Safety, pharmacokinetics and pharmacodynamics of SHR-1703, an innovative long-acting anti-interleukin-5 monoclonal antibody, in healthy subjects: a randomized, double-blind, dose-escalation, placebo-controlled phase I study.

OBJECTIVE: SHR-1703 is a novel humanized IgG1 monoclonal antibody with high IL-5 affinity and prolonged half-life, aiming to control eosinophil-related diseases. The study intended to evaluate pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of SHR-1703 in healthy subjects. METHODS: A single-center, randomized, double-blind, placebo-controlled, single-dose escalation phase I study was conducted. 42 subjects were allocated to sequentially receive single subcutaneous injection of 20, 75, 150, 300, and 400 mg SHR-1703 or placebo. RESULTS: After administration, SHR-1703 was slowly absorbed with median Tmax ranging from 8.5 to 24.5 days. Mean t1/2 in 150 to 400 mg doses was 86 to 100 days. Cmax and AUC increased in nearly dose-proportional pattern over range of 75 to 400 mg SHR-1703. After receiving SHR-1703, peripheral blood eosinophils (EOS) greatly decreased from baseline, which showed no significant change from baseline in placebo group. Magnitude and duration of reduction of EOS rose with increased dosing of SHR-1703. In 400 mg dose, remarkable efficacy of reducing EOS maintained up to approximately 6 months post single administration. Moreover, SHR-1703 exhibited low immunogenicity (2.9%), favorable safety, and tolerability in healthy subjects. CONCLUSION: Pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of SHR-1703 support further clinical development of SHR-1703 in eosinophil-associated diseases. CLINICAL TRIAL REGISTRATION: The study was registered on the ClinicalTrials.gov (identifier: NCT04480762).

Phase I study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab in Japanese patients with advanced or metastatic solid tumors.

PURPOSE: Tiragolumab is a monoclonal antibody that binds to the inhibitory immune checkpoint TIGIT (T-cell immunoreceptor with Ig and ITIM domains). In early phase clinical trials, tiragolumab in combination with the programmed death-ligand 1-inhibitor atezolizumab was well tolerated and has demonstrated preliminary anti-tumor activity in patients with advanced/metastatic solid tumors. We report the results of a phase I study of tiragolumab plus atezolizumab in Japanese patients (jRCT2080224926). METHODS: Japanese patients ≥ 20 years old received tiragolumab (600 mg) and atezolizumab (1200 mg) intravenously every 21 days until unacceptable toxicity or disease progression. Primary endpoints were safety and pharmacokinetic (PK) parameters of tiragolumab plus atezolizumab. Secondary endpoints were anti-tumor activity. RESULTS: Three patients were enrolled with diagnoses of non-small cell lung cancer, pancreatic cancer, and cholangiocarcinoma. No dose-limiting toxicities were observed. Two patients experienced treatment-related adverse events (AEs) of any grade. There were no grade ≥ 3 AEs, serious AEs, AEs leading to discontinuation, modification or withdrawal of any study drug, or AEs leading to death. At cycle 1, mean PK parameters of tiragolumab were as follows: Cmax 217 µg/mL; Cmin 54.9 µg/mL; area under the concentration-time curve from 0 to the last measurable concentration, 2000 µg·day/mL; t1/2, 17.6 days. Best overall response was stable disease in two patients. CONCLUSION: Tiragolumab plus atezolizumab was well tolerated in Japanese patients with advanced/metastatic solid tumors, and no differences in tiragolumab PK characteristics were noted between Japanese patients enrolled in this study, and non-Japanese patients enrolled in a global phase Ia/Ib study. These results may support the inclusion of Japanese patients in ongoing global phase III clinical trials. TRIAL REGISTRATION NUMBER: jRCT2080224926.

A Phase I Study of TRK-250, a Novel siRNA-Based Oligonucleotide, in Patients with Idiopathic Pulmonary Fibrosis.

