Bryce, Alan H.

5577 Background: Prostate specific antigen (PSA) has well-recognized limitations as a marker for treatment response and disease progression. A post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve mCRPC patients on enzalutamide had radiographic progression on conventional imaging with non-rising PSA. In this study, we sought to retrospectively compare PSA levels with C-11 choline positron emission tomography/ computed tomography (PET/CT) images in patients with m-CRPC on 2nd-HT with prior use of chemotherapy. Methods: We identified 123 patients with mCRPC on 2nd-HT following prior use of docetaxel chemotherapy (Abiraterone, n = 106; Enzalutamide, n = 17). Patients underwent serial PSA testing and C-11 choline PET/ CTs every 3–6 months. Disease progression was defined by the increase in blood pool corrected maximum standardized uptake value (SUVmax) of the index lesion on C-11 choline PET/CT scan. Suspicious lesions were confirmed by biopsy and/or conventional imaging. Results: Approximately 43% (n = 53) of patients had radiographic disease progression while on 2nd-HT. At time of radiographic progression, 60.4% of patients showed a parallel rise in PSA (Group-A), while 39.6% showed a paradoxical response; defined as radiographic progression with stable or down-trending PSA (Group-B). Median PSA at time of progression was 3.1 ng/ml for Group-A, and 1.3 ng/ml for Group-B (p-value = 0.0176). Median SUVmax was the same (4.9 Group-A, 4.6 Group-B; p-value = 0.6072). Bone-predominance progression was more significant in Group-B (90%) versus Group-A (65%) (p-value = 0.0309). The median time for radiographic progression was 9.5 months versus 3.9 months for Group-A and Group-B, respectively (Log-Rank = 0.0063). Conclusions: Metabolic imaging is a useful tool that should complement PSA in the evaluation of treatment response and disease progression in mCRPC patients on 2nd-HT, especially considering the paradoxical response observed in our data.

3552 Background: Delta-like 3 (DLL3) is highly and specifically expressed in solid tumors, such as neuroendocrine carcinomas (NECs), malignant melanoma (MM), and medullary thyroid carcinoma (MTC). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Methods: This Phase 1/2 study (NCT02709889) enrolled patients with relapsed/refractory DLL3+ (>1% by IHC) advanced solid tumors and ECOG performance status of 0-1. Rova-T was given IV at 0.2, 0.3, or 0.4 mg/kg on d 1 of each 6-wk cycle (q6wk) for dose escalation (3+3 design) in disease-specific cohorts in Phase I. The recommended Phase 2 dose (RP2D) was tested in Phase II. Safety and dose-limiting toxicities (DLTs) were primary endpoints; efficacy outcomes were secondary endpoints. Results: The study enrolled 200 patients; 101 had NECs (large cell NEC [n=13], neuroendocrine prostate cancer [n=21], high-grade gastroenteropancreatic NEC [n=36], other [n=31]) and 99 had other solid tumors (MM [n=20], MTC [n=13], glioblastoma [GBM; n=23], other [n=43]). The median age was 61 y (range, 28-84); 63% were male. The RP2D was 0.3 mg/kg q6wk for 2 cycles in all cohorts. There were 7 DLTs in 5 patients: 2 with 0.2 mg/kg (Grade [Gr] 3 photosensitivity reaction, Gr 3 dyspnea), 2 with 0.3 mg/kg (1 with Gr 2 effusion, Gr 3 tumor lysis syndrome, and Gr 3 rhabdomyolysis; 1 with Gr 4 kidney injury), and 1 with 0.4 mg/kg (Gr 4 thrombocytopenia). Despite only 1 DLT identified with 0.4 mg/kg, the totality of the safety data suggested that this dose is not well tolerated. Common adverse events (AEs) in patients given 0.3 mg/kg (n=145) are shown (Table). Serious AEs occurred in 77/145 patients (53%), most commonly (≥3%) malignant neoplasm progression (n=18; 12%), pleural effusion (n=7; 5%), pericardial effusion (n=6; 4%), and dyspnea (n=5; 3%). The objective response rate (ORR) was 11% (21/200): 14 had NEC, 2 had MM, 2 had MTC, 2 had small cell carcinoma (SCC) not of lung origin (all partial responses), and 1 had GBM (complete response). In patients with NECs given 0.3 mg/kg, ORR, clinical benefit rate, and progression-free survival trended in favor of those with high DLL3-expressing tumors (≥50% by IHC) which represented 51% of NECs. Conclusions: Rova-T was tolerable in patients with advanced solid tumors at 0.3 mg/kg q6wk for 2 cycles. Antitumor activity was observed in patients with NEC, MM, MTC, SCC, and GBM. Clinical trial information: NCT02709889 . [Table: see text]

