scholarly journals CAPRISA 018: a phase I/II clinical trial study protocol to assess the safety, acceptability, tolerability and pharmacokinetics of a sustained-release tenofovir alafenamide subdermal implant for HIV prevention in women

BMJ Open ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. e052880
Author(s):  
Tanuja Narayansamy Gengiah ◽  
Quarraisha Abdool Karim ◽  
Ishana Harkoo ◽  
Leila Mansoor ◽  
Nonhlanhla Yende Zuma ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Percentage Change ◽  
African Women ◽  
Control Group ◽  
Health Products ◽  
Tenofovir Alafenamide ◽  
Long Acting ◽  
Hiv Acquisition

IntroductionYoung African women bear a disproportionately high risk for HIV acquisition. HIV technologies that empower women to protect themselves are needed. Safe, potent antiretroviral agents such as tenofovir alafenamide (TAF), formulated as long-acting subdermal implants, offer an innovative solution.Methods and analysisCAPRISA 018 is a phase I/II trial to evaluate the safety, acceptability, tolerability and pharmacokinetics (PKs) of a TAF free base subdermal silicone implant containing 110 mg of TAF with an anticipated 0.25 mg/day release rate.The phase I trial (n=60) will assess the safety of one implant inserted in six participants (Group 1), followed by dose escalation components (Groups 2 and 3) assessing the safety, tolerability and PK of one to four TAF 110 mg implants releasing between 0.25 mg and 1 mg daily in 54 healthy women at low risk for HIV infection. Data from this phase I trial will be used to determine the dosing, implant location and implant replacement interval for the phase II trial.The phase II component (Group 4) will assess extended safety, PK, tolerability and acceptability of the implant in 490 at risk women, randomised in a 1:1 ratio to the TAF implant and placebo tablet or to the placebo implant and an oral pre-exposure prophylaxis tablet. Safety will be assessed by calculating the percentage change in creatinine clearance from baseline at weeks 4, 12, 24, 36, 72, 96 and 120, compared with the percentage change in the control group.Ethics and disseminationThe South African Health Products Regulatory Authority and the University of KwaZulu-Natal’s Biomedical Research Ethics Committee have approved the trial. Results will be disseminated through open access peer reviewed publications, conference presentations, public stakeholder engagement and upload of data into the clinical trials registry.Trial registration numberPACTR201809520959443.

scholarly journals Phase I and Preliminary Results of a Phase II Study (TERAPLASCoV2) of Convalescent Plasma in Patients with Severe and Life-Threatening Pneumonia Caused By Sars-Cov-2

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-31
Author(s):  
Fernando Pérez-Jacobo ◽  
Luis Villela Villela ◽  
Edgar Velásquez-Vega ◽  
Jesús Hernández ◽  
Melani Otañez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Phase Ii Study ◽  
Severe Disease ◽  
Control Group ◽  
Igg Antibody ◽  
Severe Group ◽  
Life Threatening

