and 31 in the D-Ex arm.The maximum tolerated dose(MTD)was 150 mg bid,with a half-life of 9.14 h.Grade 3/4 adverse events included anemia(7.6%)and neutropenia(5.1%).The objective response rate(ORR)was 30%(3/10)in patients with platinum-sensitive OC and 7.7%(1/13)in patients with BC.Among patients treated with fluzoparib≥120 mg/d,median progression-free survival(m PFS)was 7.2[95%confidence interval(95%CI),1.8-9.3]months in OC,9.3(95%CI,7.2-9.3)months in platinum-sensitive OC,and 3.5(range,2.0-28.0)months in BC.In patients with germline BC susceptibility gene mutation(g BRCAMut)(11/43 OC;2/16 BC),m PFS was 8.9 months for OC(range,1.0-23.2;95%CI,1.0-16.8)and 14 and 28 months for BC(those two patients both also had somatic BRCAMut).Conclusions:The MTD of fluzoparib was 150 mg bid in advanced solid malignancies.Fluzoparib demonstrated single-agent antitumor activity in BC and OC,particularly in BRCAMut and platinum-sensitive OC.展开更多
We propose a new two-/three-stage dose-finding design called Target Toxicity(TT)for phase Ⅰ clinical trials,where we link the decision rules in the dose-finding process with the conclusions from a hypothesis test.The...We propose a new two-/three-stage dose-finding design called Target Toxicity(TT)for phase Ⅰ clinical trials,where we link the decision rules in the dose-finding process with the conclusions from a hypothesis test.The power to detect excessive toxicity is also given.This solves the problem of why the minimal number of patients is needed for the selected dose level.Our method provides a statistical explanation of traditional‘3+3’design using frequentist framework.The proposed method is very flexible and it incorporates other interval-based decision rules through different parameter settings.We provide the decision tables to guide investigators when to decrease,increase or repeat a dose for next cohort of subjects.Simulation experiments were conducted to compare the performance of the proposed method with other dose-finding designs.A free open source R package tsdf is available on CRAN.It is dedicated to deriving two-/three-stage design decision tables and perform dose-finding simulations.展开更多
背景与目的:华蟾素目前广泛应用于肿瘤的治疗中,由于在80年代上市,未进行临床Ⅰ期研究,无法确定其最大耐受剂量。因此本文旨在观察华蟾素治疗肝细胞癌、肺癌和胰腺癌的最大耐受剂量和不良反应,同时评价治疗疗效。方法:Ⅲ、Ⅳ期肝细胞癌...背景与目的:华蟾素目前广泛应用于肿瘤的治疗中,由于在80年代上市,未进行临床Ⅰ期研究,无法确定其最大耐受剂量。因此本文旨在观察华蟾素治疗肝细胞癌、肺癌和胰腺癌的最大耐受剂量和不良反应,同时评价治疗疗效。方法:Ⅲ、Ⅳ期肝细胞癌、非小细胞肺癌和胰腺癌接受华蟾素治疗,采用静脉滴注,连续14 d,21 d为一疗程。如果没有出现剂量限制性毒性,治疗将持续2个疗程。剂量递增的方案为:10、20、40、60、90和120 m l/(m2.d)。结果:入组15例患者(每个剂量组为3例)中,11例为肝癌,2例胰腺癌和2例肺癌。第五剂量组结束时没有发现剂量限制性毒性(DLT)。其中14例患者可评价疗效,6例(42.9%)为SD,8例(57.1%)为PD。在第一剂量组中,1例肝癌患者肿瘤缩小20%并维持11个月。结论:本研究最高剂量达到常规剂量的8倍,尚未出现剂量限制性毒性。部分患者获得了肿瘤缩小或稳定的疗效。展开更多
文摘Phase Ⅰ of clinical trials is the first stage of clinical pharmacology and body safety evaluation,including body tolerance test and pharmacokinetics test.The aim is providing evidence for dosage regimen and be the cornerstone of the preliminary assessment of efficacy and safety of phase Ⅱ of clinical trials.This text discussed the technique and requirement of phase Ⅰ of new drugs' clinical tolerance trials.
文摘Aim To assess the safety and tolerance of adefovir dipivoxil （ADV） in Chinese healthy volunteers. Methods A total of 52 healthy volunteers, 26 males and 26 females, aged from 19 to 26 were enrolled in the study. Forty-two subjects were randomized into 5, 10, 20, 40, and 60 mg dose groups （6 - 10 subjects in each） matched by sex and weight for single-dose trial. Ten subjects were orally given 10 mg of ADV tablets once daily for 7 d for multiple-dose trial. Physical examination, vital signs examination, electrocardiography, type-B ultrasonography, chest fluoroscopy, routine blood test, routine urine test, coagulation tests, and blood biochemical test were conducted on schedule and statistically evaluated. Results Asthenia frequently occurred in multiple-dose trial, nausea, abdominal pain, and diarrhea occurred in both single- and multiple-dose trials. ALT, bilirubin, CK, and LDH were slightly elevated. All adverse reactions and laboratory abnormalities were mild, and the frequency and severity were not related to doses. Conclusion ADV is safe and well tolerated in Chinese healthy volunteers at dose of 5 - 60 mg oncedaily or 10 nag once daily for 7 d. The recommended oral dosage regimen is 10 mg once daily. Attention should be paid to renal and liver functions, CK, AMY and LDH, if we take ADV for a long period of time.