Purpose: TRK-250 is a novel single-stranded oligonucleotide carrying a human Transforming growth factor-beta 1-targeting siRNA motif tethered by two proline linkers. Nonclinical studies have shown that TRK-250 may have potency to prevent the progression of pulmonary fibrosis. Herein, a phase I study was conducted to investigate the safety and pharmacokinetics (PKs) of TRK-250 in patients with idiopathic pulmonary fibrosis (IPF). Method: In the phase I study, 34 IPF patients were partially randomized to receive a placebo or TRK-250 in 4 single doses of 2, 10, 30, and 60 mg or multiple rising doses of 10, 30, and 60 mg once per week for 4 weeks by oral inhalation. For both the single- and multiple-dose studies, the primary endpoint was safety, and the secondary endpoint was PKs. Result: In all IPF patients who orally inhaled TRK-250, no significant drug-related adverse events (AEs) were observed. The AEs were mild or moderate, except for one severe case with acute exacerbation. One of the more common AEs was coughing. One patient discontinued treatment before the last dose because of coughing. There were no medically important findings related to safety endpoints based on clinical laboratory data (clinical chemistry, hematology, or urinalysis), vital signs data, electrocardiogram data, physical examination findings, pulse oximetry data, spirometry data, or diffusing capacity of the lung for carbon monoxide data. All the bioanalytical results of PKs in the blood were below the lower limit of quantification. Conclusions: Both the single and multiple doses of TRK-250 were safe and well tolerated in this first study done in IPF patients. Furthermore, TRK-250 was not detected in the systemic circulation following inhalation, indicating low or virtually nonexistent systemic exposure. This study is registered at ClinicalTrials.gov with identifier number NCT03727802.

Bioequivalence of Reference and Biosimilar Preparations of Premixed Biphasic Insulin Aspart: A Comparative Clamp Study.

Biphasic insulin aspart 30 is a premixed formulation containing a soluble fraction of insulin aspart (30%) and a protamine-crystallized fraction (70%) that was developed to combine the rapid-acting and prolonged advantages of commercially available insulins. The aim of this bioequivalence study was to compare the pharmacokinetics (PKs) of GP-bi-asp and Novo-bi-asp, and evaluate the pharmacodynamic (PD) properties as well as the safety of these drugs in the hyperinsulinemic euglycemic clamp (HEC) procedure. This was a phase 1, randomized, double-blind, 2-sequence, 2-period crossover study. Thirty-four male volunteers who met the inclusion criteria underwent the HEC procedure following a single subcutaneous injection of 0.4 IU/kg of either GP-bi-asp or Novo-bi-asp in the abdomen. After the treatment, the subjects' plasma glucose levels were monitored for 24 hours and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. The PD parameters were calculated using GIR values. Insulin aspart concentrations were measured in blood plasma using validated ELISA assays to evaluate the PK parameters of the investigated drugs. The 90% confidence intervals for the geometric mean ratios of PK (Cins and AUCins-T ) parameters of Gp-bi-asp and Novo-bi-asp were close to 100% and within the 80%-125% limits for establishing bioequivalence. The safety profiles of both drugs were also comparable.

Pharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198, a novel, selective Autotaxin inhibitor, in healthy subjects: A phase I randomized placebo-controlled trial.

BACKGROUND: Autotaxin (ATX) and lysophosphatidic acid (LPA) play an important role in pathogenesis of idiopathic pulmonary fibrosis (IPF). FTP-198 is an oral, novel and selective ATX inhibitor indicated for treating IPF. The study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198 in healthy subjects. METHODS: A single-center, randomized, double-blind, placebo-controlled, single ascending-dose Phase I study was performed. Pharmacokinetics, pharmacodynamics, food effect on pharmacokinetics, elimination, safety and tolerability of FTP-198 were evaluated. RESULTS: A total of 30 subjects were enrolled and completed the study. After oral administration of single ascending-dose of 100 mg, 300 mg and 400 mg FTP-198 under fasted condition, FTP-198 was absorbed with median time to reach peak concentration (Tmax) of 1.75, 2.75 and 3.5 h, respectively and eliminated with mean elimination half-life (t1/2) of 8.77, 10.58 and 10.57 h, respectively. Peak concentration (Cmax), plasma area under concentration-time curve from time 0 to the last measurable concentration (AUC0-t) and to infinity (AUC0-∞) increased in dose-proportional manner for 100 mg to 400 mg FTP-198. Food intake slightly increased the Cmax, AUC0-t and AUC0-∞ and prolonged Tmax, but not affecting t1/2 of FTP-198 compared with fasted state. The pharmacodynamic biomarker plasma lysophosphatidic acid (LPA) 18:2 decreased significantly for 100 mg to 400 mg FTP-198, with inhibition rate from baseline reaching approximately 80% at 24 h post dosing, and higher dose of FTP-198 increased the time to maintain inhibitory plateau. FTP-198 was eliminated from the body almost with no unchanged drug excreted in urine and a small amount of unchanged drug detected in feces of human. Moreover, FTP-198 exhibited favorable safety and tolerability in healthy subjects. CONCLUSION: Pharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198 support further subsequent clinical development of FTP -198 in IPF patients.

