A phase I dose-escalation and pharmacokinetic study of a micellar nanoparticle with entrapped docetaxel (CPC634) in patients with advanced solid tumours

Background: CPC634 is docetaxel entrapped in core-cross linked polymeric micelles. In preclinical studies, CPC634 demonstrated enhanced pharmacokinetics and improved therapeutic index. This phase I dose escalation study is the first-in-human study with CPC634. Methods: adult patients with advanced solid tumours received CPC634 intravenously either 3-weekly (Q3W) (part 1, dose range 15–100 mg/m2 ), 2-weekly (Q2W) (part 2, 45 mg/m2 ) or Q3W with dexamethasone premedication (part 3, 60 mg/m2 ). Results: thirty-three patients were enrolled. Skin toxicity was dose limiting (DLT) at ≥60 mg/m2 in part 1 and at 45 mg/m2 in part 2 and was the most common CPC634 related grade ≥ 3 adverse event (24%). With dexamethasone premedication no DLTs were observed at 60 mg/m2 Q3W. CPC634 exhibited a dose-proportional\ud pharmacokinetic profile. At 60 mg/m2 , the plasma area under the curve was 4067.5 ± 2974.0 ng/h/mL and the peak plasma level 217.3 ± 91.9 ng/mL with a half-life of 39.7 ± 9.4 h for released docetaxel. Conclusion: CPC634 could be administered safely upon pretreatment with dexamethasone. Cumulative skin toxicity was the main DLT. The recommended phase 2 dose was determined at 60 mg/m2 Q3W with dexamethasone premedication

Phase II randomized study of Plitidepsin (Aplidin), alone or in association with L-carnitine, in patients with unresectable advanced renal cell carcinoma

This randomized phase II study evaluated two schedules of the marine compound Plitidepsin with or without co-administration of L-carnitine in patients with renal cell carcinoma. Patients had adequate performance status and organ function.The primary endpoint was the rate of disease control (no progression) at 12 weeks (RECIST).Other endpoints included the response rate and time dependent efficacy measures.The trial also assessed the efficacy of L-carnitine to prevent Plitidepsin-related toxicity. The two regimes given as 24 hour infusion every two weeks showed hints of antitumoral activity. Disease control at 12 weeks was 15.8% in Arm A (5mg/m2, no L-carnitine) and 11,1% in Arm B (7mg/m2 with L-carnitine). Two partial responses were observed in Arm A (19 patients), none in Arm B (20 patients). Both schedules had the same progression-free interval (2.1 months).The median overall survival was 7.0 and 7.6 months.The safety profile was similar in both arms of the trial and adverse events were mainly mild to moderate (NCI CTC version 2.0). Increasing the dose to 7mg/m2 did not increase the treatment efficacy but the incidence of transaminase and CPK elevations and serious AEs. Coadministration of L-carnitine did not prevent muscular toxicity or CPK-elevation associated with Plitidepsin

Phase I trial of volasertib, a Polo-like kinase inhibitor, plus platinum agents in solid tumors: safety, pharmacokinetics and activity

Summary: Background This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and activity of volasertib, a selective Polo-like kinase 1 inhibitor that induces mitotic arrest and apoptosis, combined with cisplatin or carboplatin in patients with advanced/metastatic solid tumors (NCT00969761; 1230.6). Methods Sequential patient cohorts (3+3 dose-escalation design) received a single infusion of volasertib (100-350 mg) with cisplatin (60-100 mg/m2) or carboplatin (area under the concentration versus time curve [AUC]4-AUC6) on day 1 every 3 weeks for up to six cycles. Sixty-one patients received volasertib/cisplatin (n=30) or volasertib/carboplatin (n=31) for a median of 3.5 (range, 1-6) and 2.0 (range, 1-6) treatment cycles, respectively. Results The most common cycle 1 dose-limiting toxicities (DLTs) were thrombocytopenia, neutropenia and fatigue. MTDs (based on cycle 1 DLTs) were determined to be volasertib 300 mg plus cisplatin 100 mg/m2 and volasertib 300 mg plus carboplatin AUC6. Co-administration did not affect the pharmacokinetics of each drug. Partial responses were observed in two patients in each arm. Stable disease was achieved in 11 and six patients treated with volasertib/cisplatin and volasertib/carboplatin, respectively. Conclusions Volasertib plus cisplatin or carboplatin at full single-agent doses was generally manageable and demonstrated activity in heavily pretreated patients with advanced solid tumors.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Thermal study of the effect of several solvents on polymerization of acrylonitrile and their subsequent pyrolysis