Introduction: The current coronavirus disease- 2019 (COVID-19) pandemic has caused a sudden increase in pneumonia cases, with a case-fatality rate of 10.9% in Mexico. Two inpatient groups have been defined, with different clinical evolution: cases of severe pneumonia and those with life-threatening disease (Acute respiratory distress syndrome [ARDS], invasive mechanical ventilation [IMV] requirement, and multiorgan involvement). Currently, there is no effective treatment. Convalescent plasma (CP) has been used to treat another viral infections and outbreaks since the last century. The rationale is that neutralizing antibodies contained in CP suppress viremia and produce immunoregulation. However, an established therapeutic dose during this pandemic is lacking. Aim: To evaluate in a phase I trial the minimum effective dose of CP in severe and life-threatening disease patients and then carry out a phase II study to establish the effectiveness (overall survival at 30 days) comparing it with a non-randomized control group. Methods and design. Our study is an open-label, multicenter, non-randomized and started in May, 2020 and was approved by the ethics committee at HGE & HCN Pemex; respectively. CP donor selection: pre-donors who were infected by SARS-CoV-2 were evaluated on +30 day by serum titration (≥1:320 IgG antibody); then connected to apheresis machine to obtain 600 ml of CP that were fractionated in 200 ml bags and stored. Patients: Two groups were formed: severe and life-threating disease. CP was offered to patients who were admitted on two hospitals. Patients should meet the following criteria: SARS-CoV-2 positive for qRT- PCR, respiratory rate> 30 per minute or Kirby index <300 or IMV requirement; be older than 18 years; and sign the informed consent. Statistics: For demographic variables, the differences were evaluated with parametric or non-parametric analysis. For survival, Kaplan Meier curves were assessed for each group. A p value <0.05 was considered significant. Outcomes: A total of 110 CP bags have been transfused. The median serum IgG antibody titers were 1: 960. Dosing, phase 1. Severe group (n=14): 71% received two CP bags (400 ml) and 29% three CP bags (600 mL). Life-threatening disease group (n=10): 60% received 4 CP bags (800 ml) and 40% 3 CP bags (600 ml). Dose was established at 400 ml for the severe group and 800 ml for the life-threatening group. Security: CP infusions were well tolerated, with only 3 adverse events (2.72%) reported: one case of transfusion associated circulatory overload (TACO) that resolved with the use of loop diuretics as a serious adverse event; one fever episode (grade 1) and one case of rash (grade 1) after CP infusion. Phase II: The calculated n to be included in each arm (severe vs. life-threatening disease) is 68 and 52 patients, respectively. So far, we have included a total of 42 patients treated with CP. This entire cohort was compared with a historic group of COVID-19 patients who received other treatment strategies. Clinical characteristics on both plasma (PG) and control group (CG) are presented in table 1. We observed statistically significant differences on smoking habit, D-Dimer levels and ARDS severity between groups. The median overall follow- up was 24 days [PG 28 days vs. CG 21.5 days]. Overall Survival (OS) between PG and CG was 74% vs. 54% at 30-days respectively [HR=0.43 (C.I.95%=0.23 to 0.91, p=0.021); figure 1]. We analyzed OS by group stratification: COVID-19 severity (severe disease vs. life-threatening disease) and ARDS severity. We found no difference in OS between severe disease-PG and severe disease-CG; but we observed an OS difference between life-threatening-PG and life-threatening-CG [32% vs. 5.8% at 30-days; p=0.003]. ARDS-PG vs. ARDS-CG showed OS differences in moderate [59% vs. 25% at 30 days; p=0.01, respectively] and severe ARDS [63% vs. 0%; p=0.001, respectively]; however, there was not statistically significant difference between mild ARDS-PG and CG groups [89% vs. 86%; p=0.85, respectively]. Conclusion: This is the first phase I trial aiming to establish an effective CP dose for COVID-19 patients, at least in México. For severe and life-threatening disease, 2 and 4 CP bags were suggested. This treatment was secure, with <3% of adverse events reported. OS could be modified using certain doses based on disease severity and pa02/Fi02 index. We will continue to include patients until the calculated n is reached. Disclosures Villela: Roche: Other: advisory board, Speakers Bureau; amgen: Speakers Bureau.

Intrathecal Mafosfamide: A Preclinical Pharmacology and Phase I Trial

2005 ◽  
Vol 23 (7) ◽  
pp. 1555-1563 ◽  
Author(s):  
Susan M. Blaney ◽  
Frank M. Balis ◽  
Stacey Berg ◽  
Carola A.S. Arndt ◽  
Richard Heideman ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Neoplastic Meningitis ◽  
In Vitro Cytotoxicity ◽  
Pharmacokinetic Studies ◽  
Preclinical Studies ◽  
Phase Ii Trials ◽  
Cytotoxicity Studies

Purpose Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

Phase I Trial of Escalating-Dose Irinotecan Given Weekly With Cisplatin and Concurrent Radiotherapy in Locally Advanced Esophageal Cancer

2003 ◽  
Vol 21 (15) ◽  
pp. 2926-2932 ◽  
Author(s):  
David H. Ilson ◽  
Manjit Bains ◽  
David P. Kelsen ◽  
Eileen O’Reilly ◽  
Martin Karpeh ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Phase I ◽  
Induction Chemotherapy ◽  
Phase Ii ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Phase Iii ◽  
Concurrent Radiotherapy ◽  
Minimal Toxicity ◽  
Grade 3