Cysteine-lowering treatment with mesna against obesity: Proof of concept and results from a human phase I, dose-finding study.

AIM: To investigate whether mesna-sodium-2-mercaptoethane sulfonate) can reduce diet-induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%. METHODS: C3H/HeH mice were shifted to a high-fat diet ± mesna in drinking water; body composition was measured at weeks 0, 2 and 4. In an open, phase I, single ascending dose study, oral mesna (400, 800, 1200, 1600 mg) was administered to 17 men with overweight or obesity. Mesna and tCys concentrations were measured repeatedly for a duration of 48 hours postdosing in plasma, as well as in 24-hour urine. RESULTS: Compared with controls, mesna-treated mice had lower tCys and lower estimated mean fat mass gain from baseline (week 2: 4.54 ± 0.40 vs. 6.52 ± 0.36 g; week 4: 6.95 ± 0.35 vs. 8.19 ± 0.34 g; Poverall = .002), but similar lean mass gain. In men with overweight, mesna doses of 400-1600 mg showed dose linearity and were well tolerated. Mesna doses of 800 mg or higher decreased plasma tCys by 30% or more at nadir (4h post-dosing). With increasing mesna dose, tCys AUC0-12h decreased (Ptrend < .001), and urine tCys excretion increased (Ptrend = .004). CONCLUSIONS: Mesna reduces diet-induced fat gain in mice. In men with overweight, single oral doses of mesna (800-1600 mg) were well tolerated and lowered plasma tCys efficiently. The effect of sustained tCys-lowering by repeated mesna administration on weight loss in humans deserves investigation.

Phase I study of cisplatin and nanoparticle albumin-bound-paclitaxel combined with concurrent radiotherapy in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: This phase I study aimed to assess the safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and preliminary effect of nanoparticle albumin-bound (nab)-paclitaxel in combination with concurrent chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients with locally advanced ESCC who were ineligible or refused surgery were enrolled. Nab-paclitaxel (60 mg/m2 , 75 mg/m2 , and 90 mg/m2 ) and cisplatin (25 mg/m2 ) were administered intravenously weekly on days 1, 8, 15, 22, and 29 on the basis of the 3 + 3 dose escalation method. The total dose of radiation was 50-64 Gy. The primary endpoint was the safety of chemotherapy. RESULTS: The study enrolled 12 patients across three dose levels. No treatment-related deaths occurred. One patient in the 60 mg/m2 dose level occurred dose-limiting Grade 3 febrile neutropenia. No DLT was found in the 90 mg/m2 dose level thus the MTD was not reached. The phase II study's recommended dose was 75 mg/m2 based on the available preclinical and clinical data including pharmacokinetics, pharmacodynamics, efficacy, and toxicity. The frequent hematologic toxicities were leukocytopenia (Grade 1-2 of 66.7% and Grade 3-4 of 33.3%), neutropenia (Grade 1-2 of 91.7% and Grade 3-4 of 8.3%). Nonhematologic toxicities were mild and manageable. Overall response rate (ORR) of all patients achieved 100%. CONCLUSIONS: Weekly schedule of cisplatin and nab-paclitaxel in combination with concurrent radiotherapy showed manageable toxicities and promising antitumor activity in patients with locally advanced ESCC. The recommended dose of nab-paclitaxel for further studies is 75 mg/m2 .

Safety/tolerability, efficacy and pharmacokinetics of 600-µg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m2 or higher: A phase I, randomized, double-blind, placebo-controlled study.

AIM: To assess the safety/tolerability, efficacy and pharmacokinetics of once-daily, 600-µg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m2 or higher. MATERIALS AND METHODS: This phase I, randomized, double-blind, placebo-controlled study (NCT04208620) enrolled patients to receive subcutaneous cotadutide at an escalating dose to determine the highest tolerated clinical dose (Cohort 1), then applied in Cohort 2. The primary endpoint was safety, including treatment-emergent adverse events (TEAEs); secondary endpoints included glycaemic control and body weight. RESULTS: Sixteen patients were randomly allocated to receive cotadutide or placebo in a 3:1 ratio. All patients were Asian, 62.5% were male, and the median age and body mass index were 60 years and 27.2 kg/m2 , respectively. Through the follow-up period of the study, 11/12 (91.7%) patients in the cotadutide group experienced a TEAE versus 1/4 (25.0%) patients in the placebo group. All TEAEs were mild, except for one moderate event. There were no deaths, serious TEAEs or TEAEs leading to study discontinuation. Gastrointestinal-related events were the most common TEAEs. Cotadutide-treated patients achieved significantly improved 7-day mean glucose measured by continuous glucose monitoring; the 7-day mean (standard deviation) at the end of treatment (day 70) was 112.23 (20.79) versus 206.85 (3.62) mg/dL for placebo. Mean respective changes in HbA1c were -1.13% (0.64%) and -0.17% (0.65%); and mean percentage changes in body weight were -6.93% (3.44%) and -1.23% (1.20%). CONCLUSIONS: Cotadutide was well tolerated at doses up to 600 µg; efficacy versus placebo for weight loss and glycaemic control was shown.

