Supplemental Figure 3. Best percentage change from baseline in sum of target lesions is presented for the ALK-positive evaluable patients at 200 mg who had received prior crizotinib and as second-generation ALK TKI. Dashed lines indicate RECIST v1.1 cut-offs for partial response and progressive disease. Of the 16 patients, four had partial responses and four had stable disease. The color scheme represents which second-generation ALK TKI that patient received after crizotinib. Of note, the primary lesion of one of the 16 patients was too small, and thus indeterminate, at the post-baseline assessment, therefore a change in tumor size is not available. This patient had received, in order, prior crizotinib, alectinib, and ceritinib, and developed progression on ensartinib in a non-target brain lesion prior to cycle 3. *Denotes those patients with progressive disease as the best response. >Denotes patients still on study at the time of data cutoff.

The mean concentration of ensartinib in plasma and skin at multiple time points after a single dose of 50 mg/kg is listed in Supplemental Table 2. At 12 hours post-dose, the concentration of ensartinib was 9.0 higher in the skin than in the plasma.

The key pharmacokinetic (PK) parameters (Supplemental Table 3) at the recommended phase 2 dose of 225 mg show that food has minimal impact on absorption of ensartinib.

Supplemental Figure 1. Representative example from one patient showing the rash that was most frequently observed with ensartinib. The white arrow in the top figure points to the rash that is circled in the bottom figure.

Ensartinib was tested against wild-type ALK and 17 ALK variants in the Reaction Biology panel. Ensartinib potently inhibited all evaluated ALK variants, with in vitro IC50s <4 nM.

Supplemental Figure 2. Arithmetic mean concentration-time curves for fasted patients receiving 225 mg of ensartinib on Days 1 and 22 of Cycle 1.

Abstract Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non–small cell lung cancer (NSCLC). Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible. Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%. Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771–9. ©2018 AACR.

Ensartinib is a novel, potent anaplastic lymphoma kinase (ALK) small molecule TKI with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. It has demonstrated anti-tumor activity in patients who have previously received a second generation ALK TKI.

Ensartinib (X-396) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. We report data on the ALK TKI-naïve and crizotinib (C)-resistant NSCLC pts treated with ensartinib. Clinical trial information: NCT01625234. In this multicenter expansion study, pts with ALK+ NSCLC were treated with ensartinib 225 mg daily on a 28-day schedule. Pts had measurable disease, ECOG PS 0-1, and adequate organ function. Untreated brain metastases (CNS) and leptomeningeal disease were allowed. Next Generation Sequencing (NGS) was performed on plasma samples collected at baseline and on study and compared with central tissue results (FISH/IHC). All pts were assessed for response to therapy using RECIST 1.1 and for adverse events (AEs) using CTCAE version 4.03. 80 pts (51% female) have been enrolled. Median age 54 (20-79) years, 64% ECOG PS 1. Of 40 ALK+ NSCLC pts evaluable for response; partial response (PR) was achieved in 23 pts (58%) and stable disease (SD) in 8 pts (20%). In the C-naïve pts (n = 8), PRs were observed in 7 pts (88%). In the 22 pts with prior C but no other ALK TKI, 14 pts (64%) achieved PR and 6 (27%) SD. In the 10 pts who had received two or more prior ALK TKIs, there was 2 PR, 2 SD (40% DCR). CNS responses (50% PR) have been observed in both C-naïve and C-resistant pts. Plasma and tissue genotyping were available on 27 pts (26 ALK+ and 1 ALK-). ALK was detected in plasma in 16 pts, all of whom had a response to therapy. 2 pts with PD were tissue +ve and plasma -ve. 9 plasma samples were unevaluable. Serial sequencing demonstrated a decrease in ALK in pts responding and an increase at the time of progression. The most common drug-related AEs (≥ 20% of pts) included rash (53%), nausea (32%), vomiting (26%), fatigue (23%), and pruritus (21%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs were rash (8 pts), fatigue (2 pts), pruritus (2 pts), edema (2 pts), decreased appetite (1 pt), nausea (1pt), and vomiting (1pt). Ensartinib is well-tolerated with response in both C-naïve and C-resistant ALK+ NSCLC pts, as well as pts with CNS disease. Plasma sequencing appears to be promising to select pts for therapy and monitor for response and development of acquired resistance.