2054 Background: Systematic reviews that summarize the toxicity of Immune checkpoint inhibitors (ICIs) become outdated very soon after publication. Therefore, we reported results of a toxicity meta-analysis at 2019 ASCO meeting and informed the intent to create a living systematic review (LSR). LSRs combine human and machine effort and support rapid evidence synthesis and living clinical practice guidelines. Now, we report our experience maintaining a LSR on toxicity of ICIs. Methods: Steps include quarterly literature searches to identify new clinical trials reporting ICI-associated adverse events (AEs), AI-enabled screening of new citations which meet the inclusion criteria, automated cumulative meta-analysis and an online reporting platform. Standard data formats and protocols were designed for inputting text, tables and graphics. Software was written to interpret these data and output the information in the appropriate format, such as a forest plot and summary tables. Finally, a dynamic interface that enables user inputs and displays the associated output was designed. Results: The LSR is continuously updated incorporating toxicity data from new clinical trials as it becomes available. We have screened 8000 relevant citations and summarized the odds of Grade 3 or higher AEs and AEs of special interest in patient receiving ICIs. The results are updated on quarterly basis and are available online. The results are updated on quarterly basis and will be available on a website at the time of publication. Prototype with dummy data is available at this link . This interface can also be manipulated via user input to organize and sort data tables and forest plots by type of cancer, name or mechanism (PD-1 or PD-L1) of ICI agent, single agent or combination, type of control arm, line of treatment and several other clinically relevant filters. For example, a user can instantaneously generate a meta-analysis summarizing the risk of colitis or pneumonitis in metastatic lung cancer trials with pembrolizmuab. Conclusions: This LSR engine can prospectively synthesize toxicity data from ICI trials in an efficient manner providing accurate and timely information for advanced clinical decision support at point-of-care. Efforts are ongoing to improve efficiency of screening, improve AI-enabled processes for automated screening and data abstraction, and test across multiple clinical questions.

PURPOSE In prostate cancer, inactivating CDK12 mutations lead to gene fusion–induced neoantigens and possibly sensitivity to immunotherapy. We aimed to clinically, pathologically, and molecularly characterize CDK12-aberrant prostate cancers. METHODS We conducted a retrospective multicenter study to identify patients with advanced prostate cancer who harbored somatic loss-of-function CDK12 mutations. We used descriptive statistics to characterize their clinical features and therapeutic outcomes (prostate-specific antigen [PSA] responses, progression-free survival [PFS]) to various systemic therapies, including sensitivity to poly (ADP-ribose) polymerase and PD-1 inhibitors. RESULTS Sixty men with at least monoallelic (51.7% biallelic) CDK12 alterations were identified across nine centers. Median age at diagnosis was 60.5 years; 71.7% and 28.3% were white and nonwhite, respectively; 93.3% had Gleason grade group 4-5; 15.4% had ductal/intraductal histology; 53.3% had metastases at diagnosis; and median PSA was 24.0 ng/mL. Of those who underwent primary androgen deprivation therapy for metastatic hormone-sensitive disease (n = 59), 79.7% had a PSA response, and median PFS was 12.3 months. Of those who received first-line abiraterone and enzalutamide for metastatic castration-resistant prostate cancer (mCRPC; n = 34), 41.2% had a PSA response, and median PFS was 5.3 months. Of those who received a first taxane chemotherapy for mCRPC (n = 22), 31.8% had a PSA response, and median PFS was 3.8 months. Eleven men received a PARP inhibitor (olaparib [n = 10], rucaparib [n = 1]), and none had a PSA response (median PFS, 3.6 months). Nine men received a PD-1 inhibitor as fourth- to sixth-line systemic therapy (pembrolizumab [n = 5], nivolumab [n = 4]); 33.3% had a PSA response, and median PFS was 5.4 months. CONCLUSION CDK12-altered prostate cancer is an aggressive subtype with poor outcomes to hormonal and taxane therapies as well as to PARP inhibitors. A proportion of these patients may respond favorably to PD-1 inhibitors, which implicates CDK12 deficiency in immunotherapy sensitivity.