The polymerization of acrylonitrile to polyacrylonitrile (PAN) has been studied using several solvents: N,N-dimethylformamide (DMF), hexane, toluene, water, and in bulk form (no solvent). The addition of DMF is the only case where both monomer and polymer are soluble in the solvent. Thermal analyses of the resultant products after polymerization have been performed by differential scanning calorimetry and pyrolysis–gas chromatography: mass spectrometry. The effect of the solvents employed as media for polymerization is interpreted from the results of the thermal and structural (X-ray diffraction) methods. The polymer samples obtained when using water or toluene as solvents have the greater content of amorphous components compared to the others. The amide molecules are difficult to completely eliminate in the product obtained after the polymerization reaction and even after prolonged heating at 110°C and remain occluded. DMF can be considered to exert a plasticized effect on PAN and is even capable of forming complexes by dipolar bonding. As a result of this interaction, the thermogram is quite different from the other samples studied in the present work, showing a single sharp exothermic peak. This is associated with nitrile group polymerization (cyclization) of PAN. It is deduced that the amount of heat evolved as well as the temperature interval over which it is released are influenced by the chemical processing of PAN, in particular when using DMF as solvent for both monomer and polymer. Pyrolysis of the different PAN samples revealed the release of occluded solvent molecules, mainly when using DMF, and compounds produced from the thermal degradation processes. Different types of cyclized compounds, such as pyridine derivatives and aromatic nitriles were identified. All these compounds could be derived from cyclized PAN structures which are not completely degraded by the thermal treatment of pyrolysis. Alkyldinitriles have also been tentatively identified associated with the final molecular breakdown of cyclized structures with six-member rings by pyrolysis. Valuable complementary information on the structure of the PAN samples (homopolymer) obtained using the different processing approaches involving several solvent media has been provided by pyrolysis. The present results will improve our understanding of the evolution of the structure and properties of carbon and activated carbon fibres which will enable us to establish processing strategies in order to obtain these materials under adequate and reproducible conditions.Peer reviewe

Talazoparib, a Poly(ADP-ribose) Polymerase Inhibitor, for Metastatic Castration-resistant Prostate Cancer and DNA Damage Response Alterations: TALAPRO-1 Safety Analyses

BACKGROUND: The phase II TALAPRO-1 study (NCT03148795) demonstrated durable antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Here, we detail the safety profile of talazoparib. PATIENTS AND METHODS: Men received talazoparib 1 mg/day (moderate renal impairment 0.75 mg/day) orally until radiographic progression, unacceptable toxicity, investigator decision, consent withdrawal, or death. Adverse events (AEs) were evaluated: incidence, severity, timing, duration, potential overlap of selected AEs, dose modifications/discontinuations due to AEs, and new clinically significant changes in laboratory values and vital signs. RESULTS: In the safety population (N = 127; median age 69.0 years), 95.3% (121/127) experienced all-cause treatment-emergent adverse events (TEAEs). Most common were anemia (48.8% [62/127]), nausea (33.1% [42/127]), decreased appetite (28.3% [36/127]), and asthenia (23.6% [30/127]). Nonhematologic TEAEs were generally grades 1 and 2. No grade 5 TEAEs or deaths were treatment-related. Hematologic TEAEs typically occurred during the first 4-5 months of treatment. The median duration of grade 3-4 anemia, neutropenia, and thrombocytopenia was limited to 7-12 days. No grade 4 events of anemia or neutropenia occurred. Neither BRCA status nor alteration origin significantly impacted the safety profile. The median (range) treatment duration was 6.1 (0.4-24.9) months; treatment duration did not impact the incidence of anemia. Only 3 of the 15 (11.8% [15/127]) permanent treatment discontinuations were due to hematologic TEAEs (thrombocytopenia 1.6% [2/127]; leukopenia 0.8% [1/127]). CONCLUSION: Common TEAEs associated with talazoparib could be managed through dose modifications/supportive care. Demonstrated efficacy and a manageable safety profile support continued evaluation of talazoparib in mCRPC. CLINICALTRIALS.GOV IDENTIFIER: NCT0314879

Phase II Study of Biweekly Plitidepsin as Second-Line Therapy for Advanced or Metastatic Transitional Cell Carcinoma of the Urothelium

The objective of this exploratory, open-label, single-arm, phase II clinical trial was to evaluate plitidepsin (5 mg/m2) administered as a 3-hour continuous intravenous infusion every two weeks to patients with locally advanced/metastatic transitional cell carcinoma of the urothelium who relapsed/progressed after first-line chemotherapy. Treatment cycles were repeated for up to 12 cycles or until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. The primary efficacy endpoint was objective response rate according to RECIST. Secondary endpoints were the rate of SD lasting ≥ 6 months and time-to-event variables. Toxicity was assessed using NCI-CTC v. 3.0. Twenty-one patients received 57 treatment cycles. No objective tumor responses occurred. SD lasting <6 months was observed in two of 18 evaluable patients. With a median follow-up of 4.6 months, the median PFR and the median OS were 1.4 months and 2.3 months, respectively. The most common AEs were mild to moderate nausea, fatigue, myalgia and anorexia. Anemia, lymphopenia, and increases in transaminases, alkaline phosphatase and creatinine were the most frequent laboratory abnormalities. No severe neutropenia occurred. Treatment was feasible and generally well tolerated in this patient population; however the lack of antitumor activity precludes further studies of plitidepsin in this setting