Ensartinib (X-396) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. We report data on the ALK TKI-naïve and crizotinib (C)-resistant NSCLC pts treated with ensartinib. Clinical trial information: NCT01625234 In this multicenter expansion study, pts with ALK+ NSCLC were treated with ensartinib 225 mg daily on a 28-day schedule. Pts had measurable disease, ECOG PS 0-1, and adequate organ function. Untreated brain metastases (CNS) and leptomeningeal disease were allowed. Next Generation Sequencing (NGS) was performed on plasma samples collected at baseline and on study and compared with central tissue results (FISH/IHC). All pts were assessed for response to therapy using RECIST 1.1 and for adverse events (AEs) using CTCAE version 4.03. 83 pts (51% female) have been enrolled. Median age 54 (20-79) years, 64% ECOG PS 1. Of 42 ALK+ NSCLC pts evaluable for response; partial response (PR) was achieved in 25 pts (60%) and stable disease (SD) in 6 pts (14%). In the C-naïve pts (n = 9), PRs were observed in 7 pts (77%). In the 22 pts with prior C but no other ALK TKI, 16 pts (73%) achieved PR and 4 (18%) SD. In the 10 pts who had received two or more prior ALK TKIs, there were 2 PR, 2 SD (40% DCR). CNS responses (53% PR) have been observed in both C-naïve and C-resistant pts. Plasma and tissue genotyping were available on 27 pts (26 ALK+ and 1 ALK-). ALK was detected in plasma in 16 pts, all of whom had a response to therapy. 2 pts with PD were tissue +ve and plasma -ve. 9 plasma samples were unevaluable. Serial sequencing demonstrated a decrease in ALK in pts responding and an increase at the time of progression. The most common drug-related AEs (≥ 20% of pts) included rash (53%), nausea (33%), vomiting (27%), fatigue (22%), and pruritus (23%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs in ≥2 pts were rash (9 pts), pruritus (3 pts), and fatigue (2 pts). Ensartinib is generally well-tolerated and induces response in both C-naïve and C-resistant ALK+ NSCLC pts, as well as pts with CNS disease. Plasma sequencing appears to be promising to select pts for therapy and monitor for response and development of resistance.

9056 Background: X-396 is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. We report data on ALK TKI-naive and crizotinib (C)-resistant NSCLC pts treated with X-396. Methods: In this multicenter expansion study, pts with ALK+ NSCLC were treated with X-396 225 mg daily on a 28-day schedule. Pts had measurable disease, ECOG PS 0-1, untreated brain metastases (CNS) and leptomeningeal disease were allowed. NGS on plasma samples was performed at baseline and on study and compared with central tissue results (FISH/IHC). All pts were assessed for response to therapy using RECIST 1.1, adverse events (AEs) using CTCAE version 4.03 were recorded. Results: 60 pts (53% female) have been enrolled. Median age 56 (20-79) years, 67% ECOG PS 1. Of 30 ALK+ NSCLC pts evaluable for response; partial response (PR) was achieved in 19 pts (60%) and stable disease (SD) in 2 pts (7%). In the C-naïve pts (n = 8), PRs were observed in 7 pts (88%). In the 12 pts with prior C but no other ALK TKI, 10 pts (83%) achieved PR and 1 (8%) SD. Median duration of response was 24 - 128 wks. In the 8 pts who had received two or more prior ALK TKIs, there was 1 PR, 3 SD (50% DCR) with response duration of 8-32 wks. CNS responses have been observed in both C naïve and C resistant pts. Plasma and tissue genotyping are available on 27 pts (26 ALK + and 1 ALK -) ALK was detected in plasma in 16 pts all had a response to therapy, two pts were tissue +ve and -ve on plasma testing and had PD, 9 plasma samples were inevaluable. Serial sequencing demonstrated a decrease in ALK in pts responding and an increase at the time of progression. The most common drug-related AEs ( ≥ 20% of pt s) included rash (48%), nausea (26%), vomiting (23%), and fatigue (21%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs were rash (8 pts), fatigue (1 pt), decreased appetite (1 pt), pruritus (1 pt), and face edema (1 pt). Conclusions: X-396 is well-tolerated and induces response in both C-naive and C-resistant ALK+ NSCLC pts, as well as pts with CNS disease. Plasma sequencing may be used to select pts for therapy and monitor for response and development of acquired resistance. Clinical trial information: NCT01625234.