文摘While ovarian cancer （OvCa） responds well to surgery and conventional chemotherapy, a high recurrence rate of advanced OvCa is observed. In this phase Ⅰ/Ⅱ study, 10 OvCa patients with minimal residual disease were treated with autologous dendritic cells （DCs） and IL-2 to evaluate the safety and feasibility of this therapeutic strategy and to characterize the antigen-specific immune alterations induced through this treatment. Approximately 4 months after initial debulking and chemotherapy, patients received two subcutaneous doses of autologous monocyte-derived DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin （KLH） at 4-week intervals. After each DC inoculation, low-dose （200 mlU） IL-2 was introduced for 14 consecutive days as an immune adjuvant. The vaccination was well tolerated. In three out of 10 patients, the inclusion status after the initial therapy showed the maintenance of complete remission （CR） after DC vaccination for 83, 80.9 and 38.2 months without disease relapse. One patient with stable disease （SD） experienced the complete disappearance of tumor after DC vaccination, and this status was maintained for 50.8 months until tumor recurrence. In two patients with partial response （PR） was not responding to DC vaccination and their disease recurred. In the three patients with disease free long-term survival, significant immune alterations were observed, including increased natural killer （NK） activity, IFN-γ-secreting T cells, immune-stimulatory cytokine secretion and reduced immune-suppressive factor secretion after DC vaccination. Thus, in patients with NED status and increased overall survival, DC vaccination induced tumor-related immunity, potentially associated with long-term clinical responses against OvCa.
文摘Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-Esc and D-Ex)trial in patients with advanced solid cancer.Methods:This was a 3+3 phaseⅠD-Esc trial with a 3-level D-Ex at 5 hospitals in China.Eligible patients for DEsc had advanced solid tumors refractory to standard therapies,and D-Ex enrolled patients with ovarian cancer(OC).Fluzoparib was administered orally once or twice daily(bid)at 11 dose levels from 10 to 400 mg/d.Endpoints included dose-finding,safety,pharmacokinetics,and antitumor activity.Results:Seventy-nine patients were enrolled from March,2015 to January,2018[OC(47,59.5%);breast cancer(BC)(16,20.3%);colorectal cancer(8,10.1%),other tumors(8,10.1%)];48 patients were treated in the D-Esc arm and 31 in the D-Ex arm.The maximum tolerated dose(MTD)was 150 mg bid,with a half-life of 9.14 h.Grade 3/4 adverse events included anemia(7.6%)and neutropenia(5.1%).The objective response rate(ORR)was 30%(3/10)in patients with platinum-sensitive OC and 7.7%(1/13)in patients with BC.Among patients treated with fluzoparib≥120 mg/d,median progression-free survival(m PFS)was 7.2[95%confidence interval(95%CI),1.8-9.3]months in OC,9.3(95%CI,7.2-9.3)months in platinum-sensitive OC,and 3.5(range,2.0-28.0)months in BC.In patients with germline BC susceptibility gene mutation(g BRCAMut)(11/43 OC;2/16 BC),m PFS was 8.9 months for OC(range,1.0-23.2;95%CI,1.0-16.8)and 14 and 28 months for BC(those two patients both also had somatic BRCAMut).Conclusions:The MTD of fluzoparib was 150 mg bid in advanced solid malignancies.Fluzoparib demonstrated single-agent antitumor activity in BC and OC,particularly in BRCAMut and platinum-sensitive OC.
文摘We propose a new two-/three-stage dose-finding design called Target Toxicity(TT)for phase Ⅰ clinical trials,where we link the decision rules in the dose-finding process with the conclusions from a hypothesis test.The power to detect excessive toxicity is also given.This solves the problem of why the minimal number of patients is needed for the selected dose level.Our method provides a statistical explanation of traditional‘3+3’design using frequentist framework.The proposed method is very flexible and it incorporates other interval-based decision rules through different parameter settings.We provide the decision tables to guide investigators when to decrease,increase or repeat a dose for next cohort of subjects.Simulation experiments were conducted to compare the performance of the proposed method with other dose-finding designs.A free open source R package tsdf is available on CRAN.It is dedicated to deriving two-/three-stage design decision tables and perform dose-finding simulations.
文摘背景与目的:华蟾素目前广泛应用于肿瘤的治疗中,由于在80年代上市,未进行临床Ⅰ期研究,无法确定其最大耐受剂量。因此本文旨在观察华蟾素治疗肝细胞癌、肺癌和胰腺癌的最大耐受剂量和不良反应,同时评价治疗疗效。方法:Ⅲ、Ⅳ期肝细胞癌、非小细胞肺癌和胰腺癌接受华蟾素治疗,采用静脉滴注,连续14 d,21 d为一疗程。如果没有出现剂量限制性毒性,治疗将持续2个疗程。剂量递增的方案为:10、20、40、60、90和120 m l/(m2.d)。结果:入组15例患者(每个剂量组为3例)中,11例为肝癌,2例胰腺癌和2例肺癌。第五剂量组结束时没有发现剂量限制性毒性(DLT)。其中14例患者可评价疗效,6例(42.9%)为SD,8例(57.1%)为PD。在第一剂量组中,1例肝癌患者肿瘤缩小20%并维持11个月。结论:本研究最高剂量达到常规剂量的8倍,尚未出现剂量限制性毒性。部分患者获得了肿瘤缩小或稳定的疗效。
