Phase 1/2 Trial Results of a Large Surface Area Microparticle Docetaxel for the Treatment of High-Risk Nonmuscle-Invasive Bladder Cancer
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Abstract
Purpose:
We investigated the safety, preliminary efficacy, and immune effects of large surface area microparticle docetaxel (LSAM-DTX) administered by direct injection after transurethral resection of bladder tumor (TURBT), and by intravesical instillation in high-risk nonmuscle-invasive bladder cancer.
Materials and Methods:
The trial followed an open-label 3+3 dose escalation with additional enrollment at the high dose. After TURBT, subjects received direct injection LSAM-DTX into the resection site and intravesical LSAM-DTX, followed by 6-week induction and 3-week maintenance intravesical LSAM-DTX courses. Tumor recurrence was evaluated by cytology, cystoscopy, or biopsy. Pharmacokinetic analysis of blood and multiplex immunofluorescence of tumor microenvironment occurred pre- and post-LSAM-DTX.
Results:
Nineteen subjects were enrolled, 14 with prior bacillus Calmette-Guérin exposure and 16 with ≥1 prior TURBT. Direct injection and intravesical LSAM-DTX were well tolerated. In the 3 lowest dose escalation cohorts the median recurrence-free survival was 5.4 months (10 patients, median followup 8.6 months). In the high-dose and expansion cohorts median recurrence-free survival was significantly increased (p <0.05, hazard ratio 0.29) to 12.2 months (9 patients, median followup 12.4 months). Systemic docetaxel exposure was negligible and increases in antitumor immune cells were found in the tumor microenvironment along with elevations in the PD-1, PD-L1 and CTLA-4 immune checkpoint inhibitor targets.
Conclusions:
Post-TURBT direct injection and intravesical LSAM-DTX were well tolerated and demonstrated clinical response for patients with high-risk nonmuscle-invasive bladder cancer. Favorable immune cell infiltration and checkpoint receptor increases following LSAM-DTX treatment warrants investigation alone as well as in combination with immune checkpoint inhibitor therapy.
| AE |
adverse event |
| BCG |
bacillus Calmette-Guérin |
| CR |
complete response |
| LSAM-DTX |
large surface area microparticle docetaxel |
| LSAM-PTX |
large surface area microparticle paclitaxel |
| MDSC |
myeloid derived suppressor cells |
| NK |
natural killer |
| NMIBC |
nonmuscle-invasive bladder cancer |
| PanCK |
pan-cytokeratin |
| RFS |
recurrence-free survival |
| TURBT |
transurethral resection of bladder tumor |
Most patients with high-risk nonmuscle-invasive bladder cancer (NMIBC) are treated with transurethral resection of bladder tumor (TURBT) followed by bacillus Calmette-Guérin (BCG) intravesical therapy.1,2 However, approximately half of high-risk NMIBC patients treated with BCG will have recurrence within 2 years, and many of these patients will become BCG unresponsive.3,4 Despite moderate efficacy with intravesical chemotherapy for BCG-exposed NMIBC, there remains a need to enhance therapeutic options to improve the efficacy of these treatments.
Large surface area microparticle docetaxel (LSAM-DTX; CritiTech, Inc., Lawrence, Kansas) are docetaxel microparticles formulated for tissue entrapment and sustained local drug release. LSAM-DTX is engineered using a precipitation with compressed antisolvent process that employs fluid state carbon dioxide held at or above its critical temperature and pressure (supercritical) and acetone to generate pure docetaxel microparticles with well-characterized particle size distribution and large surface area.5,6
Studies of intratumoral injections of LSAM-DTX demonstrate significant tumor reduction and immune cell infiltrate into the tumor microenvironment in uro-oncologic xenografts. Intratumoral LSAM-DTX resulted in high concentrations of docetaxel in tumors for up to 50 days and an influx of immune effector cells.7 Intratumoral LSAM-DTX in combination with systemic anti-CTLA-4 in a mouse model of metastatic breast cancer showed reduction in tumor progression and metastatic disease, and the combination was well tolerated. Significant changes in peripheral or local effector T cells and dendritic cells, natural killer (NK) cells, and myeloid derived suppressor cells (MDSC) were detected.6
The study described here (ClinicalTrials.gov identifier NCT03636256) evaluated the safety and tolerability of LSAM-DTX in patients with high-risk NMIBC. Blood was collected for pharmacokinetic analysis and tissue was collected for multiplex immunofluorescence quantitative immunophenotyping.
