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A solid tumor is an organ composed of cancer and host cells embedded in an extracellular matrix and nourished by blood vessels. A prerequisite to understanding tumor pathophysiology is the ability to distinguish and monitor each component in dynamic studies. Standard fluorophores hamper simultaneous intravital imaging of these components. Here, we used multiphoton microscopy techniques and transgenic mice that expressed green fluorescent protein, and combined them with the use of quantum dot preparations. We show that these fluorescent semiconductor nanocrystals can be customized to concurrently image and differentiate tumor vessels from both the perivascular cells and the matrix. Moreover, we used them to measure the ability of particles of different sizes to access the tumor. Finally, we successfully monitored the recruitment of quantum dot–labeled bone marrow–derived precursor cells to the tumor vasculature. These examples show the versatility of quantum dots for studying tumor pathophysiology and creating avenues for treatment.

BackgroundProbody® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing ‘off-tumor’ toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1).MethodsIn the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1).ResultsAn MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1).ConclusionsPacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression.Trial registration numberNCT03013491.

BackgroundProbody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing ‘off-tumor’ toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab.MethodsAdults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1).ResultsTwenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3–4 adverse events (AEs) and grade 3–4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients.ConclusionsThe MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile.

PROBODY therapeutics (Pb‐Tx) are protease‐activatable prodrugs of monoclonal antibodies (mAbs) designed to target tumors where protease activity is elevated while avoiding normal tissue. They are composed of a parental mAb, a mask that inhibits antibody binding to target, and a protease‐cleavable substrate between the mask and the mAb. We report a quantitative systems pharmacology model for the rational design and clinical translation of Pb‐Tx. The model adequately described monkey pharmacokinetic data following the administration of six anti‐CD166 Pb‐Tx of varying mask strength and substrate cleavability and captured the trend of decreasing Pb‐Tx systemic clearance with increasing mask strength. Projections to humans suggested both higher levels of Pb‐Tx in tumor relative to parental mAb and an optimal mask strength for maximizing tumor receptor–mediated uptake. Simulations further suggested the majority of circulating species in humans would be intact/masked Pb‐Tx, with no significant flux of cleaved/activated species from tumor to the systemic compartment.

Neurotrophins such as nerve growth factor (NGF) may be useful for treating diseases in the central nervous system; our ability to harness the potential therapeutic benefit of NGF is directly related to our understanding of the fate of exogenously supplied factors in brain tissue. We utilized multiphoton microscopy to quantify the dynamic behavior of NGF in coronal, 400- μm thick, fresh rat brain tissue slices. We administered a solution containing bioactive rhodamine nerve growth factor conjugate via pressure injection and monitored the dispersion in the striatal region of the coronal slices. Multiphoton microscopy facilitated repeated imaging deep (∼200 μm) into tissue slices with minimal photodamage of tissue and photobleaching of label. The pressure injection paradigm approximated diffusion from a point source, and we therefore used the corresponding solution to the diffusion equation to estimate an apparent diffusion coefficient in brain tissue ( D b(34°C)) of 2.75 ± 0.24 × 10 −7 cm 2/s (average ± SE). In contrast, we determined a corresponding free diffusion coefficient in buffered solution ( D f(34°C)) of 12.6 ± 0.9 × 10 −7 cm 2/s using multiphoton fluorescence photobleaching recovery. The tortuosity, defined as the square root of the ratio of D f to D b, was 2.14 and moderate in magnitude.

Purpose To gain a better understanding of the impact of dose and other prognostic factors on safety and efficacy of docetaxel in second-line non-small-cell lung cancer patients. Methods A model-based meta‐analysis (MBMA) of a published docetaxel monotherapy data in 6085 second‐line non-small-cell lung cancer patients from 46 trials was conducted. Results The logit of grade 3/4 neutropenia incidence was a linear function of dose, with a 5 % increase in the odds of neutropenia per mg/m 2 increase in dose [odds ratio (OR) 1.05, 95 % confidence interval (CI) 1.04–1.06], and a Japanese study effect (OR 17.1, 95 % CI 6.05–48.4). The logit of overall response rate (ORR) was a linear function of cumulative dose (0.4 % increase in the odds of response per mg/m 2 increase; OR 1.004, 95 % CI 1.001–1.008) and median population age (OR 1.08 per year, 95 % CI 1.02–1.15). A Japanese study effect was identified for overall survival (OS) in addition to prognostic factors identified by a previous meta-analysis. Conclusions This current MBMA identified docetaxel dose–response relationships for both neutropenia and ORR, an effect of age on ORR, and Japanese study effects on both neutropenia and OS.

