A phase I study of Hemay022, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor in Chinese patients with HER2-positive advanced breast cancer.

Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics, tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients. Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles. Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks. Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea (85.7%), vomiting (28.6%), nausea (25.0%) and decreased appetite (17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response (CR), and three achieved partial response (PR). The objective response rate (ORR) and disease control rate (DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival (PFS) was 3.98 months. Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase III trial (No. NCT05122494).

Phase I dose escalation study and pilot efficacy analysis of LXI-15029, a novel mTOR dual inhibitor, in Chinese subjects with advanced malignant solid tumors.

BACKGROUND: The mammalian target of rapamycin (mTOR) kinase, a central component of the PI3K/AKT/mTOR pathway, plays a critical role in tumor biology as an attractive therapeutic target. We conducted this first-in-human study to investigate the safety, pharmacokinetics (PK), and pilot efficacy of LXI-15029, an mTORC1/2 dual inhibitor, in Chinese patients with advanced malignant solid tumors. METHODS: Eligible patients with advanced, unresectable malignant solid tumors after failure of routine therapy or with no standard treatment were enrolled to receive ascending doses (10, 20, 40, 60, 80, 110, and 150 mg) of oral LXI-15029 twice daily (BID) (3 + 3 dose-escalation pattern) until disease progression or intolerable adverse events (AEs). The primary endpoints were safety and tolerability. RESULTS: Between June 2017 and July 2021, a total of 24 patients were enrolled. LXI-15029 was well tolerated at all doses. Only one dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in the 150 mg group, and the maximum tolerated dose was 110 mg BID. The most common treatment-related AEs were leukocytopenia (41.7%), increased alanine aminotransferase (20.8%), increased aspartate aminotransferase (20.8%), prolonged electrocardiogram QT interval (20.8%), and hypertriglyceridemia (20.8%). No other serious treatment-related AEs were reported. LXI-15029 was absorbed rapidly after oral administration. The increases in the peak concentration and the area under the curve were greater than dose proportionality over the dose range. Eight patients had stable disease. The disease control rate was 40.0% (8/20; 95% CI 21.7-60.6). In evaluable patients, the median progression-free survival was 29 days (range 29-141). CONCLUSIONS: LXI-15029 demonstrated reasonable safety and tolerability profiles and encouraging preliminary antitumor activity in Chinese patients with advanced malignant solid tumors, which warranted further validation in phase II trials. TRIAL REGISTRATION: NCT03125746(24/04/2017), http://ClinicalTrials.gov/show/NCT03125746.

Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study of the Penetration of a Monoclonal Antibody Combination (ASN100) Targeting Staphylococcus aureus Cytotoxins in the Lung Epithelial Lining Fluid of Healthy Volunteers.

ASN100 is a novel antibody combination of two fully human IgG1(κ) monoclonal antibodies (MAbs), ASN-1 and ASN-2, which neutralize six Staphylococcus aureus cytotoxins, alpha-hemolysin (Hla) and five bicomponent leukocidins. We assessed the safety, tolerability, and serum and lung pharmacokinetics of ASN100 in a randomized, double-blind, placebo-controlled single-dose-escalation first-in-human study. Fifty-two healthy volunteers were enrolled and randomized to receive either ASN-1, ASN-2, a combination of both MAbs (ASN100), or a corresponding placebo. Thirty-two subjects in the double-blind dose escalation portion of the study received ASN-1 or ASN-2 at a 200-, 600-, 1,800-, or 4,000-mg dose, or placebo. Eight subjects received both MAbs simultaneously in a 1:1 ratio (ASN100) at 3,600 or 8,000 mg, or they received placebos. Twelve additional subjects received open-label ASN100 at 3,600 or 8,000 mg to assess the pharmacokinetics of ASN-1 and ASN-2 in epithelial lining fluid (ELF) by bronchoalveolar lavage fluid sampling. Subjects were monitored for 98 days (double-blind cohorts) or 30 days (open-label cohorts) for safety assessment. No dose-limiting toxicities were observed, and all adverse events were mild and transient, with only two adverse events considered possibly related to the investigational product. ASN100 exhibited linear serum pharmacokinetics with a half-life of approximately 3 weeks and showed detectable penetration into the ELF. No treatment-emergent anti-drug antibody responses were detected. The toxin neutralizing potency of ASN100 in human serum was confirmed up to 58 days postdosing. The favorable safety profile, ELF penetration, and maintained functional activity in serum supported the further clinical development of ASN100.