Purpose: To identify the maximum-tolerated dose and dose-limiting toxicity (DLT) of weekly irinotecan combined with cisplatin and radiation in esophageal cancer. Patients and Methods: Nineteen patients with clinical stage II to III esophageal squamous cell or adenocarcinoma were treated on this phase I trial. Induction chemotherapy with weekly cisplatin 30 mg/m2 and irinotecan 65 mg/m2 was administered for four treatments during weeks 1 to 5. Radiotherapy was delivered weeks 8 to 13 in 1.8-Gy daily fractions to a dose of 50.4 Gy. Cisplatin 30 mg/m2 and escalating-dose irinotecan (40, 50, 65, and 80 mg/m2) were administered on days 1, 8, 22, and 29 of radiotherapy. DLT was defined as a 2-week delay in radiotherapy for grade 3 to 4 toxicity. Results: Minimal toxicity was observed during chemoradiotherapy, with no grade 3 or 4 esophagitis, diarrhea, or stomatitis. DLT caused by myelosuppression was seen in two of six patients treated at the 80-mg/m2 dose level, thus irinotecan 65 mg/m2 was defined as the recommended phase II dose. Dysphagia improved or resolved after induction chemotherapy in 13 (81%) of 16 patients who reported dysphagia before therapy. Only one patient (5%) required a feeding tube. Six complete responses (32%) were observed, including four pathologic complete responses in 15 patients selected to undergo surgery (27%). Conclusion: Cisplatin, irinotecan, and concurrent radiotherapy can be administered on a convenient schedule with relatively minimal toxicity and an acceptable rate of complete response in esophageal cancer. Further phase II evaluation of this regimen is ongoing. A phase III comparison to fluorouracil or taxane-containing chemoradiotherapy should be considered.

scholarly journals LIPid Intensive Drug therapy for Sepsis Pilot (LIPIDS-P): Phase I/II clinical trial protocol of lipid emulsion therapy for stabilising cholesterol levels in sepsis and septic shock

BMJ Open ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. e029348 ◽  
Author(s):  
Faheem W Guirgis ◽  
Lauren Page Black ◽  
Martin Daniel Rosenthal ◽  
Morgan Henson ◽  
Jason Ferreira ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Drug Therapy ◽  
High Density Lipoprotein ◽  
Phase I ◽  
Cholesterol Level ◽  
Phase Ii ◽  
Lipid Emulsion ◽  
Density Lipoprotein ◽  
Control Group ◽  
Cholesterol Levels

IntroductionSepsis is a life-threatening, dysregulated response to infection. Both high-density lipoprotein and low-density lipoprotein cholesterol should protect against sepsis by several mechanisms; however, for partially unknown reasons, cholesterol levels become critically low in patients with early sepsis who experience poor outcomes. An anti-inflammatory lipid injectable emulsion containing fish oil is approved by the Food and Drug Administration as parenteral nutrition for critically ill patients and may prevent this decrease in serum cholesterol levels by providing substrate for cholesterol synthesis and may favourably modulate inflammation. This LIPid Intensive Drug therapy for Sepsis Pilot clinical trial is the first study to attempt to stabilise early cholesterol levels using lipid emulsion as a treatment modality for sepsis.Methods and analysisThis is a two-centre, phase I/II clinical trial. Phase I is a non-randomised dose-escalation study using a Bayesian optimal interval design in which up to 16 patients will be enrolled to evaluate the safest and most efficacious dose for stabilising cholesterol levels. Based on phase I results, the two best doses will be used to randomise 48 patients to either lipid injectable emulsion or active control (no treatment). Twenty-four patients will be randomised to one of two doses of the study drug, while 24 control group patients will receive no drug and will be followed during their hospitalisation. The control group will receive all standard treatments mandated by the institutional sepsis alert protocol. The phase II study will employ a permuted blocked randomisation technique, and the primary endpoint will be change in serum total cholesterol level (48 hours − enrolment). Secondary endpoints include change in cholesterol level from enrolment to 7 days, change in Sequential Organ Failure Assessment score over the first 48 hours and 7 days, in-hospital and 28-day mortality, lipid oxidation status, inflammatory biomarkers, and high-density lipoprotein function.Ethics and disseminationInvestigators are trained and follow good clinical practices, and each phase of the study was reviewed and approved by the institutional review boards of each institution. Results of each phase will be disseminated through presentations at national meetings and publication in peer-reviewed journals. If promising, data from the pilot study will be used for a larger, multicentre, phase II clinical trial.Trial registration numberNCT03405870.