Abstract Introduction: Type II Cryoglobulinemia (CG) is a heterogeneous disorder caused by a monoclonal antibody with activity against polyclonal antibodies. No standard therapy exists, but two small recent studies have suggested a role for rituximab. We describe our experience with 8 patients with Type II CG who were treated with Rituximab. Methods: The data was obtained from a prospectively held dysproteinemia database and by directly reviewing patient records. Follow up time ranged from 7 to 63 months. All patients had symptomatic disease with a monoclonal IgMκ Type II cryoglobulin and had undergone previous therapy for CG. Results: Six of the patients had an underlying lymphoproliferative disorder (LPD), with two of these also having hepatitis C, and two others having Sjogren syndrome. One patient had essential CG and one had Gaucher disease with hyperslpenism. A total of 14 courses of treatment were given, as some patients received rituximab on multiple occasions. Five patients received rituximab either alone or with low dose prednisone initially, with one of these later receiving rituximab with cyclophosphamide and prednisone. One patient was treated initially with R-CHOP and subsequently with rituximab alone, one received rituximab with chlorambucil and prednisone, and one received rituximab with plasma exchange and prednisone. The patients were treated for a variety of indications including cutaneous ulcers, progressive renal failure, the underlying LPD, and biochemical recurrence of disease. Six of 8 patients experienced an improvement in their clinical status. Of the two patients who did not improve, one had end stage liver disease at the time of rituximab and died 2 years later, and the other had a progressive chronic B cell lymphoproliferative disorder leading to sepsis and death. Though lab values were not available on one patient, 4 of the remaining 7 demonstrated improvement in cryocrit, total complement, C4, and/or rheumatoid factor. The lab values correlated well with the clinical response, as treatment failures showed no laboratory changes. Cutaneous manifestations including rash and ulceration were the most responsive to treatment. Renal disease generally failed to improve, and the response of LPDs were variable. No adverse events associated with rituximab were reported, including no flares of hepatitis. Conclusion: The high prevalence of LPD associated cryoglobulinemia distinguishes our results from the previous studies which had focused on patients with hepatitis C. Given the lack of any cryoglobulinemia specific therapy, and the potential toxicity of other immunosuppressive or anti viral therapies, rituximab remains a reasonable, safe, and effective therapeutic choice. Treatment Regimens and Responses Patient Comorbid Condition Symptom Regimen Response: Clinical/Lab LPD= lymphoproliferative disorder; HCV= Hepatitis C Virus; ESRD= End Stage Renal Disease; Y=Yes; N= No; U= Unknown 1 B Cell LPD Leg Ulcers Rituxan Prednisone Y/Y 1 Leg Ulcers Rituxan Prednisone Y/U 2 None Rash, Paresthesia Rituxan Prednisone Y/Y 2 Pupura Rituxan Prednisone Y/Y 2 Pupura Rituxan Prednisone Y/Y 2 Pupura Rituxan Prednisone Cytoxan Y/Y 3 HCV, low grade NHL Renal Failure Rituxan N/N 4 MALToma, Sjogren Disease MALToma R-CHOP Y/U 4 MALToma Rituxan N/U 5 Gaucher with hypersplenia Renal Failure Rituxan Y/Y 6 Lymphoplasmacytic Lymphoma, HCV, ESRD Lymphoma Rituxan Y/U 6 Lymphoma Rituxan N/N 7 B Cell LPD Renal Failure, ulcers, rash, LPD Rituxan chlorambucil prednisone N/N 8 MALToma Sjogren Disease Rash, Fatigue Rituxan Prednisone Y/Y