MATERIALS AND METHODS
Inclusion Criteria
Prior to subject enrollment, this study was reviewed and approved by clinical sites’ Institutional Review Boards (HonorHealth IRB: 1374606-1; Johns Hopkins IRB: IRB00198864; WIRB: 1256662; UTHSA IRB: HSC20190312H; Columbia University IRB: IRB-AAAS3837) and Ethics Committees. All subjects provided written informed consent with guarantees of confidentiality. Participants were ≥18 years with high-risk NMIBC including high-grade T1, recurrent high-grade Ta, high-grade Ta >3 cm (or multifocal), carcinoma in situ, BCG-naïve or -exposed, variant histology, or lymphovascular invasion including high-grade prostatic urethral involvement2 confirmed by biopsy, imaging, and/or cytology. Inclusion criteria included Eastern Cooperative Oncology Group 0-2 performance status at study entry, life expectancy ≥6 months, and adequate marrow, liver, and renal function.
Exclusion Criteria
Patients were excluded due to metastatic disease, a history of nonbladder malignancy except for nonmelanoma skin cancer within 12 months, intravesical therapy within 4 weeks of consent, resection surface area >8 cm2, bladder perforation during TURBT, and/or upper tract and urethral disease within 18 months.
Treatment
LSAM-DTX, an investigational product not yet approved for use by the U.S. Food & Drug Administration, is prepared at time of use as a suspension in saline with minimal excipients. Immediately following standard of care TURBT, subjects received ≤8 LSAM-DTX injections into a single tumor resection bed in ≤0.5 ml increments up to 4 ml. Injections were administered in 1 cm grid into the largest resection bed (<8 cm2) via adjustable cystoscopy needles (2 and 3–4 mm length for injections in the dome and side area of the bladder, respectively) up to 5 mm outside the resection margin. Direct injection LSAM-DTX dosing followed a standard 3+3 dose-escalation (0.75, 1.5, 2.5, or 3.75 mg/ml). After the dose escalation phase, an additional 6 subjects received the direct injection dose most suitable for the expansion phase.
Within 2 hours of LSAM-DTX injection, subjects received intravesical (25 ml) LSAM-DTX for up to 30 minutes. After ≥4 weeks subjects began a 6-week intravesical induction course followed by 6 weeks of rest and 3 weeks maintenance. Intravesical therapy occurred weekly during induction and maintenance for up to 120 minutes. Intravesical LSAM-DTX 50 mg was administered at 2.0 mg/ml at the initial intravesical instillation and during the first 3 weeks of induction during dose-escalation. If tolerated, subject’s treatments were escalated individually to 3.0 mg/ml (75 mg). Following confirmation of safety, all future subjects received 75 mg (3.0 mg/ml).
Dose escalations (3+3 direct injection, individual and cohort intravesical therapy) were reviewed and approved by an independent Data Safety Management Board.
Safety and Preliminary Efficacy
Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities version 22.0 terminology and assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Subjects were evaluated for tumor recurrence or disease progression by cystoscopy and cytology prior to induction initiation, at 12 and 24 weeks post-induction initiation, and when indicated. Biopsy via cystoscopy was at the discretion of the Investigator. Chart review of data up to 12 months post-initiation of LSAM-DTX was conducted to confirm 6-month complete response (CR). GraphPad Prism 9.3.0 (GraphPad Software, LLC, San Diego, California) was used to determine recurrence-free survival (RFS) via Kaplan-Meier analysis with log-rank (Mantel-Cox) test for curve comparisons; hazard ratios were determined using the Mantel-Haenszel test.
Pharmacokinetics
Blood was collected prior to direct injection and at 1, 2, 6, and 24 hours after, at 2 weeks following injection; at the first week of induction prior to intravesical therapy and 1, 2, 6, and 24 hours after; and prior to instillation during induction and maintenance. A validated method for the determination of docetaxel in human plasma by high-performance liquid chromatography-mass spectrometry (lower limit of quantification 10 ng/ml) was used.