Oral HDAC Inhibitor HBI8000 in Japanese Patients with Non-Hodgkin Lymphoma (NHL): Phase I Safety and Efficacy Results

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1827-1827 ◽  
Author(s):  
Makoto Onizuka ◽  
Kiyoshi Ando ◽  
Makoto Yoshimitsu ◽  
Takashi Ishida ◽  
S Yoshida ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Phase I Trial ◽  
Cell Lymphoma ◽  
Japanese Patients ◽  
Dose Cohort ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Background: HBI-8000 is an orally bioavailable member of the benzamide class of histone deacetylase inhibitors (HDACi), that inhibits cancer-associated HDAC enzymes (Class I and IIb). HBI-8000 has anti-tumor activity through various mechanisms of action, including epigenetic reprogramming and immunomodulation. It was recently approved by the Chinese FDA under the name chidamide (Epidaza) for relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) with a recommended dose of 30 mg twice weekly (BIW). HBI-8000 is also being manufactured in the USA for clinical development outside of China. The preliminary results of a phase I trial of HBI-8000 to confirm the safety and maximum tolerated dose (MTD) in Japanese patients (pts) with advanced NHL are presented (NCT02697552). Methods: This is a multicenter, prospective phase I trial in Japan. Inclusion criteria: patients are eligible if they have histologically or cytologically proven NHL and no other standard therapy is available. The primary endpoint is the MTD based on the frequency of dose-limiting toxicities (DLTs) observed within 28 days of the first dose. Secondary endpoints include pharmacokinetic (PK) profile and anti-tumor activity. At the time of this abstract submission, the trial is still ongoing. Results: Thirteen out of 14 pts were eligible for the 1st cycle DLT assessment (6 pts in the 30 mg, 7 pts in the 40 mg cohort). Median age was 68 years, gender well balanced, and the majority of pts had ≥ 2 prior treatment regimens. Five pts had the diagnosis of adult T-cell leukemia-lymphoma (ATL), 2 pts presented with PTCL, 3 with diffuse large B-cell lymphoma (DLBLC), 2 with follicular lymphoma (FL), 1 with cutaneous T-cell lymphoma (CTCL), and 1 with marginal zone lymphoma. Overall, the treatment was well tolerated, and adverse drug reactions (ADRs) were predominantly hematologic, consistent with the previous experiences. There were 7 pts in the 40 mg dose cohort because one of the first 3 pts had to be replaced for incomplete dosing due to grade 3 hypertriglyceridemia which was not regarded as DLT by the Data Monitoring Safety Committee (DMC/SMC). In the 40 mg cohort, 2 pts were considered as DLTs by definition in the protocol: grade 4 neutropenia and grade 3 alanine transaminase (ALT) increase. Both pts were asymptomatic. The grade 4 neutropenia promptly resolved with the administration of G-CSF and the grade 3 ALT elevation resolved with dose interruption. The 30 mg dose cohort completed with no DLT after the 1st cycle in 6 pts. The following hematologic grade 3/4 toxicities were noted in the 40 mg dose cohort (N=7): leukopenia (2 pts, 29%), neutropenia (3 pts, 43%), and thrombocytopenia (3 pts, 43%). Non-hematologic ADRs included fatigue, nausea, diarrhea, decreased appetite, erythema and pyrexia. The preliminary pharmacokinetic (PK) results from the 3 patients in the 30 mg cohort, and 7 patients in the 40 mg dose cohort show inter-patient variability as expected of an oral agent. Mean half-life (t ½ ) was between16.5 and 20 hours (h) with a Tmax between 2.5 and 3.5h and consistent with previous findings. Mean Cmax and AUC increased with dose (30 mg: 210 ng/mL; 3660 h*ng/mL and 40 mg: 590 ng/mL; 7200 h*ng/mL). The patient with neutropenia as DLT presented with the highest exposure. Cardiovascular assessments including serial ECGs and troponin assessments did not reveal clinically relevant findings. Best overall response was noted in 40 mg BIW cohort (N=7): 1 CR (10%), 5 PR (30%), 1 SD (20%). Four of the partial responders were ATL patients. In the 30 mg BIW dose cohort, 4/6 patients had stable disease after the 1st cycle. Summary: In this phase l trial evaluating the safety of twice weekly 30 mg and 40 mg doses, HBI-8000 was well tolerated with expected toxicities that could be managed with dose interruptions/reductions. Tumor response results in pts who completed at least one cycle of treatment indicate some clinical benefit especially in pts who started with the 40 mg dose level. The DMC/SMC has provided an opinion that the 2 observed DLTs with HBI-8000 in the phase I trial were clinically manageable and that 40 mg BIW would be recommended as the dosage for subsequent phase II studies. Registration enabling phase II trials to evaluate efficacy and safety in R/R ATL pts (Japan) and R/R PTCL pts (Japan and Korea) are being initiated. Disclosures Ando: SymBio Pharmaceuticals: Research Funding. Yoshimitsu:HUYA Bioscience International: Research Funding. Ishida:Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Celgene KK: Research Funding; Bayer Pharma AG: Research Funding. Hidaka:Chugai-pharm: Research Funding. Nagashima:HUYA Bioscience International: Employment. Miyazato:HUYA Bioscience International: Employment. Schupp:HUYA Bioscience International: Employment. Rolland:HUYA Bioscience International: Employment. Gillings:HUYA Bioscience International: Employment. Lee:HUYA Bioscience International: Employment. Tobinai:Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; HUYA Bioscience: Honoraria; Janssen Pharmaceuticals: Honoraria, Research Funding; Kyowa Hakko Kirin: Research Funding; Mundipharma: Honoraria, Research Funding; Ono Pharmaceuticals: Research Funding; Servier: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Chugai Pharma: Research Funding; Celgene: Research Funding; Abbvie: Research Funding.