A first-in-human study investigating biodistribution, safety and recommended dose of a new radiolabeled MAb targeting FZD10 in metastatic synovial sarcoma patients.

BACKGROUND: Synovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases. We report a first-in-human phase I of monoclonal antibody (OTSA-101) targeting FZD10, overexpressed in most SS but not present in normal tissues, labelled with radioisotopes and used as a molecular vehicle to specifically deliver radiation to FZD10 expressing SS lesions. METHODS: Patients with progressive advanced SS were included. In the first step of this trial, OTSA-101 in vivo bio-distribution and lesions uptake were evaluated by repeated whole body planar and SPECT-CT scintigraphies from H1 till H144 after IV injection of 187 MBq of 111In-OTSA-101. A 2D dosimetry study also evaluated the liver absorbed dose when using 90Y-OTSA-101. In the second step, those patients with significant tumor uptake were randomized between 370 MBq (Arm A) and 1110 MBq (Arm B) of 90Y-OTSA-101 for radionuclide therapy. RESULTS: From January 2012 to June 2015, 20 pts. (median age 43 years [21-67]) with advanced SS were enrolled. Even though 111In-OTSA-101 liver uptake appeared to be intense, estimated absorbed liver dose was less than 20 Gy for each patient. Tracer intensity was greater than mediastinum in 10 patients consistent with sufficient tumor uptake to proceed to treatment with 90Y-OTSA-101: 8 were randomized (Arm A: 3 patients and Arm B: 5 patients) and 2 were not randomized due to worsening PS. The most common Grade ≥ 3 AEs were reversible hematological disorders, which were more frequent in Arm B. No objective response was observed. Best response was stable disease in 3/8 patients lasting up to 21 weeks for 1 patient. CONCLUSIONS: Radioimmunotherapy targeting FZD10 is feasible in SS patients as all patients presented at least one lesion with 111In-OTSA-101 uptake. Tumor uptake was heterogeneous but sufficient to select 50% of pts. for 90Y-OTSA-101 treatment. The recommended activity for further clinical investigations is 1110 MBq of 90Y-OTSA-101. However, because of hematological toxicity, less energetic particle emitter radioisopotes such as Lutetium 177 may be a better option to wider the therapeutic index. TRIAL REGISTRATION: The study was registered on the NCT01469975 website with a registration code NCT01469975 on November the third, 2011.

Safety, pharmacokinetics and pharmacodynamics of single rising doses of BI 655064, an antagonistic anti-CD40 antibody in healthy subjects: a potential novel treatment for autoimmune diseases.

PURPOSE: The CD40-CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis. The safety, pharmacokinetics and pharmacodynamics of BI 655064, a novel humanised antagonistic anti-CD40 monoclonal antibody, were investigated in this first-in-human trial. METHODS: Healthy male subjects (n = 72) were randomised 3:1, within each BI 655064 dose group, to single intravenous (IV; 0.2-120 mg) or subcutaneous (SC; 40-120 mg) doses of BI 655064 or placebo. Safety, plasma exposure, CD40 receptor occupancy and CD40L-induced CD54 upregulation were assessed over 12 weeks. RESULTS: Adverse events (AEs) were reported in 43% of subjects (n = 31). Frequency and intensity of AEs were generally similar between BI 655064 and placebo and showed no dose relationship. The most frequent AEs were headache and nasopharyngitis. One mild rash and one local reaction occurred with SC BI 655064; two serious AEs were reported, both judged unrelated to BI 655064. Pharmacokinetic evaluation demonstrated a more than proportional increase in plasma exposure relative to BI 655064 dose, with a terminal half-life between 4 h and 4 days IV and approximately 5 days SC; doses ≥ 20 mg IV and 120 mg SC showed > 90% CD40 receptor occupancy and inhibition of CD54 upregulation, which lasted 7 days in the 120 mg IV and SC groups. CONCLUSIONS: Single doses up to 120 mg BI 655064 IV and SC were well tolerated and showed a high potential to block the CD40-CD40L pathway, supporting further clinical development of BI 655064 in patients with autoimmune disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01510782.

Autonomy and Fear of Synthetic Biology: How Can Patients' Autonomy Be Enhanced in the Field of Synthetic Biology? A Qualitative Study with Stable Patients.