Multiplex Immunofluorescence
Multiplex immunofluorescence was performed when pre-treatment and post-treatment bladder tumor resections or biopsies were collected. Hematoxylin and eosin-stained slides were reviewed by a pathologist blinded for treatment to determine if sufficient non‐necrotic tumor microenvironment was present for multiplex immunofluorescence analysis. MultiOmyxTM (NeoGenomics Laboratories, Fort Myers, Florida) technology was utilized to evaluate a panel of 17-biomarkers on formalin-fixed paraffin-embedded bladder tumor samples. Staining occurred on a single 4 µM formalin-fixed paraffin-embedded slide as previously described.8 GraphPad Prism 9.3.0 was used for calculation of descriptive statistics and graphical presentations of multiplex immunofluorescence data.
RESULTS
Between 2019 and 2020, 19 subjects with high-risk NMIBC were enrolled. The median age was 72 years, 74% were male, and 95% identified as White. Median time from NMIBC diagnosis to day 1 treatment was 17.0 months (range 0.7–107.0). Fourteen subjects (74%) had prior BCG exposure and 16 (84%) had undergone ≥1 prior TURBT (median prior TURBT procedures 2, 7, 4, 3, and 1 for cohorts 1, 2, 3, 4, and expansion, respectively; Table 1). Screening tumor stages were all high grade and included 7 (37%) Ta, 8 (42%) Tis, and 4 (21%) T1.
| Characteristic | |
| No. pts | 19 |
| Median yrs age (range) | 72 (56–82) |
| No. male (%) | 14 (74) |
| No. race (%): | |
| Black/African American | 1 (5) |
| Caucasian | 18 (95) |
| Time from diagnosis to day 1 (mos): | |
| Median (mean) | 17.0 (23.9) |
| Range | 0.7–107 |
| No. tumor stage at screening (%): | |
| High-grade Ta | 7 (37) |
| High-grade Tis | 8 (42) |
| High-grade T1 | 4 (21) |
| No. prior BCG use (%): | |
| Dose-escalation cohorts | 10/13 (77) |
| Expansion cohort | 4/6 (67) |
| No. prior TURBTs (%): | |
| 0 | 3 (16) |
| 1–2 | 8 (42) |
| 3–4 | 4 (21) |
| 6 | 2 (11) |
| 7–8 | 2 (11) |
Four concentrations of LSAM-DTX (dose 3 to 15 mg) were administered as direct injection (Table 2). The total amount of intravesical LSAM-DTX administered in the dose escalation and expansion cohorts was 50 to 90 mg and 50 to 75 mg, respectively. The number of intravesical cycles ranged from 7 to 10 (Table 2), and volume delivered ranged from 25 to 30 ml.
| Cohort | No. Pts | Direct Injection LSAM-DTX | Intravesical LSAM-DTX | ||||
| Concentration (mg/ml) | Mean Total mg Administered
|
Concentration Induction, Maintenance (mg/ml) | Mean No. Administrations (range) | Mean Total mg Administered
|
|||
| 1 | 4 | 0.75 | 3.00 | 2.00, 3.00 | 10 | 645 (630–650) | |
| 2 | 3 | 1.50 | 4.50 (3.75–6.00) | 2.00, 3.00 | 9 (7–10) | 625 (510–714) | |
| 3 | 3 | 2.50 | 7.92 (6.25–10.00) | 2.00, 3.00 | 9 (7–10) | 575 (425–650) | |
| 4 | 3 | 3.75 | 15.00 | 2.00, 3.00 | 9 (8–10) | 600 (500–650) | |
| Expansion | 6 | 3.75 | 14.06 (9.38–15.00) | 3.00,* 3.00 | 10 | 746 (725–750) | |
Direct injection and intravesical LSAM-DTX were well tolerated with no drug-related systemic or local serious AEs. Thirty-one local treatment emergent AEs were assessed as grade 1 or 2, and no grade 3 or higher events were reported. Of these, 1 event was probably related (hematuria) and 30 events were possibly related, including most frequently hematuria (7), dysuria (5), and urinary tract infections (4). Systemic treatment emergent AEs were minimal, with 5 reports from a single subject of possibly related grade 1 treatment emergent AEs, which included diarrhea (1), fatigue (1), and elevated liver enzymes (3; Table 3). Pharmacokinetic analysis demonstrated negligible systemic concentrations with docetaxel below the lower limit of quantification in all plasma samples.