A phase I trial of S-1 plus vinorelbine in patients with unresectable advanced or metastatic non-small cell lung cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19098-e19098
Author(s):  
H. Suyama ◽  
Y. Shigeoka ◽  
T. Igishi ◽  
S. Matsumoto ◽  
M. Kodani ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Dose Level ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Phase I Trial ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung

e19098 Background: We reported the efficacy of the combination treatment of tegafur-uracil (UFT) and vinorelbine (VNR) for the elderly patients (pts) (>70) with advanced non-small cell lung cancer (NSCLC) in ASCO 2007 (Abstract - No. 18075). Although the cisplatin-based doublets are still milestone for the pts with advanced NSCLC, non-platinum based doublet regimens remain as a matter of development judging from recent meta-analysis. Tegafur-5-chloro-2,4-dihydroxypyridine-potassium oxonate (S-1), a new oral fluoropyrimidine, has been studied extensively, and appears promising for various kinds of cancers including NSCLC. Thus, we conducted this phase I trial using VNR and new oral fluoropyrimidine, S-1. Methods: Pts with advanced NSCLC, who had received at least one prior platinum-containing regimen, were eligible. In this phase I study, VNR was infused on days 1 and 8, and S-1 was administered from day 2 to day 6 and from day 9 to day 13 of a 3-week cycle. The starting dose of S-1 was 80 mg/m2/day and, if necessary, the dose was decreased to 65 mg/m2/day; VNR was increased from 20 to 25 mg/m2 in this trial. Results: From August 14, 2007 to April 1, 2008, 8 pts enrolled in this study. Median age was 61 (range 49–75). Dose limiting toxicity (DLT) was evaluated during the first 6 weeks of the treatment. No DLT was observed at dose level I (80 mg/m2/day S-1, 20 mg/m2 VNR). At dose level II (80 mg/m2/day S-1, 25 mg/m2 VNR), DLT in the form of neutropenia, hyperglycemia and hyponatremia was observed in 3 of 5 pts. The maximum tolerated dose (MTD) for the present treatment was 80 mg/m2/day S-1 and 25 mg/m2 VNR; the recommended tolerable dose for future phase II trials is therefore 80 mg/m2/day S-1 and 20 mg/m2 VNR. Conclusions: Three-week cycle of VNR (20 mg/m2), infused on days 1 and 8; S-1 (80 mg/m2/day), administered from day 2 to day 6 and from day 9 to day 13, is being examined in our phase II trial for first-or second-line treatment of NSCLC. No significant financial relationships to disclose.