Safety, Tolerability, and Pharmacokinetics of Senaparib, a Novel PARP1/2 Inhibitor, in Chinese Patients With Advanced Solid Tumors: A Phase I Trial.

BACKGROUND: Senaparib, a novel poly(ADP-ribose) polymerase 1/2 inhibitor, demonstrated antitumor activity in preclinical studies. This phase I, first-in-human, dose-escalation/-expansion study explored the pharmacokinetics, safety and tolerability, and preliminary antitumor activity of senaparib in Chinese patients with advanced solid tumors. PATIENTS AND METHODS: Adults with advanced solid tumors who had failed ³1 line of prior systemic treatment were enrolled. Senaparib (once daily [QD]) dose was escalated from 2 mg until the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) using a modified 3 + 3 design. Dose expansion included: dose groups with ≥1 objective response and one dose higher, as well as those at the MTD/RP2D. Primary objectives were to evaluate the safety and tolerability, and determine the MTD and/or RP2D of senaparib. RESULTS: Fifty-seven patients were enrolled across 10 dose groups (2-120 mg QD, and 50 mg twice daily). No dose-limiting toxicities were observed. The most common senaparib-related adverse events were anemia (80.9%), white blood cell count decreased (43.9%), platelet count decreased (28.1%), and asthenia (26.3%). Senaparib exposure increased dose proportionately at 2-80 mg; absorption saturated at 80-120 mg. Senaparib accumulation was minimal after repeated QD administration (accumulation ratio=1.1-1.5). The objective response rate was 22.7% (n=10/44) overall (all partial responses) and 26.9% (n=7/26) for patients harboring BRCA1/BRCA2 mutations. Disease control rates were 63.6% and 73.1%, respectively. CONCLUSIONS: Senaparib was well tolerated and demonstrated promising antitumor activity in Chinese patients with advanced solid tumors. The RP2D for this clinical study in China was identified as 100 mg QD. CLINICALTRIALS.GOV IDENTIFIER: NCT03508011.

Total marrow lymphoid irradiation and cyclophosphamide is associated with low toxicity and good outcomes in patients undergoing hematopoietic stem cell transplantation for acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crises - A phase I study.

INTRODUCTION: Total marrow lymphoid irradiation (TMLI) can deliver higher doses of irradiation without increasing toxicity compared to Total body irradiation (TBI). METHODS: Twenty adult patients undergoing hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia with lymphoid blast crises (CML-LBC) received TMLI and cyclophosphamide for conditioning. Ten patients each received 13.5 or 15 Gy of TMLI. The graft source was peripheral blood stem cells in all, and donors included matched related (n = 15), haplo-identical (n = 3) or matched unrelated donors (n = 2). RESULTS: The median cell dose infused was 9 × 106 CD34/kg (range 4.8-12.4). Engraftment occurred in all (100%) at a median of 15 days (range: 14-17). Toxicity was low with hemorrhagic cystitis seen in two but no sinusoidal obstruction syndrome. Acute GVHD occurred in 40% while chronic GVHD was seen in 70.5%. Viral infections were seen in 55% while blood stream bacterial infections occurred in 20% and invasive fungal disease (IFD) in 10%. The Day 100 non-relapse mortality (NRM) was 10%. At a median follow up of 25 months (range 2-48), two patients have relapsed. Overall survival at 2 years is 80% while the disease-free survival is 75%. CONCLUSIONS: The combination of TMLI and cyclophosphamide for myeloablative conditioning is associated with low toxicity and favorable early outcomes in patients undergoing HSCT for ALL and CML-LBC.

Phase I Single Ascending Dose and Food Effect Study in Healthy Adults and Phase I/IIa Multiple Ascending Dose Study in Patients with Pulmonary Tuberculosis to Assess Pharmacokinetics, Bactericidal Activity, Tolerability, and Safety of OPC-167832.