| No. Events | |
| No. serious AEs: | |
| Grade 1—local, not related (kidney stone) | 1 |
| Systemic | 0 |
| No. treatment-emergent AEs: | |
| Grade 1—local, possibly related: | 19 |
| Bladder pain | 1 |
| Dysuria | 5 |
| Hematuria | 6* |
| Pain, tip of penis | 1 |
| Pos urine culture† | 1 |
| Urinary frequency | 1 |
| Urinary retention‡ | 2 |
| Urinary urgency | 1 |
| Urinary hesitancy | 1 |
| Grade 2—local, possibly related: | 11 |
| Abnormal urinalysis | 1 |
| Bladder spasms | 1 |
| Decreased urinary stream | 1 |
| Hematuria | 1 |
| Pos urine culture† | 1 |
| Urinary frequency | 1 |
| Urinary retention‡ | 1 |
| Urinary tract infection | 4§ |
| Grade 1—local, probably related (hematuria) | 1 |
| Grade 1—systemic, possibly related: | 5 |
| Abnormal elevated ALT | 1 |
| Abnormal elevated AST | 1 |
| Diarrhea | 1 |
| Elevated total bilirubin | 1 |
| Worsening fatigue | 1 |
| No. local and systemic treatment-emergent AEs, unlikely or not related | 132 |
Median followup time for the 3 lowest dose cohorts was 8.6 months (range 3.5 to 13.8). During this time, 9/10 (90%) subjects developed recurrence at a median of 5.4 months, and estimated RFS at 3 and 6 months was 90% and 40%, respectively. Median followup time for the high-dose and expansion cohorts was 12.4 months (range 9.2 to 14.1). During this time, 5/9 (56%) subjects developed recurrence at a median of 12.2 months, and estimated RFS at 3, 6, and 12 months was 100%, 78%, and 50%, respectively (Fig. 1). On univariate analysis, administration of LSAM-DTX in the high-dose escalation and expansion cohorts was associated with significantly increased RFS compared to lower doses (hazard ratio 0.29, p <0.05).
![Figure 1.RFS as a proportion of subjects in the escalation cohorts 1–3 (10 patients; dotted line) vs the high-dose and expansion cohorts (solid line). Median RFS in the low-dose escalation cohorts was 5.4 months vs 12.2 months in the high-dose and expansion cohorts. Significance (*p <0.05) was determined using log-rank Mantel-Cox test (HR [Mantel-Haenszel] 0.29, 95% CI 0.09–0.88).](/cms/asset/0bc48abd-0751-4e43-9f51-560fbf93ba67/ju.0000000000002778f1.gif)
Figure 1. RFS as a proportion of subjects in the escalation cohorts 1–3 (10 patients; dotted line) vs the high-dose and expansion cohorts (solid line). Median RFS in the low-dose escalation cohorts was 5.4 months vs 12.2 months in the high-dose and expansion cohorts. Significance (*p <0.05) was determined using log-rank Mantel-Cox test (HR [Mantel-Haenszel] 0.29, 95% CI 0.09–0.88).
Following completion of LSAM-DTX administration, 26% of subjects went on to subsequent bladder sparing therapies without grade 3-4 toxicities and 1 subject in cohort 2 underwent cystectomy at 10.2 months.
Nine subjects had resection or biopsy samples collected pre- and post-LSAM-DTX therapy, and 6 sets of tissues were acceptable for multiplex immunofluorescence analysis with 1 set subsequently disqualified due to tissue loss. Of the 5 subjects who had tissue analyzed, 4 were BCG-naïve with a median of 2 TURBT procedures prior to study (range 0 to 3). There were no other treatments, including BCG or additional TURBTs, performed between collection of pre- and post-LSAM-DTX tissue. In the 5 subjects with tissue evaluated with multiplex immunofluorescence, 2 subjects developed recurrence by 6 months, 1 subject was recurrence-free at 6 months and was not further evaluated, and 2 subjects were recurrence-free at 12 months.