A phase I/II trial of erlotinib S-1 therapy in patients with non-small cell lung carcinoma: Thoracic Oncology Reseach Group (TORG) 0808/0913.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18099-e18099
Author(s):  
Naoyuki Nogami ◽  
Tetsu Shinkai ◽  
Toshiyuki Kozuki ◽  
Atsuko Ogino ◽  
Yuka Kato ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Phase Ii Trial ◽  
Phase Ii Study ◽  
Synergistic Effects ◽  
Small Cell Lung Carcinoma ◽  
Mrna Levels ◽  
Cell Lung Carcinoma ◽  
Basic Studies

e18099 Background: Gefitinib has been shown in basic studies to reduce the expression of thymidilate synthase, the target enzyme for the 5-FU-based chemotherapy, at the protein and mRNA levels, and synergistic effects of gefitinib used in combination with S-1 have been reported. Erlotinib also reduced TS expression and activity. The present studies were designed as study aimed at evaluating the efficacy and safety of erlotinib/ S-1 combination therapy as a 2nd/3rd-line therapy for recurrent/advanced NSCLC. Methods: Chemotherapy consisted of two 3-week cycles of erlotinib and S-1 treatment. Erlotinib was orally administered once daily at a dose of 150 mg/body, and patients received an oral dose of S-1 twice daily after meals from days 1 to 14 of each 21-day cycle. In phase I trial(TORG0808), the primary endpoint was to evaluate the DLT and the MTD for the following phase II study, and the secondary endpoint was to evaluate the antitumor activity and safety. Based on the phase I trial, we conducted a phase II trial (TORG0913) of this combination with pretreated EGFR negative NSCLC to determine the ORR. The secondary endpoints were PFS, disease control rate, OS, and safety. Results: 7 patients with good PS (0 or 1) and 10 patients with PS 0-2 participated in phase I and phase II trial. In phase I trial, the recommended doses for the phase II study were determined to be 150mg/body and 80mg/m2. The ORR was 67%, and 3/4 responders are EGFR positive patients. In phase II trial, the ORR was very low (only one patient).Myelosuppression was relatively mild, but Grade 3 or worse non-hematological toxicities including diarrhea, mucositis, and dermatitis were observed in 6 patients, which resulted in two treatment-related deaths. Data and Safety Monitoring Committee recommended the early termination, and the clinical trial was terminated due to adverse events. Conclusions: Phase I study showed the favorable efficacy and moderate safety profiles of this combination especially in EGFR positive patients, but less effective and too toxic in EGFR negative patients in phase II trial.

Intermodal Stimulus Generalization and Retention of Habituation in Earthworms

1978 ◽  
Vol 42 (3) ◽  
pp. 683-690 ◽  
Author(s):  
Andrew R. Gilpin ◽  
Stanley C. Ratner
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
White Light ◽  
Intertrial Interval ◽  
The Other ◽  
Phase Iii ◽  
Stimulus Generalization ◽  
Control Group ◽  
Three Phases

50 mature earthworms ( L. terrestris) were assigned randomly to one of five stimulus conditions in an experiment with three phases. In Phase I Group Light-Vibration-Light received 2-sec. presentations of white light (with an 18-sec. intertrial interval) to an habituation criterion; in Phase II vibration was presented on the same schedule; and in Phase III, which began 2 hr. after the end of Phase I, presentations of light were given. Group Vibration-Light-Vibration received vibration in Phases I and III and light in Phase II; Groups Vibration-Rest-Vibration and Light-Rest-Light received no stimulation in Phase II. A control group was observed on the same schedule but received no stimuli. Results indicated that previous habituation to one stimulus reduced responses to the other stimulus, regardless of the type of stimulation (stimulus generalization). Retention of habituation from Phase I to Phase III was reduced in Group Light-Vibration-Light but not Group Vibration-Light-Vibration, relative to their counterparts receiving rest in Phase II. Thus results indicated that the effects of habituation in this organism depend on the presence of stimuli from other modalities.

scholarly journals Effectivness of the GnRH analogue deslorelin as a reversible contraceptive in a neotropical primate, the Common Marmoset Callithrix Jacchus (Mammalia: Primates: Callitrichidae)