We analyzed stable patients' views regarding synthetic biology in general, the medical application of synthetic biology, and their potential participation in trials of synthetic biology in particular. The aim of the study was to find out whether patients' views and preferences change after receiving more detailed information about synthetic biology and its clinical applications. The qualitative study was carried out with a purposive sample of 36 stable patients, who suffered from diabetes or gout. Interviews were transcribed verbatim, translated and fully anonymized. Thematic analysis was applied in order to examine stable patients' attitudes towards synthetic biology, its medical application, and their participation in trials. When patients were asked about synthetic biology in general, most of them were anxious that something uncontrollable could be created. After a concrete example of possible future treatment options, patients started to see synthetic biology in a more positive way. Our study constitutes an important first empirical insight into stable patients' views on synthetic biology and into the kind of fears triggered by the term "synthetic biology." Our results show that clear and concrete information can change patients' initial negative feelings towards synthetic biology. Information should thus be transmitted with great accuracy and transparency in order to reduce irrational fears of patients and to minimize the risk that researchers present facts too positively for the purposes of persuading patients to participate in clinical trials. Potential participants need to be adequately informed in order to be able to autonomously decide whether to participate in human subject research involving synthetic biology.

Safety and patient response as indicated by biomarker changes to binding immunoglobulin protein in the phase I/IIA RAGULA clinical trial in rheumatoid arthritis.

OBJECTIVES: Binding immunoglobulin protein (BiP) is a human endoplasmic reticulum-resident stress protein. In pre-clinical studies it has anti-inflammatory properties due to the induction of regulatory cells. This randomized placebo-controlled, dose ascending double blind phase I/IIA trial of BiP in patients with active RA, who had failed accepted therapies, had the primary objective of safety. Potential efficacy was measured by DAS28-ESR and changes in biomarkers. METHODS: Twenty-four patients with active RA who had failed one or more DMARDs were sequentially assigned to three groups each of eight patients randomly allocated to receive placebo (two patients) or BiP (six patients), 1, 5 or 15 mg. Patients received a single i.v. infusion over 1 h and were observed as inpatients overnight. A 12-week follow-up for clinical, rheumatological and laboratory assessments for safety, efficacy (DAS28-ESR) and biomarker analysis was performed. RESULTS: No infusion reactions or serious adverse drug reactions were noted. Adverse events were evenly distributed between placebo and BiP groups with no BiP-related toxicities. Haematological, renal and metabolic parameters showed no drug-related toxicities. Remission was only achieved by patients in the 5 and 15 mg groups, and not patients who received placebo or 1 mg BiP. Good DAS28-ESR responses were achieved in all treatment groups. The BiP responding patients showed significantly lower serum concentrations of CRP, 2 weeks post-infusion compared with pre-infusion levels, and of VEGF and IL-8 from the placebo group. CONCLUSION: BiP (⩽15 mg) is safe in patients with active RA. Some patients had clinical and biological improvements in RA activity. BiP merits further study. TRIAL REGISTRATION: ISRCTN registry, http://isrctn.com, ISRCTN22288225 and EudraCT, https://eudract.ema.europa.eu, 2011-005831-19.

First report of a novel polymer-free dual-drug eluting stent in de novo coronary artery disease: results of the first in human BICARE trial.

BACKGROUND: Persistence of stent polymer coating has been associated with incomplete endothelialization, expansive vessel remodeling, neoatherosclerosis, and delayed healing associated with inflammation that may contribute to late adverse events. METHODS: The BICARE (Lepu Medical, Beijing, China) stent is a novel polymer-free, nanotechnology-based stent eluting sirolimus and probucol. As a first in human feasibility study, patients with a single de novo native coronary stenosis <30 mm in length and with reference vessel diameter from 2.5 to 4.0 mm underwent revascularization with the BICARE stent. The primary endpoint of target lesion failure (TLF) was assessed at 30 days. Secondary endpoints included in-stent late lumen loss and proportion of uncovered or malapposed stent struts by optical coherence tomography at 4-month angiographic surveillance. RESULTS: Among 32 consecutive patients (age, 55.7 ± 8.7 years; men, 62.5%; diabetes, 18.8%), the average baseline reference vessel diameter and lesion length were 2.85 ± 0.48 mm and 15.0 ± 5.6 mm, respectively. At 30 days there was no occurrence of TLF. At 4 months (angiographic follow-up, N=32), angiographic in-stent late loss was 0.14 ± 0.19 mm, and the in-stent binary restenosis rate was 3.1%. Complete strut coverage was 98.2% with 0.2% malapposition among 16,751 analyzed struts. At 18 months, TLF occurred in 3 (9.4%) patients related to repeat revascularization with no adverse safety events identified. CONCLUSIONS: The preliminary feasibility and safety of a polymer-free, dual-drug eluting stent are demonstrated by absence of early adverse safety events and favorable angiographic suppression of neointimal hyperplasia. Stent imaging suggests favorable healing with extensive stent strut coverage and very low malapposition. These findings further inform comparison with biopermanent polymer DES.