Although disease state was heterogeneous in the 5 subjects evaluated with multiplex immunofluorescence, data trends were observed in the densities of immune cells. Increases in CD4+ T cells, memory CD45RO+ T cells, and PD-1+ CD4+T cells were found in the tumor microenvironment following LSAM-DTX treatment (4/5 subjects increased for all co-expressions). CD8+, CD45RO+ memory, and PD-1+ CD8+ T cell effects were less pervasive but did show, on average, increases in density following LSAM-DTX therapy. Increases in Treg concentrations including PD-L1+ and CTLA-4+ were found after LSAM-DTX treatment. Macrophages, including PD-L1+, and large infiltrations of NK cells were found in the tumor microenvironment of 3/5 subjects treated with LSAM-DTX. Changes in myeloid cells and MDSC were variable across the different CD11b+ populations and an increased density in PD-L1+ pan-cytokeratin (PanCK)+ cells was also detected.
Multiplex immunofluorescence data were available from 2 BCG-naïve subjects with no prior TURBTs in the expansion cohort who had CR at 12 months. Although these results are limited due to sample availability, they demonstrated favorable antitumor immune cell changes (Fig. 2).
Figure 2. Multiplex immunofluorescence data from bladder biopsies collected pre- and post-LSAM-DTX therapy in the only 2 BCG-naïve high-risk NMIBC subjects who had no TURBT procedures prior to day 1. Both subjects had CR at 12 months and showed increases in post-LSAM-DTX density of adaptive and innate immune cells including increases in the immune checkpoint inhibitor targets PD-1 (increased on CD4+ helper T, CD8+ cytotoxic T), PD-L1 (increased on Treg, macrophages, and PanCK+ cells) and CTLA-4 (increased on Treg) compared to pre-LSAM-DTX (collected at TURBT). Cell types are identified using marker (CD11b, CD14, CD15, CD3, CD4, CD8, CD20, CD33, CD45RO, CD56, CD68, HLA-DR, FOXP3, CTLA4, PD-1, PD-L1, and PanCK) co-expression over regions of interest within the tumor microenvironment per slide. Region of interest was selected by a pathologist blinded to treatment status on a hematoxylin and eosin-stained slide. Cell type density is the total number of cells counted divided by the total area (sum of all region of interest areas) per slide. A, widespread increases in adaptive immune cells, including increased density of effector T cells as well as increases in PD-L1+PanCK+ cells in biopsy collected after LSAM-DTX treatment completion (end of study at 5.3 months post-TURBT) compared to pre-treatment biopsy is seen in the first subject. B, changes in innate immunity in the first subject include increased density of myeloid angiogenic cells and myeloid cells within the tumor microenvironment in biopsy collected at end of study. C, following LSAM-DTX treatment, a second subject demonstrates increase in components of adaptive immunity within the tumor microenvironment in biopsy collected 4.0 months post-TURBT; specifically increases in CD4+ T cells (including memory and PD-1+) and Treg cells (including PD-L1+ and CTLA-4+). D, changes in innate immunity in tumor microenvironment of a second subject following LSAM-DTX therapy include increases in density of myeloid angiogenic cells, myeloid cells (including CD33+), MDSC, G-MDSC and tumor-associated neutrophils.
DISCUSSION
Local treatment of solid tumors has the potential to overcome the limitations of intravenous chemotherapy9,10 by increasing tumor dwell time and reducing systemic toxicities. Sharma et al reported that locally advanced pancreatic cancer patients demonstrated regression or lack of disease progression following intratumoral treatment with similar large surface area microparticle paclitaxel (LSAM-PTX),11 and Verco et al reported that local administration of LSAM-PTX exposed primary tumors to therapeutic levels of chemotherapeutic for several weeks.5 Clinical trials of local LSAM-PTX in a variety of primary carcinomas12,13 are completed or ongoing (ClinicalTrials.gov identifiers: NCT00666991, NCT03029585, NCT03077659, NCT03077685, and NCT04314895).
For high-risk BCG-naïve subjects treated with TURBT plus BCG induction and maintenance, the estimated RFS is 90% at 3 months, 80% at 6 months, and 75% at 12 months.14 A recent retrospective analysis found that high-risk BCG-naïve NMIBC (including carcinoma in situ, T1, and micropapillary disease) treated with TURBT and intravesical gemcitabine/docetaxel resulted in RFS rates of 89%, 85%, and 82% at 6, 12, and 24 months, respectively.15 In the study reported here, of the 9 subjects who received the high doses of LSAM-DTX, 9 (100%), 7 (78%), and 4 (50%) remained recurrence-free at 3, 6, and 12 months, respectively, with 1 subject declining 12-month followup.