Abstract Background: Primary systemic amyloidosis is an uncommon plasma cell dyscrasia characterized by organ deposition of immunoglobulin light or heavy chain fragments. It is related to the other plasma cell dyscrasias such as multiple myeloma and monoclonal gammopathy of undetermined significance. cIg-FISH on bone marrow plasma cells has become well established in the initial evaluation of myeloma as the t(4;14), t(14;16),13q-, and the 17p- abnormality are of major prognostic value. The corresponding data does not exist in amyloidosis, as there are only three small studies published to date. Methods: Using a prospectively held dysproteinemia database, we reviewed all cases of amyloidosis seen at our institution who had cIg-FISH or cytogenetics performed as part of their routine clinical testing. Three hundred thirty nine patients were identified with amyloidosis and cytogenetic testing. Of these 69 had cIg-FISH testing results. cIg-FISH was performed with fluorescent-tagged antibodies to kappa/lambda immunoglobulin and FISH probes corresponding to the following anomalies: trisomies 3, 7, 9 and 15; del17p/-17; -13/del13q; 14q32 split; and t(11;14). CCND1/IGH. If an IGH rearrangement was detected that did not involve CCNDI, we also evaluated t(4;14) or IGH/FGFR3 and t(14;16) or IGH/c-MAF. These probes constitute the standard screening panel used in MM at our institution. Results: The study population had a median age of 61 years with a male to female ratio of 1.6:1. Median follow up time was 13.5 months. By conventional cytogenetics, 88% of patients had no detectable abnormality. In contrast, only 33% were normal by cIg-FISH. The abnormalities demonstrated were 28% 13-/del13q, 42% IgH translocation, 33% t(11;14), and 3% t(14;16). No patients had a -17/del 17p- or t(4;14). Nine patients had del13q/-13 with an IgH translocation, with 7 of these having t(11;14). Both t(14;16) patients had del 13q. A trend towards increased mortality was seen in patient with any abnormality (p=0.11), but this could not be demonstrated for any single abnormality, likely due to lack of statistical power. There was no correlation between renal involvement or cardiac involvement and cIg-FISH results. Conclusion: The majority of chromosomal abnormalities in amyloidosis are undetected by conventional cytogenetics. With further study, chromosomal abnormalities may carry the same prognostic value in amyloidosis that they currently enjoy in myeloma. This effect may be independent of currently recognized risk factors. Chromosomal abnormalities in Amyloidosis as detected by cIg-FISH Abnormality Amyloidosis % (n=69) Normal 33(23) −13/del13q 28(19) IgH Abnormality 42(29) t(4;14) 0(0) t(11;14) 33(23) t(14;16) 3(2) del 17 0(0) Other 3(2)

We review and synthesize key findings and limitations of mathematical models for prostate cancer, both from theoretical work and data-validated approaches, especially concerning clinical applications. Our focus is on models of prostate cancer dynamics under treatment, particularly with a view toward optimizing hormone-based treatment schedules and estimating the onset of treatment resistance under various assumptions. Population models suggest that intermittent or adaptive therapy is more beneficial to delay cancer relapse as compared to the standard continuous therapy if treatment resistance comes at a competitive cost for cancer cells. Another consensus among existing work is that the standard biomarker for cancer growth, prostate-specific antigen, may not always correlate well with cancer progression. Instead, its doubling rate appears to be a better indicator of tumor growth. Much of the existing work utilizes simple ordinary differential equations due to difficulty in collecting spatial data and due to the early success of using prostate-specific antigen in mathematical modeling. However, a shift toward more complex and realistic models is taking place, which leaves many of the theoretical and mathematical questions unexplored. Furthermore, as adaptive therapy displays better potential than existing treatment protocols, an increasing number of studies incorporate this treatment into modeling efforts. Although existing modeling work has explored and yielded useful insights on the treatment of prostate cancer, the road to clinical application is still elusive. Among the pertinent issues needed to be addressed to bridge the gap from modeling work to clinical application are (1) real-time data validation and model identification, (2) sensitivity analysis and uncertainty quantification for model prediction, and (3) optimal treatment/schedule while considering drug properties, interactions, and toxicity. To address these issues, we suggest in-depth studies on various aspects of the parameters in dynamical models such as the evolution of parameters over time. We hope this review will assist future attempts at studying prostate cancer.