OPC-167832, an inhibitor of decaprenylphosphoryl-ß-d-ribose 2'-oxidase, demonstrated potent antituberculosis activity and a favorable safety profile in preclinical studies. This report describes the first two clinical studies of OPC-167832: (i) a phase I single ascending dose (SAD) and food effects study in healthy participants; and (ii) a 14-day phase I/IIa multiple ascending dose (MAD; 3/10/30/90 mg QD) and early bactericidal activity (EBA) trial in participants with drug-susceptible pulmonary tuberculosis (TB). OPC-167832 was well tolerated at single ascending doses (10 to 480 mg) in healthy participants and multiple ascending doses (3 to 90 mg) in participants with TB. In both populations, nearly all treatment-related adverse events were mild and self-limiting, with headache and pruritus being the most common events. Abnormal electrocardiograms results were rare and clinically insignificant. In the MAD study, OPC-167832 plasma exposure increased in a less than dose-proportional manner, with mean accumulation ratios ranging from 1.26 to 1.56 for Cmax and 1.55 to 2.01 for area under the concentration-time curve from 0 to 24 h (AUC0-24h). Mean terminal half-lives ranged from 15.1 to 23.6 h. Pharmacokinetics (PK) characteristics were comparable to healthy participants. In the food effects study, PK exposure increased by less than ~2-fold under fed conditions compared to the fasted state; minimal differences were observed between standard and high-fat meals. Once-daily OPC-167832 showed 14-day bactericidal activity from 3 mg (log10 CFU mean ± standard deviation change from baseline; -1.69 ± 1.15) to 90 mg (-2.08 ± 0.75), while the EBA of Rifafour e-275 was -2.79 ± 0.96. OPC-167832 demonstrated favorable pharmacokinetic and safety profiles, as well as potent EBA in participants with drug-susceptible pulmonary TB.

Pyrotinib alone or in combination with docetaxel in refractory HER2-positive gastric cancer: A dose-escalation phase I study.

AIM: Pyrotinib (an irreversible pan-ErbB small-molecular tyrosine kinase inhibitor) was approved in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and showed great antitumor activity in preclinical studies of gastric cancer (GC). This study was first designed to prospectively assess pyrotinib in pretreated HER2-positive GC. METHODS: This multicenter, phase I study followed a standard "3 + 3" design and included two parts. In the pyrotinib part, pyrotinib was administered orally, once per day at dose levels of 240, 320, 400, and 480 mg. In the pyrotinib plus docetaxel part, patients received pyrotinib (qd, d1-21, q3W) combined with docetaxel (60 mg/m2 , d1, q3W) at dose levels of 240, 320, and 400 mg. Primary endpoints were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of pyrotinib as monotherapy or coadministered with docetaxel. RESULTS: A total of 25 patients were enrolled and received pyrotinib (n = 15) or pyrotinib plus docetaxel (n = 10). One DLT was observed in pyrotinib monotherapy part (Grade 3 uncontrolled diarrhea after supportive care) and pyrotinib plus docetaxel part (Grade 4 neutropenia and leukopenia). In the pyrotinib monotherapy part, MTD was not reached. Diarrhea, anemia, neutropenia, and leukopenia were the most common treatment-related adverse events (TRAEs). The RP2D for pyrotinib monotherapy was recommended as 400 mg. After combining with docetaxel, the risk of leukopenia and neutropenia was increased. Grade ≥3 TRAEs were reported for four patients in the monotherapy part and for eight patients in the combination part. Mean t1/2 was approximately 20 h. Pyrotinib exposure was dose-dependent with a nonlinear relationship versus dose. There were five patients who had confirmed partial response (monotherapy: one each at 240, 400, and 480 mg dose cohort; combination therapy: two at 240 mg dose cohort), resulting in an objective response rate of 21% and 20%, respectively. CONCLUSIONS: Pyrotinib alone and combined with docetaxel showed acceptable toxicities in patients with pretreated HER2-positive GC. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov, NCT02378389.

First-in-human, phase I study of AK109, an anti-VEGFR2 antibody in patients with advanced or metastatic solid tumors.