X-396 is a novel, potent ALK small molecule TKI with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. We report on data from pts that includes detection/monitoring of ALK fusions by plasma next-generation sequencing (NGS). Pts with advanced solid tumors and ECOG PS 0-1 were tx'd with X-396 225 mg qd on a continuous 28-day schedule. In expansion phase, required to have measurable ALK+ NSCLC. Asymptomatic brain metastases allowed. Tissue confirmed centrally via FISH or IHC. Targeted NGS of cfDNA was performed retrospectively at baseline and on study and compared with tissue results. As of April 15, 71 pts (35 men, 36 women) enrolled. Median age 54 (20-79) yrs, 66% had ECOG PS 1. 37 ALK+ NSCLC pts tx'd at doses ≥ 200 mg evaluable for response; partial response (PR) achieved in 21 pts (76%), stable disease (SD) in 8 (22%). In crizotinib-naïve pts (n = 8), responses in 7 (88%). In 20 pts with prior crizotinib but no other ALK TKI, 12 (60%) had PR, 7 (35%) SD. Tissue via FISH (F) and Plasma genotyping (P) available on 42 pts: RR for 25 F + P+ pts 52%, 6 F-P- pts 0%, 11 F + P- pts 55%. Concordance between F and P was 74%. Tissue via NGS (N) and P genotyping available on 13 pts with 27 mutations and fusions identified; RR for 18 T + P+ pts 78%, 4 T-P+ pts 100%, 5 T + P- pts 75%. 2 samples were T-P-. Concordance between N and P was 74%. Responses were seen in pts with L1196M, G1296M, G1202R, and T1151M resistant mutations. Serial sequencing demonstrated decrease in ALK in responding pts and increase at time of progression. CNS responses observed in crizotinib naïve and resistant pts. Median duration of tx in the 37 evaluable ALK+ pts is 23.6 wks, longest being 139+ wks. Most common drug-related AEs (>20% of pts) included rash (48%), nausea (28%), fatigue (25%), vomiting (23%). Most AEs were Grade (G) 1-2. Most common G3 tx-related AE was rash (8 pts). No G3 related GI AEs or liver enzyme elevations reported. X-396 is well-tolerated and induces responses in crizotinib-naïve & resistant ALK+ NSCLC pts, and pts with CNS lesions. Plasma sequencing may be used to select pts for tx and monitor for response and development of acquired resistance. Enrollment ongoing.