A novel orf virus vector-based COVID-19 booster vaccine shows cross-neutralizing activity in the absence of anti-vector neutralizing immunity.

Next-generation COVID-19 vaccines are being developed to expand the breadth of coverage against existing and future variants and to extend the duration of protection. Prime-2-CoV_Beta is an orf virus (ORFV) based multi-antigen COVID-19 vaccine that co-expresses Spike (S) and Nucleocapsid (N) antigens. The safety and immunogenicity of Prime-2-CoV_Beta is investigated in a phase 1 first-in-human (FIH) dose-finding trial (ORFEUS study, ClinicalTrials.gov: NCT05367843). Participants of two age groups (18-55 and 65-85 years) who previously completed at least two doses of mRNA vaccines were enrolled and sequentially assigned to different dose groups to receive one intramuscular dose of 3 × 105, 3 × 106, 1.5 × 107, or 3 × 107 plaque-forming units (PFU) of Prime-2-CoV_Beta on day 1 and a second dose on day 29. Here, we report safety and immunogenicity data collected up to 6 months after the first study vaccination. Prime-2-CoV_Beta is safe and well tolerated and elicits immune responses at higher dose levels in participants aged 18-55. A single dose of 3 × 107 PFU boosted binding and cross-neutralizing antibody responses that are maintained through 6 months after the first booster vaccination. Polyfunctional S-specific CD4+ and CD8+ T cell responses are observed after vaccination. No pre-existing or vaccine-induced neutralizing anti-vector antibodies are detected. Our findings highlight the potential of the ORFV vector as a safe platform for future vaccine design, which provides the ability to deliver multiple antigens and allows for repeat immunization.

Organizational aspects of tissue engineering clinical translation: insights from a qualitative case study.

Background: Tissue engineering is a multidisciplinary field that combines principles from cell biology, bioengineering, material sciences, medicine and surgery to create functional and viable bioproducts that can be used to repair or replace damaged or diseased tissues in the human body. The complexity of tissue engineering can affect the prospects of efficiently translating scientific discoveries in the field into scalable clinical approaches that could benefit patients. Organizational challenges may play a key role in the clinical translation of tissue engineering for the benefit of patients. Methods: To gain insight into the organizational aspects of tissue engineering that may create impediments to efficient clinical translation, we conducted a retrospective qualitative case study of one tissue engineering multi-site translational project on knee cartilage engineered tissue grafts. We collected qualitative data using a set of different methods: semi-structured interviews, documentary research and audio-visual content analysis. Results: Our study identified various challenges associated to first-in-human trials in tissue engineering particularly related to: logistics and communication; research participant recruitment; clinician and medical student participation; study management; and regulation. Conclusions: While not directly generalizable to other types of advanced therapies or to regenerative medicine in general, our results offer valuable insights into organizational barriers that may prevent efficient clinical translation in the field of tissue engineering.

First-in-human trial of Center Wire for neuroendovascular therapy to avoid guidewire-related complications.

BACKGROUND: An exchange maneuver is useful for the delivery of devices to target vessels. However, hemorrhagic complications can occur due to vessel perforation during an exchange maneuver. In addition, the exchange is often challenging due to unfavorable anatomy. Center Wire is an exchange-length wire with a nondetachable stent that was developed to improve navigation and stability during exchange maneuvers. The aim of this study is to investigate the safety and efficacy of Center Wire of the anchor wire technique during neuroendovascular treatment. METHODS: Ten patients with intracranial aneurysms were treated after signing a Certified Review Board-approved consent. Anchor wire technique was used in all patients to navigate catheters to the target vessel for aneurysm treatment. RESULTS: Anchor wire technique was successfully applied in all 10 cases using Center Wire. One device-related incident of vasospasm occurred which was asymptomatic. No device-related dissection, perforation, or thromboembolic events occurred. One patient had intraoperative aneurysm rupture during coil placement which was treated immediately without clinical consequences. Two patients had postoperative ischemic strokes due to thrombotic occlusion of branches originating from the aneurysm which were unrelated to the device. CONCLUSIONS: This first-in-human trial of Center Wire demonstrated the safety and efficacy of the anchor wire technique for neuroendovascular treatment in a strictly regulated prospective registry trial.