BACKGROUND: Vascular endothelial growth factor receptor 2 (VEGFR2) plays a key role in antiangiogenesis which has been an essential strategy for cancer treatment. We report the first-in-human study of AK109, a novel anti-VEGFR2 monoclonal antibody, to characterize the safety profile and pharmacokinetics/pharmacodynamics (PK/PD) properties, and explore the preliminary antitumor efficacy in patients with solid tumors. PATIENTS AND METHODS: This was a multicenter, open-label, phase I study, including dose escalation and dose expansion (NCT04547205). Patients with advanced cancers were treated 2 and 3 weekly with escalating doses of AK109. A 3 + 3 design was used to determine the maximum tolerated dose. Blood was sampled for PK/PD analysis. The primary endpoint was safety and recommended phase II dose (RP2D). RESULTS: A total of 40 patients were enrolled. No dose-limiting toxicity was observed. However, 38 patients reported treatment-related adverse events (TRAEs); grade ≥3 TRAEs occurred in 10 patients. The most common TRAEs were proteinuria (n = 24, 60%), hypertension (n = 13, 32.5%), increased aspartate transaminase (n = 11, 27.5%), thrombopenia (n = 10, 25%), and anemia (n = 10, 25%). A total of 28 patients (70%) reported adverse events of special interest (AESIs). The most common AESIs were proteinuria (60%), hypertension (32.5%), and hemorrhage (32.5%), mainly including gum bleeding and urethrorrhagia. AK109 exhibited an approximately linear PK exposure with dose escalation at 2-12 mg/kg. PD analyses showed rapid target engagement. Among the 40 patients, 4 achieved partial response and 21 achieved stable disease with an objective response rate of 10% and a disease control rate of 62.5%. Based on the safety profile, the PK/PD profile, and preliminary antitumor activities, 12 mg/kg Q2W and 15 mg/kg Q3W were selected as RP2D. CONCLUSIONS: AK109 showed manageable safety profile and promising antitumor activity, supporting further clinical development in a large population.

Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of Gerilimzumab (GB224), a recombinant humanized interleukin-6 monoclonal antibody, in healthy Chinese adults: A randomized controlled dose-escalation study.

OBJECTIVES: This study aimed to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of Gerilimzumab (GB224), a recombinant humanized IgG1λ monoclonal antibody against interleukin-6, in healthy Chinese adults. METHODS: Fifty-eight subjects were randomly assigned to receive a single subcutaneous dose of 2, 5, 10, 15, 20, 30 mg GB224 or placebo. Safety assessments were performed, and blood samples were collected for PK, PD, and immunogenicity analyses during a follow-up of 112 days. RESULTS: The most frequent adverse event was decreased fibrinogen (43.1%). GB224 was absorbed relatively fast with a median Tmax of 48 h (24-168 h) but eliminated slowly with a long mean half-life (839.38-981.63 h). Dose proportionality was shown to be in the dose range of 10-30 mg. A dose-dependent increase in serum interleukin-6 concentration from baseline was observed in the subjects receiving GB224. Only two subjects tested positive for antidrug antibodies after administration of GB224. CONCLUSION: GB224 had a well-tolerated safety profile, desirable PK, and a low immunogenicity following a single-dose subcutaneous administration in healthy Chinese subjects. These findings warrant further investigation.

A Phase 1 Safety Study of Avelumab Plus Stereotactic Body Radiation Therapy in Malignant Pleural Mesothelioma.

Introduction: Single-agent monoclonal antibody therapy against programmed death-ligand 1 (PD-L1) has modest effects in malignant pleural mesothelioma. Radiation therapy can enhance the antitumor effects of immunotherapy. Nevertheless, the safety of combining anti-PD-L1 therapy with stereotactic body radiation therapy (SBRT) is unknown. We present the results of a phase 1 trial to evaluate the safety of the anti-PD-L1 antibody avelumab plus SBRT in patients with malignant pleural mesothelioma. Methods: This was a single-arm, investigator-initiated trial in patients who progressed on prior chemotherapy. Avelumab was delivered every other week, and SBRT was delivered to one lesion in three to five fractions (minimum of 30 Gy) followed by continuation of avelumab up to 24 months or until disease progression. The primary end point of the study was safety on the basis of grade 3+ nonhematologic adverse events (AEs) within 3 months of SBRT. Results: Thirteen assessable patients received a median of seven cycles (range: 2-26 cycles) of avelumab. There were 27 grade 1, 17 grade 2, four grade 3, and no grade 4 or 5 avelumab-related AEs. The most common were infusion-related allergic reactions (n = 6), anorexia or weight loss (n = 6), fatigue (n = 6), thyroid disorders (n = 5), diarrhea (n = 3), and myalgia or arthralgias (n = 3). There were 10 grade 1, four grade 2, one grade 3, and no grade 4 or 5 SBRT-related AEs. The most common were diarrhea (n = 3), chest pain/myalgia (n = 2), fatigue (n = 2), cough (n = 2), dyspnea (n = 2), and nausea/vomiting (n = 2). Conclusions: Combination avelumab plus SBRT seems tolerable on the basis of the prespecified toxicity end points of the first stage of this Simon two-stage design phase 1 study.