X-396 is a novel, potent anaplastic kinase lymphoma (ALK) small tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1, SLK. It has demonstrated significant anti-tumor activity in both ALK TKI-naive and crizotinib-resistant models of ALK fusion-positive NSCLC. In this multicenter phase I/II study, patient (pts) with advanced solid tumors enrolled in the phase I dose escalation portion of the study and given X-396 on a continuous 28-day schedule (NCT01625234). Doses from 25 up to 250 mg once daily were evaluated and 225 mg was selected for further evaluation in the phase II expansion. Patients in this phase were required to have ALK + NSCLC and measurable disease. Cohorts included pts who were 1) ALK-TKI naive, 2) Pts who progressed on prior crizotinib and had not received a second generation ALK TKI, 3) Pts who progressed on a second generation ALK TKI (may also have received crizotinib), 4) Pts with central nervous system (CNS) metastases, 5) Pts with leptomeningeal disease. All pts were assessed for adverse events (AEs) using CTCAE version 4.03, response to therapy was assessed using RECIST 1.1. As of December 09, 2015 data cutoff, 57 pts (31 men, 26 women) have been enrolled. Median age is 56 (20-79) years, the majority of pts had ECOG performance status 1 (67%). The most common drug-related AEs included rash (49%), nausea (28%), vomiting (25%), and fatigue (23%). Most AEs were grade (G) 1-2. The G3 treatment-related AEs were rash (7 pts), fatigue (1 pt), decreased appetite (1 pt), dehydration (1 pt), pruritus (1 pt), and face edema (1 pt). In particular, no G3 treatment-related gastrointestinal toxicity or liver enzyme elevation has been reported. To date 27 ALK+ NSCLC pts treated at doses 200 mg or greater are evaluable for response; partial response (PR) was achieved in 19 pts (70%) and stable disease (SD) in 2 pts (7%). In the crizotinib-naive pts (n=8), responses were observed in 7 pts (88%). In the 12 pts with prior crizotinib, but no other ALK TKIs, 10 pts (83%) achieved PR and 1 (8%) SD. CNS responses have been observed in both crizotinib-naive and crizotinib resistant pts. The median duration of treatment in the 27 evaluable ALK+ pts is 16+ weeks, with the longest being 128+ weeks. X-396 is well tolerated and induces responses in both crizotinib-naive and crizotinib-resistant ALK+ NSCLC pts, as well as patients with CNS lesions. Enrollment is ongoing in the expansion cohorts.

X-396 is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. It has demonstrated significant anti-tumor activity in both ALK TKI-naive and crizotinib-resistant models of ALK fusion-positive NSCLC. In this multicenter phase I/II study, patients (pts) with advanced solid tumors were enrolled in the phase I dose escalation portion of the study and given X-396 on a continuous 28-day schedule (NCT01625234). Doses from 25 up to 250 mg once daily were evaluated and 225 mg was selected for further evaluation in the phase II expansion. Patients in this phase were required to have ALK+ NSCLC and measurable disease. Cohorts included pts who were 1) ALK TKI-naïve, 2) pts who progressed on prior crizotinib and had not received a 2nd generation ALK TKI, 3) pts who progressed on a 2nd generation ALK TKI (may also have received crizotinib), 4) pts with central nervous system (CNS) metastases, and 5) pts with leptomeningeal disease. All pts were assessed for adverse events (AEs) using CTCAE version 4.03, response to therapy was assessed using RECIST 1.1. As of the October 15, 2015 data cutoff, 53 pts (29 men, 24 women) have been enrolled. Median age is 56 (20-79) years, the majority of patients had ECOG performance status 1 (68%). The most common drug-related AEs included rash (47%), nausea (28%), vomiting (25%), and fatigue (23%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs were rash (6 pts), fatigue (1 pt), decreased appetite (1 pt), dehydration (1 pt), pruritus (1 pt), and face edema (1 pt). In particular, no G3 treatment-related gastrointestinal toxicity or liver enzyme elevation has been reported. To date, 24 ALK+ NSCLC pts treated at doses ≥ 200 mg are evaluable for response; partial response (PR) was achieved in 16 pts (67%) and stable disease (SD) in 3 pts (13%). In the crizotinib-naïve pts (n=8), responses were observed in 6 pts (75%) and SD in 1 pt (13%). In the 12 pts with prior crizotinib but no other ALK TKI, 10 pts (83%) achieved PR and 1 (8%) SD. CNS responses have been observed in both crizotinib naïve and crizotinib resistant pts. The median duration of treatment in the 24 evaluable ALK+ pts is 23.8+ weeks, with the longest being 112+ weeks. X-396 is well-tolerated and induces responses in both crizotinib-naïve and crizotinib-resistant ALK+ NSCLC pts, as well as patients with CNS lesions. Enrollment is ongoing in the expansion cohorts.