Safety and efficacy of atezolizumab in patients with autoimmune disease: subgroup analysis of the SAUL study in locally advanced/metastatic urinary tract carcinoma

Aim Patients with pre-existing autoimmune disease (AID) are typically excluded from clinical trials of immune checkpoint inhibitors, and there are limited data on outcomes in this population. The single-arm international SAUL study of atezolizumab enrolled a broader ‘real-world’ patient population. We present outcomes in patients with a history of AID. Methods Patients with locally advanced/metastatic urinary tract carcinoma received atezolizumab 1200 mg every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary end-point was safety. Overall survival (OS) was a secondary end-point. Subgroup analyses of AID patients were prespecified. Results Thirty-five of 997 treated patients had AID at baseline, most commonly psoriasis ( n = 15). Compared with non-AID patients, AID patients experienced numerically more adverse events (AEs) of special interest (46% versus 30%; grade ≥3 14% versus 6%) and treatment-related grade 3/4 AEs (26% versus 12%), but without relevant increases in treatment-related deaths (0% versus 1%) or AEs necessitating treatment discontinuation (9% versus 6%). Pre-existing AID worsened in four patients (11%; two flares in two patients); three of the six flares resolved, one was resolving, and two were unresolved. Efficacy was similar in AID and non-AID patients (median OS, 8.2 versus 8.8 months, respectively; median progression-free survival, 4.4 versus 2.2 months; disease control rate, 51% versus 39%). Conclusions In 35 atezolizumab-treated patients with pre-existing AID, incidences of special- interest and treatment-related AEs appeared acceptable. AEs were manageable, rarely requiring atezolizumab discontinuation. Treating these patients requires caution, but pre-existing AID does not preclude atezolizumab therapy

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population

The role of the erythrocyte in antitumour drug transport

The area of research on the substance-carrier capacity of the erythrocyte is rather limited and it remains difficult to estimate the impact of erythrocyte drug level monitoring in the clinic. Although equilibrium between blood and tissues based on the dissolution of compounds in the plasma water phase is often used in kinetic models, other models suggest that tissue levels correspond more closely to the protein-bound fraction than to the free fraction. For erythrocytes, the same may be true: tissues on the other side of capillary endothelium, or the capillary endothelium itself, may be more exposed to compounds accumulated on/in these cells. Since the introduction of the measurement of sediment (MESED) device, 100 µl of almost pure erythrocytes can be isolated with only 3.4 % trapped plasma. These RBCs are unwashed and thus maintained in their natural environment, without disruption of the normal equilibrium existing between red cells and plasma in whole blood. The first studies with ifosfamide and metabolites show that only minor chemical changes result in large changes of partitioning of the drugs between erythrocytes and plasma (chapter 1). While there is little detailed knowledge of the processes involved in uptake, transport and release, available data indicate a significant capacity of erythrocyte mediated substance transport. Various anticancer agents can induce severe shape deformations of the erythrocyte resulting in decreased membrane deformability, which could be of importance in the microcirculation when the erythrocyte must deform to negotiate its entrance into narrow capillaries (chapter 2). It is difficult to estimate the impact of shape changes on the in vivo behaviour of anticancer drugs, but they could occasionally have pathophysiological consequences. Chapter 3 stresses the importance of therapeutic drug monitoring (TDM) in both red blood cells and plasma during clinical drug development of anticancer agents and in individualising therapy. Data of plasma monitoring during several phase I/II trials (section III) raised questions which we tried to solve by performing in-vitro incubation studies with several cytotoxic drugs in human volunteer blood (section II). With the use of the MESED device and new validated analytical methods, it was possible to determine the partition ratios (concentration RBC/concentration plasma) of those drugs at different incubation concentrations, to look at gender differences and at the influence of smoking habits on the partition. The choice of the three tested anticancer drugs, docetaxel, gemcitabine and irinotecan, was inspired by several phase I/II clinical trials performed in our Department with those drugs. In some of these trials, we had the opportunity to collect also data on the red blood cell fraction and we compared these data with those generated during our in vitro experiments. The results of this thesis are indicative for further studies concerning the role of the erythrocyte in the (in-)efficacy of anticancer agents. There is no serious limitation anymore for simultaneous RBC and plasma monitoring in routine sessions. We should utilize positive and/or negative effects of substance uptake, transport and delivery by erythrocytes in future cancer treatment and in the development of new anticancer drugs