Safety, Tolerability, and Pharmacokinetics of Nebulized Hydroxychloroquine: A Pilot Study in Healthy Volunteers.

Background: Early in the coronavirus disease 2019 (COVID-19) pandemic, hydroxychloroquine (HCQ) drew substantial attention as a potential COVID-19 treatment based on its antiviral and immunomodulatory effects in vitro. However, HCQ showed a lack of efficacy in vivo, and different groups of researchers attributed this failure to the insufficient drug concentration in the lung following oral administration (HCQ is only available in the market in the tablet form). Delivering HCQ by inhalation represents a more efficient route of administration to increase HCQ exposure in the lungs while minimizing systemic toxicity. In this pilot study, the safety, tolerability, and pharmacokinetics of HCQ nebulizer solution were evaluated in healthy volunteers. Methods: Twelve healthy participants were included in this study and were administered 2 mL of HCQ01 solution (equivalent to 25 mg of HCQ sulfate) through Aerogen® Solo, a vibrating mesh nebulizer. Local tolerability and systemic safety were assessed by forced expiratory volume in the first and second electrocardiograms, clinical laboratory results (e.g., hematology, biochemistry, and urinalysis), vital signs, and physical examinations. Thirteen blood samples were collected to determine HCQ01 systemic exposure before and until 6 hours after inhalation. Results: The inhalation of HCQ01 was well tolerated in all participants. The mean value of Cmax for the 12 participants was 9.66 ng/mL. Tmax occurred at around 4.8 minutes after inhalation and rapidly decreased thereafter. The reported systemic exposure was very low with a mean value of 5.28 (0.6-15.6) ng·h/mL. Conclusion: The low systemic concentrations of HCQ01 of 9.66 ng/mL reported by our study compared with 1 µg/mL previously predicted after 200 mg BID oral administration, and the safety and tolerability of HCQ01 administered as a single dose through nebulization, support the assessment of its efficacy, safety, and tolerability in further studies for the treatment of COVID-19.

Phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma.

Previous studies showed antitumor activity for plitidepsin plus dexamethasone (DXM) in relapsed/refractory multiple myeloma (r/r MM), and in vitro synergism with bortezomib (BTZ) or DXM against MM cells. This phase I trial evaluated plitidepsin (3-h intravenous infusion Day 1 and 15), BTZ (subcutaneous bolus Day 1, 4, 8, and 11), and DXM (orally Day 1, 8, 15, and 22), every 4 weeks in 36 r/r MM patients. Twenty-two patients were treated using a standard dose escalation design (10 at the recommended dose [RD] cohort), and 14 additional patients were treated to expand the RD cohort. No dose-limiting toxicities (DLTs) occurred during dose escalation. The highest dose level evaluated (plitidepsin 5.0 mg/m2 , BTZ 1.3 mg/m2 , DXM 40.0 mg) was the RD for phase II studies. Results shown herein are focused on this RD. Two patients had DLTs (grade 3 diarrhea, and grade 3 nausea/vomiting refractory to antiemetic therapy). Grade ≥ 3 hematological toxicity (thrombocytopenia 46%, anemia 33%, and neutropenia 17%) was manageable and did not result in treatment discontinuation. Transient and manageable grade 3 ALT increase (26%) was the most common biochemical abnormality. At the RD cohort, overall response rate was 22.2% (95%CI, 6.4%-47.6%), including one stringent complete response, one very good partial response, and two partial responses in r/r patients to BTZ and/or lenalidomide. The clinical benefit rate was 77.8% (95%CI, 52.4-93.6%). No major pharmacokinetic drug-drug interaction was found. In conclusion, the triple combination of plitidepsin, BTZ, and DXM showed an acceptable safety profile and had moderate activity in adult patients with r/r MM.

Oral formulation of bendamustine hydrochloride for patients with advanced solid tumors; a phase 1 study.