2016 ◽  
Vol 8 (4) ◽  
pp. 8652 ◽  
Author(s):  
Derek A. Rosenfield ◽  
P. Viau ◽  
C. A. Oliveira ◽  
Cristiane Schilbach Pizzutto
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Common Marmoset ◽  
Callithrix Jacchus ◽  
Phase Iii ◽  
Primate Species ◽  
Control Group ◽  
Gnrh Analogue ◽  
Cyclic Activity ◽  
Neotropical Primate

Deslorelin is a synthetic GnRH analogue, which is being used as a contraceptive in animals by acting as a gonadal suppressant.  The product Suprelorin (Virbac, Australia) contains deslorelin as a biocompatible, slow release subcutaneous implant. The continuous release of deslorelin provokes a down-regulation of GnRH receptors, and subsequently, inhibition of the synthesis and release of the gonadotropins FSH and LH, necessary for gonadal activities.  The intention of this study was to investigate the effectiveness of a subcutaneous deslorelin acetate implant (2,35mg) in suppressing ovarian cyclic activity and inhibiting ovulation in captive Common Marmoset Callithrix jacchus, and investigate the reversibility of the treatment.  Two experimental groups were formed, group deslorelin (D) with three couples and control group (C) with two couples.  To monitor the effect of the implants, hormones indicating ovarian cyclic activity were monitored non-invasively by enzyme immunoassay (fecal monoclonal antibody anti-progesterone CL 425).  Fecal samples were collected three times a week from all females during three trial phases (phase I: month 1,2,3 and 4; phase II: month: 5,6 and 7 and phase III: month 8,9 and 10).  In contrast to expectations the results of this trial indicated that there was no suppression of the ovarian cyclic activity, nor inhibition of the ovulation after the application of the implants.  The outcome of our trial can possibly be explained by the fact that the dosage of 2.35mg of deslorelin is not effective in C. jacchus.  We confirmed significant changes (p<0.05) of P4 metabolites from phase I to phase II due to the treatment after the implantation of the GnRH analogue Deslorelin.  The employed non-invasive fecal progesterone monitoring could be biologically validated and proved to be efficient in the detection of ovarian cyclic activity in this neotropical primate species, C. jacchus. 

scholarly journals Phase I trial of the MET inhibitor tepotinib in Japanese patients with solid tumors

2020 ◽  
Vol 50 (8) ◽  
pp. 859-866 ◽  
Author(s):  
Kohei Shitara ◽  
Kentaro Yamazaki ◽  
Takahiro Tsushima ◽  
Tateaki Naito ◽  
Nobuaki Matsubara ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Standard Therapy ◽  
Phase I Trial ◽  
Japanese Patients ◽  
Once Daily ◽  
The Usa ◽  
Met Inhibitor ◽  
Recommended Phase Ii Dose

Abstract Objectives Tepotinib (MSC2156119J) is an oral, potent and highly selective small molecule mesenchymal-epithelial transition factor (MET) inhibitor for which the recommended Phase II dose of 500 mg once daily has been defined, based on the first-in-man trial conducted in the USA and Europe. We carried out a multicenter Phase I trial with a classic `3 + 3' design to determine the recommended Phase II dose in Japanese patients with solid tumors (NCT01832506). Methods Patients aged ≥20 years with advanced solid tumors (refractory to standard therapy or for whom no effective standard therapy was available) received tepotinib at 215, 300 or 500 mg once daily in a 21-day cycle. Occurrence of dose-limiting toxicities during cycle 1 was used to determine the maximum tolerated dose. Efficacy, safety and pharmacokinetics were also evaluated to support the dose assessment. Results Twelve patients were treated. Tepotinib was generally well tolerated with no observed dose-limiting toxicities; treatment-related adverse events were mainly grades 1–2. The tolerability profile of tepotinib was similar to that observed in non-Japanese populations. Pharmacokinetics in Japanese and Western patients was comparable. One patient with gastric cancer and one patient with urachal cancer had stable disease of ≥12 weeks in duration. The observed safety profile and pharmacokinetics are comparable with those in patients from the USA and Europe, and the recommended Phase II dose of tepotinib in Japanese patients was confirmed as 500 mg once daily. Conclusions These results, including initial signals of antitumor activity, support further development of tepotinib in Japanese patients with cancer.

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