Purpose The potential effect of onartuzumab, when administered with or without bevacizumab in combination with weekly paclitaxel, on the corrected QT interval (QTc) and other electrocardiogram (ECG) parameters, was investigated in a randomized, phase 2 study OAM4861g of first- or second-line therapy in patients with locally recurrent or metastatic triple-negative breast cancer. Methods Triplicate 12-lead ECGs were recorded at screening, pre- and post-dose on day 1 of cycles 1, 2, and 4, and at the study drug discontinuation visit (SDDV). Onartuzumab serum samples were collected pre- and post-dose on day 1 of cycles 1–4 and at the SDDV. Fridericia’s correction was applied to QT recordings (QTcF), and change from baseline (ΔQTcF) was calculated. Post-baseline measurements were reported as baseline-adjusted control arm (placebo plus bevacizumab plus paclitaxel)-corrected values (ΔΔQTcF). Categorical ECG findings were noted. Linear mixed effects modeling evaluated a potential concentration–ΔQTcF relationship. Results Out of 185 enrolled patients, 165 patients had ECG-evaluable data for analyses. Similar ΔQTcF and ΔΔQTcF values were observed across all treatment arms, with mean increase <10 and <7 ms, respectively, across all time points. Similar changes in heart rate, PR interval, and QRS duration were noted across all treatment arms. Incidences of abnormal ECG findings of clinical interest were comparable in the onartuzumab-containing arms and the control arm. No concentration–ΔQTcF relationship was evident at onartuzumab serum concentrations up to 1,200 μg/ml. Conclusions These data suggest that onartuzumab, at the dose and exposures studied in this clinical trial, does not meaningfully affect the QTcF interval.

Quantum dots permit in vivo imaging of tumors at various length scales.

Purpose Ridaforolimus, a potent inhibitor of the mammalian target of rapamycin (mTOR), is under development for the treatment for solid tumors. This open-label, randomized, 3-period crossover study investigated the effect of food on the pharmacokinetics of ridaforolimus 40 mg as well as safety and tolerability of the study medication. Methods Ridaforolimus was administered to 18 healthy, male subjects (mean age 36.4 years) in the fasted state, following ingestion of a light breakfast, and following a high-fat breakfast. Whole blood samples were collected from each subject pre-dose and 1, 2, 3, 4, 6, 8, 24, 48, 72, 96, and 168 h post-dose. Results The geometric mean (95 % confidence interval, CI) fasted blood area under the curve (AUC 0-∞ ) and maximum concentration ( C max ) were 1940 (1510, 2500) ng h/mL and 116 (87, 156) ng/mL, respectively, and median time to C max ( T max ) and average apparent terminal half-life ( t 1/2 ) were 6.0 and 64.5 h, respectively. Both T max and t 1/2 were similar in the fasted and fed states. With a light breakfast, the geometric mean intra-individual ratios (GMRs) for AUC 0-∞ and C max (fed/fasted) and 90 % CIs were 1.06 (0.85, 1.32) and 1.15 (0.83, 1.60); following a high-fat breakfast, the AUC 0-∞ and C max GMRs (90 % CI) were 1.46 (1.18, 1.81) and 1.12 (0.81, 1.53), respectively. Conclusions Increases in ridaforolimus exposure following both the light and high-fat breakfasts were not considered to be clinically meaningful. Ridaforolimus was generally well tolerated, and there were no discontinuations due to drug-related AEs. Ridaforolimus should be given without regard to food.

Purpose Ridaforolimus is an inhibitor of the mammalian target of rapamycin protein, with potent activity in vitro and in vivo. Ridaforolimus is primarily cleared by metabolism via cytochrome P450 3A (CYP3A) and is a P-glycoprotein (P-gp) substrate. Since potential exists for ridaforolimus to be co-administered with agents that affect CYP3A and P-gp activity, this healthy volunteer study was conducted to assess the effect of rifampin or ketoconazole on ridaforolimus pharmacokinetics. Methods Part 1: single-dose ridaforolimus 40 mg followed by rifampin 600 mg daily for 21 days and single-dose ridaforolimus 40 mg on day 14. Part 2: single-dose ridaforolimus 5 mg followed by ketoconazole 400 mg daily for 14 days and single-dose ridaforolimus 2 mg on day 2. Results Part 1: the geometric mean ratios (GMRs) (90% confidence interval [CI]) for ridaforolimus area under the concentration–time curve to the last time point with a detectable blood concentration (AUC 0–∞ ) and maximum blood concentration ( C max ) (rifampin + ridaforolimus/ridaforolimus) were 0.57 (0.41, 0.78) and 0.66 (0.49, 0.90), respectively. Both time to C max ( T max ) and apparent half-life ( t 1/2 ) were similar. Part 2: the GMRs (90% CI) based on dose-normalized AUC 0–∞ and C max (ketoconazole + ridaforolimus/ridaforolimus alone) were 8.51 (6.97, 10.39) and 5.35 (4.40, 6.52), respectively. Ridaforolimus apparent t 1/2 was ~1.5-fold increased for ketoconazole + ridaforolimus; however, T max values were similar. Conclusions Rifampin and ketoconazole both have a clinically meaningful effect on the pharmacokinetics of ridaforolimus.