Abstract Background: X-396 is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. It has demonstrated significant anti-tumor activity in both ALK TKI-naive and crizotinib-resistant models of ALK fusion-positive NSCLC. Methods: In this multicenter phase I/II study, patients (pts) with advanced solid tumors were enrolled in the phase I dose escalation portion of the study and given X-396 on a continuous 28-day schedule (NCT01625234). Doses from 25 up to 250 mg once daily were evaluated and 225mg was selected for further evaluation in the phase II expansion. Patients in this phase were required to have ALK+ NSCLC and measurable disease. Cohorts included pts who were 1) ALK TKI-naïve, 2) pts who progressed on prior crizotinib and had not received a 2nd generation ALK TKI, 3) pts who progressed on a 2nd generation ALK TKI (may also have received crizotinib), 4) pts with untreated or recurrent central nervous system (CNS) metastases, and 5) pts with leptomeningeal disease. All pts were assessed for adverse events (AEs) using CTCAE version 4.03, response to therapy was assessed using RECIST 1.1. Results: As of the December 09, 2015 data cutoff, 57 pts (31 men, 26 women) have been enrolled. Median age is 56 (20-79) years, the majority of patients had ECOG performance status 1 (67%). The most common drug-related AEs included rash (49%), nausea (28%), vomiting (25%), and fatigue (23%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs were rash (7 pts), fatigue (1 pt), decreased appetite (1 pt), dehydration (1 pt), pruritus (1 pt), and face edema (1 pt). In particular, no G3 treatment-related gastrointestinal toxicity or liver enzyme elevation has been reported. To date, 27 ALK+ NSCLC pts treated at doses ? 200 mg are evaluable for response; partial response (PR) was achieved in 19 pts (70%) and stable disease (SD) in 2 pts (7%). In the crizotinib-naïve pts (n = 8), responses were observed in 7 pts (88%). In the 12 pts with prior crizotinib but no other ALK TKI, 10 pts (83%) achieved PR and 1 (8%) SD. CNS responses have been observed in both crizotinib naïve and crizotinib resistant pts. The median duration of treatment in the 27 evaluable ALK+ pts is 16+ weeks, with the longest being 128+ weeks. Conclusion: X-396 is well-tolerated and induces responses in both crizotinib-naïve and crizotinib-resistant ALK+ NSCLC pts, as well as patients with CNS lesions. Enrollment is ongoing in the expansion cohorts. Citation Format: Christine M. Lovly, Jeffrey R. Infante, George R. Blumenschein, Karen Reckamp, Heather Wakelee, Corey A. Carter, Saiama N. Waqar, Joel Neal, Jon P. Gockerman, Gary Dukart, Kimberly Harrow, Chris Liang, James J. Gibbons, Leora Horn. Phase I/II trial of X-396, a novel anaplastic lymphoma kinase (ALK) inhibitor, in patients with ALK+ non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT088.

Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5(+) CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV(H) mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice.

Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and ‘CLL-like’ MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5+CD20dimsIgdim), 11 atypical MBL (CD5+CD20+sIg+) and 7 CD5neg MBL (CD5negCD20+sIgneg). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.

The continuing organ shortage requires evaluation of all potential donors, including those with malignant disease. In the United States, no organized approach to assessment of risk of donor tumor transmission exists, and organs from such donors are often discarded. The ad hoc Disease Transmission Advisory Committee (DTAC) of the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) formed an ad hoc Malignancy Subcommittee to advise on this subject. The Subcommittee reviewed the largely anecdotal literature and held discussions to generate a framework to approach risk evaluation in this circumstance. Six levels of risk developed by consensus. Suggested approach to donor utilization is given for each category, recognizing the primacy of individual clinical judgment and often emergent clinical circumstances. Categories are populated with specific tumors based on available data, including active or historical cancer. Benign tumors are considered in relation to risk of malignant transformation. Specific attention is paid to potential use of kidneys harboring small solitary renal cell carcinomas, and to patients with central nervous system tumors. This resource document is tailored to clinical practice in the United States and should aid clinical decision making in the difficult circumstance of an organ donor with potential or proven neoplasia.