To determine the maximum tolerated dose (MTD) and recommended dose (RD) of orally-administered bendamustine in Japanese patients with advanced solid tumors. The optimal dosing schedule, safety, pharmacokinetics, and preliminary antitumor effects were also evaluated. A multicenter, open-label trial with a standard 3 + 3 design and dose escalation by dose-limiting toxicity (DLT) was conducted. The treatment schedules were once daily for 7, 14, and 21 days every 3 weeks as one cycle. The total dose per cycle was increased from 175 to 840 mg/m2. Eighteen patients were enrolled in this study. DLT occurred in one of six patients at 75 mg/m2/day × 7 days, and one of three patients at 37.5 mg/m2/day × 14 days and 25 mg/m2/day × 21 days. However, the delayed recovery from a decrease in neutrophil or platelet count hampered the start of subsequent treatment cycles, and the trend was more prominent at 37.5 mg/m2/day × 14 days and 25 mg/m2/day × 21 days than in 75 mg/m2/day × 7 days. MTD was determined as 75 mg/m2/day × 7 days to allow acceptable hematologic recovery. The pharmacokinetics of orally-administered bendamustine were generally dose-dependent; however, the inter-individual variability is relatively large. The major adverse events were hematologic toxicities; gastrointestinal disorders were generally mild. Adverse drug reactions did not lead to the discontinuation of the drug. A partial response was observed in two of six patients (prostatic small cell carcinoma and thymic carcinoma) at 75 mg/m2/day × 7 days. The RD and optimal dosing schedule of orally-administered bendamustine was 75 mg/m2 once daily for 7 days every 3 weeks for the treatment of advanced solid tumors. (Trial registration number ClinicalTrials.gov NCT03604679. Registration date July 27, 2018).

Neoadjuvant toripalimab plus platinum-paclitaxel chemotherapy in stage II-III non-small cell lung cancer: a single-center, single-arm, phase I study in China.

BACKGROUND: Neoadjuvant and adjuvant immune checkpoint inhibitor treatments for non-small cell lung cancer (NSCLC) patients with resectable disease have presented promising results. This is a phase I study to evaluate the safety and efficacy of neoadjuvant toripalimab in combination with chemotherapy for NSCLC. METHODS: Treatment-naive patients with resectable NSCLC (stage II-IIIB) received two to four cycles of toripalimab (240 mg, intravenously, q3w) combined with platinum-paclitaxel chemotherapy. Surgical operation was performed approximately 4 weeks after the last cycle. The primary end point was safety. The efficacy endpoints included radiographic and pathological response rates, expression of programmed death ligand 1 (PD-L1) and molecular targets. RESULTS: A total of 11 patients were enrolled, consisting of 2 patients (18%) with adenocarcinoma and 9 patients (82%) with squamous cell carcinoma. All patients received two to four cycles of toripalimab plus chemotherapy and underwent radical resection. Regarding safety, 5 of 11 patients (45%) had neoadjuvant treatment-related adverse events, and 1 patient (9%) experienced grade 3 or worse treatment-related adverse events. Radiographic partial response was achieved in 10 patients, with an objective response rate of 91%. Among 11 patients, 6 (55%) achieved pathological complete response, including 1 PD-L1-negative patient. CONCLUSION: Neoadjuvant toripalimab plus platinum-paclitaxel chemotherapy was tolerable and induced a pathological complete response in 55% of resectable NSCLC patients.

Clinical Phase I Study of TAS102/Irinotecan/Bevacizumab Combination Therapy in Japanese Patients With Unresectable Metastatic Colorectal Cancer (mCRC).

BACKGROUND: In this phase I study, we aimed to examine the safety of a triple combination (TAS-102/irinotecan/bevacizumab) therapy in patients with previously treated metastatic colorectal cancer (mCRC). METHODS: In the TAS-102 dose-escalation phase, we determined dose-limiting toxicity (DLT), estimated the maximum tolerated dose (MTD), and determined the recommended dose (RD); in the expansion phase, we evaluated safety. The RD was administered in advance for 10 patients. The TAS-102 dose was increased to 25-35 mg/m2 and administered orally twice on days 1-5 and 8-12. Irinotecan (100 mg/m2) and bevacizumab (5 mg/m2) were administered on days 1 and 15 of the treatment, respectively. RESULTS: Fifteen patients were enrolled in dose-escalation Levels 1-3, and ten in the expansion phase. A 30 mg/m2 TAS-102 dose at Level 2 was administered to three patients, with one presenting grade 4 neutropenia. A 35 mg/m2 TAS-102 dose at Level 3 was administered to five patients, with three patients presenting grade 4 neutropenia and grade 3 DLTs. We added three patients at Level 2 and set the MTD at 30 mg/m2, with no DLTs. The RD was fixed at 25 mg/m2, with no DLTs (N = 10) or treatment-related deaths. One patient showed complete response at Level 2, four presented partial response, and eleven individuals maintained stable disease for over four months. The median progression-free survival duration was 7.6 months, while the median overall survival period was 16.9 months. CONCLUSION: The TAS-102/irinotecan/bevacizumab combination therapy was safe, effective, and well-tolerated in patients previously treated with mCRC.