First-in-human study to assess the safety, tolerability, pharmacokinetics and immunogenicity of DS002, an anti-nerve growth factor monoclonal antibody.

Purpose: To evaluate the safety, tolerability, pharmacokinetics and immunogenicity of DS002 injection, an anti-nerve growth factor (anti-NGF) monoclonal antibody for treating pain conditions, in healthy Chinese subjects. Methods: This study was a single-center, randomized, double-blind, single-dose escalation, placebo-controlled design (CTR20210155). A total of 53 healthy subjects, 27 male and 26 female, were enrolled in this study, and one subject withdrew from the study before administration. Seven dose groups were set up, which were 0.5 mg, 1.0 mg, 2.0 mg, 4.0 mg, 7.0 mg, 12.0 mg and 20.0 mg, respectively. The drug was administered by single subcutaneous injection. Four subjects were enrolled in the first dose group (0.5 mg) received DS002. Other dose groups enrolled eight subjects each, six of whom received DS002 while the other two received a placebo. Safety, tolerability, pharmacokinetic parameters and immunogenicity of DS002 were assessed. Results: DS002 was well tolerated; all adverse events were Grade 1-2, and did not reach the termination standard of dose increment within the range of 0.5-20.0 mg. Adverse event rates were generally similar across treatments. After a single subcutaneous injection, the median Tmax in different dose groups ranged 167.77-337.38 h; mean t1/2 ranged 176.80-294.23 h, the volume of distribution (Vz) ranged 5265.42-7212.00 ml, and the clearance rate (CL) ranged 12.69-24.75 ml/h. In the dose range of 0.5-20.0 mg, Cmax ranged from 51.83 ± 22.74 ng/ml to 2048.86 ± 564.78 ng/ml, AUC0-t ranged from 20615.16 ± 5698.28 h·ng/mL to 1669608.11 ± 387246.36 h·ng/mL, and AUC0-inf ranged from 21852.45 ± 5920.21 h·ng/mL to 1673504.66 ± 389106.13 h·ng/mL. They all increased with dose escalation, and Cmax and AUC0-t did not have a significant dose-linear relationship, whilst AUC0-t was not dose-dependent at all. anti-drug antibody test results of each group of all subjects in this trial were negative. Conclusion: DS002 showed satisfactory safety within the dose range of 0.5 mg-20.0 mg. The absorption and metabolism of DS002 were slow, it exhibited a low volume of distribution and the clearance rate was low. These data suggest that DS002, by blocking nerve growth factor, is expected to become a novel, safe and non-addictive treatment for pain conditions.

First-In-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of SHR2285, a Small-Molecule Factor XIa Inhibitor in Healthy Subjects.

Background: Targeting factor XI (FXI) is a promising therapeutic strategy for the treatment and prevention of thrombosis without increasing the risk of bleeding. Here, we assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR2285, a novel FXIa inhibitor, in healthy subjects. Methods: In this randomized, double-blinded, placebo-controlled, dose-ascending single-dosing trial (NCT03769831), eligible volunteer subjects receive either SHR2285 or placebo in a 3:1 ratio. Subjects assigned to the SHR2285 group received a single oral dose of SHR2285 at 50 mg, which was subsequently escalated to 100 mg, 200 mg, and 400 mg. Safety, pharmacokinetics, and pharmacodynamics parameters were assessed. All subjects were followed for 6 days. Results: SHR2285 was well tolerated. All adverse events were grade 1, and there was no evidence of bleeding events. The PK results revealed a rapid onset of action of SHR2285 (median time to maximum plasma concentration [Tmax] in different dose groups ranged 3.0-4.0 h) and the mean half-life ranged from 7.6 to 15.8 h. The metabolite SHR164471 had a slightly longer Tmax than the parent SHR2285, reaching a peak at a median of 6.0-7.0 h, and its mean half-life were 10.1-14.7 h in different dose groups. The sums of the area under the concentration-time curve from zero to time infinity of SHR2285 and SHR164471 in the 200 and 400 mg groups were similar, indicating the sum pharmacological activity of SHR2285 and SHR164471 showed a saturation trend between 200 and 400 mg. PD analysis showed that the inhibition of FXI activity was synchronized with prolonged activated partial thromboplastin time after SHR2285 administration, but the serum prothrombin time and international normalized ratio levels were not affected by SHR2285. Conclusion: SHR2285 demonstrated favorable safety, PK, and PD profiles in the dose range of 50 mg-400 mg. This first-in-human study supports the further development of SHR2285 for indications requiring anticoagulation. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03769831, identifier [NCT03769831].