Bladder biopsies from subjects in this study show an increase in tumor microenvironment immunogenicity, including increases in adaptive (T cells) and innate (NK cells) effector cells. Notably, immune checkpoint receptor expression was increased across all cell types evaluated, including T cells, macrophages and PanCK+ cells, suggesting LSAM-DTX in combination with immune checkpoint inhibitor therapy may provide additional benefit in treatment of high-risk NMIBC. Compared to the 3 subjects with recurrence, the antitumor immunophenotypes were more pronounced in the 2 subjects with RFS at 12 months, suggesting an association between a more immunogenic tumor microenvironment and a positive clinical outcome (Fig. 2). Both subjects were BCG-naïve and had not undergone TURBT procedures prior to study entry, suggesting that the changes in the tumor microenvironment were directly related to study treatments. As not all subjects in the study had pre- and post-LSAM-DTX treatment biopsy or resection samples available, the current immune analysis is limited.
Tumor cell necrosis in response to chemotherapy may provide immunological stimulation that is both proinflammatory and immunogenic.16 Docetaxel has been shown to favorably mediate the anticancer response of macrophages, CD8+ T cells, B cells, and NK cells. The prolonged residence of docetaxel within the tumor microenvironment following intratumoral LSAM-DTX may facilitate tumor cell death via necroptosis, concentrating tumor antigens while eliminating immunosuppressive tumor cells.7 Increases in immune cell density following LSAM-DTX supports the hypothesis that local LSAM-DTX administration initiates both tumor cell death via direct cytotoxic effects and indirect stimulation of effector immune cells.5,17 Efficacy of immune checkpoint inhibitors may be improved by prior administration of a neoadjuvant local chemotherapy that would enhance the availability and antigenicity of tumor cells and fragments thereby increasing tumor recognition and eradication by immune effector cell.18–21
Thirty-three percent (2/6) of the subjects who received the highest dose of LSAM-DTX were BCG-naïve; investigations in BCG-exposed populations to confirm if efficacy is extended to this population are needed. Although 14/19 subjects in this study were BCG-exposed, the type of BCG failure was not defined. Other limitations of this study, including small sample size, heterogeneous tumor stage, wide range of number of prior TURBT procedures, limited immune analysis, short maintenance period, and the short study followup period, suggest studies with more homogeneous populations and longer followup are warranted. Lack of safety concerns and negligible systemic docetaxel levels are encouraging, and suggest additional administrations and/or increased dose of LSAM-DTX may provide further benefit. Local LSAM-DTX treatment has the potential to overcome the limitations of conventional intravenous chemotherapy, which include systemic exposure and rapid clearance resulting in short tumor-dwell time, immune suppression, and systemic toxicities.
CONCLUSIONS
Preliminary efficacy data suggest post-TURBT direct injection and intravesical therapy of high dose LSAM-DTX may provide therapeutic benefits to patients with high-risk NMIBC. Direct injection and intravesical LSAM-DTX were well-tolerated with few drug-related treatment-emergent AEs or serious AEs and negligible systemic docetaxel exposure. The data show favorable immune cell infiltration and suggest potential for enhanced sensitivity to checkpoint inhibitors. These preliminary findings support larger trials with longer term followup to determine if LSAM-DTX treatment is better suited as a stand-alone treatment or may provide benefit as a neoadjuvant with follow-on immune checkpoint inhibitor therapy.
ACKNOWLEDGMENTS
NanoPac® and NanoDoce® are registered trademarks of NanOlogy, LLC. The Authors thank Rose Marie Cavanna-Mast and Helen Thomas for assistance in study administration, Dr. Max Wattenberg for assistance with multiplex immunofluorescence data analysis, and Ashley Tornio, Dr. Ashish M. Kamat, and Dr. James M. McKiernan for their input in the study design.
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Submitted January 27, 2022; accepted May 5, 2022; published May 16, 2022.
Support: This work was supported by NanOlogy, LLC.
Conflict of Interest: Max Kates: NanOlogy, Janssen, Pacific Edge.
Ethics Statement: Study received Institutional Review Board approval (HonorHealth IRB: 1374606-1; Johns Hopkins IRB: IRB00198864; WIRB: 1256662; UTHSA IRB: HSC20190312H; Columbia University IRB: IRB-AAAS3837).