Safety verification of a new peripheral intravenous catheter placed in the upper arm vein for administration of drugs with high irritant potential.

Despite the widespread use of peripheral intravenous catheters, unscheduled catheter failure before completion of treatment occurs frequently. If a large vein is selected, catheter failures may be prevented despite administering a highly irritant drug. In this study, we attempted to use a catheter that can be placed in a large upper arm vein. The new catheter was 88 mm long but had no guidewire to reduce contamination risk. This study aimed to evaluate the safety of the first-in-human trial for the new catheter with the administration of highly irritant drugs. This study was conducted at a university hospital in Tokyo, Japan. Eight Japanese adults were hospitalized adults with planned administration of non-cancer drugs with high irritant potential using a peripheral catheter. A trained nurse catheterized with the new catheter in the upper arm using ultrasonography. The catheterization site was monitored by staff and a research nurse once every 24 hours for up to 7 days. No adverse events or catheter failure occurred and the catheter placement success rate was 100%. In two patients, a temporary occlusion alarm of the infusion pump occurred, possibly due to the flexion of the catheter base. The new peripheral intravenous catheter did not interrupt medical treatments as is common after placement, but safety administered the irritant drugs. However, because this catheter may be easily affected by the contraction of the muscle at the fixation position, the position and method of catheter fixation in the upper arm need to be carefully considered.

A phase 1 study of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor in Chinese patients with advanced breast cancer.

BACKGROUND: Dalpiciclib (SHR6390) is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models. This first-in-human study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of dalpiciclib in patients with advanced breast cancer (ABC). METHODS: In this open-label, phase 1 study, Chinese patients who had failed standard therapy were enrolled to receive oral dalpiciclib in 3 + 3 dose-escalation pattern at doses of 25-175 mg. Eligible patients were given a single-dose of dalpiciclib in week 1, followed by once daily continuous doses for 3 weeks, and 1 week off in 28-day cycles. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8-10 patients. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics. RESULTS: Between Apr 15, 2016 and Dec 21, 2018, 40 patients were enrolled; all were diagnosed of hormone receptor-positive and HER2-negative ABC. Dalpiciclib 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 patients. No dose-limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade 3 or 4 were observed in 22 (55.0%) of 40 patients, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50-175 mg, steady state areas under the concentration-time curve and peak concentration increased almost proportionally with dose. The disease control rate (DCR) was 62.5% (25/40, 95% CI: 45.8-77.3). Two patients (5%; 125 mg and 150 mg cohorts) achieved partial response, with responses lasting 169 and 356+ days, respectively. Among the three expansion cohorts, the 150 mg cohort had the numerically highest DCR of 80.0% (95% CI: 44.4-97.5) and longest median progression-free survival of 8.4 months (95% CI: 2.1-not reached). CONCLUSIONS: Dalpiciclib showed acceptable safety profile and dose-dependent plasma exposure in Chinese patients with ABC. The recommended phase 2 dose was 150 mg. Preliminary evidence of clinical activity was observed, which warrants further validation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02684266 . Registered Feb 17, 2016.

Combined integrated protocol/basket trial design for a first-in-human trial.

BACKGROUND: Innovative trial designs are sought to streamline drug development in rare diseases. Basket- and integrated protocol designs are two of these new strategies and have been applied in a handful oncologic trials. We have taken the concept outside the realm of oncology and report about a first-in-human integrated protocol design that facilitates the transition from phase Ia in healthy volunteers to phase Ib in patients with rare complement-mediated disorders driven by the classical pathway. RESULTS: We have been conducting a prospective, double-blind, randomized, placebo-controlled first-in-human study with TNT009, which is a humanized monoclonal antibody directed against the C1s subunit of human complement component C1. The trial consisted of three subparts, including normal healthy volunteers (part one and two) and a single cohort of patients in part three. Patients suffered from various complement-mediated diseases sharing the same pathophysiological mechanism, i.e. bullous pemphigoid, antibody-mediated rejection of organ transplants, cold agglutinin disease and warm autoimmune hemolytic anemia. Primary objective of the trial has been to evaluate the safety and tolerability of TNT009 in humans. CONCLUSIONS: This trial provides probably the first example that basket trials may not be limited to single genetic aberrations, which is overly restrictive, but our trial design demonstrates that pathway specificity is a viable paradigm for defining baskets. This will hopefully serve as a role model that could benefit other innovative drug development programs targeting rare diseases.