8523 Background: ISIS 481464 is a synthetic bicyclic nucleic acid-containing antisense oligonucleotide that is complementary to the mRNA for signal transducer and activator of transcription 3 (STAT3). Methods: Primary objective of the dose-escalation study (3+3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included safety, tumor response, pharmacokinetics (PK), and pharmacodynamics (PD) using IL-6 and tumor markers. Patient (pt) eligibility included : >18 yrs old, solid tumors or lymphomas refractory to at least 1 prior systemic therapy. ISIS 481464 was administered IV as a loading dose on Days 1, 3, and 5 and then weekly. Results: 15 pts were dosed (4 at 2 mg/kg and 11 at 4 mg/kg). 6 pts had advanced lymphoma (3 DLBCL, 2 Hodgkin’s lymphoma, 1 mantle cell lymphoma) and 9 pts solid tumors. There was one dose limiting toxicity (DLT), a possibly related thrombotic microangiopathy at 4 mg/kg. Treatment emergent thrombocytopenia was observed with an average reduction of approximately 70% from baseline. Three pts, 1 at 2 mg/kg and 2 at 4 mg/kg, experienced nadirs in platelet count below 50x109/L (range 16 to 33x109/L). MTD was not reached; however, given the thrombocytopenia at 4mg/kg, the RP2D was 2mg/kg. Partial responses were observed in 2/3 DLBCL pts. The 1st DLBCL pt (2 mg/kg) with 10 prior treatments had a durable 55% reduction in tumor size and is ongoing treatment at 11 months. This pt had a 76% reduction in IL-6. The 2nd DLBCL pt (4 mg/kg) with 2 prior treatments had a 65% reduction for 4 months and was able to undergo autologous stem cell transplantation. There were no responses in the solid tumor pts. PKs revealed increased plasma trough levels (indicative of tissue concentrations) with increased dose. Conclusions: ISIS 481462 was well-tolerated and the RP2D was determined to be 2 mg/kg. Initial tumor activity was observed in DLBCL pts and a dose expansion in advanced lymphomas is ongoing. Clinical trial information: NCT01563302.

e16065 Background: Estrogens, in addition to androgen may contribute to the progression of prostate cancer.The combination of bicalutamide, a non-steroidal anti-androgen, and raloxifene, a selective estrogen receptor modulator, has a synergistic effect on cell death of prostate cancer cell lines such as DU145 and PC3. We investigated the safety of combined treatment of bicalutamide and raloxifene on quality of life in patients affected by hormone-resistant prostate cancer. Methods: Eligibility requirements included metastatic hormone-resistant prostate cancer, Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the combination of bicalutamide, 50 mg, and raloxifene, 60 mg, daily in 28 day cycles for a maximum of 6 cycles. The primary endpoint was to describe the adverse event profile of combined treatment with bicalutamide and raloxifene. The secondary endpoint was to describe the quality of life of patients receiving the combination. Adverse events were graded by the investigator using the NCI Common Terminology Criteria for Adverse Events version 4.0 and the quality of life was assessed by the patient using aLinear Analog Scale Assessment (scale of 0-100). Serum levels of estradiol and testosterone were monitored during treatment. Results: Eighteen evaluable patients were included in the statistical analysis after an initial run-in safety cohort of six patients. Two patients completed 6 cycles per protocol, the remaining sixteen patients were taken off protocol after disease progression. Patients completed a median of 2 cycles. There were no grade 4 events and grade 3 adverse events consisted of hypertension (5.6%) and back pain (5.6%). Erectile dysfunction (grade 1) was the most common adverse event (77.8%). Patient assessment of quality of life (mental, physical, social, emotional, spiritual) did not reveal any statistically different changes after 2 cycles of treatment. An analysis of testosterone and estradiol levels will be reported. Conclusions: We conclude that combination of bicalutamide and raloxifene is well-tolerated. The combination of androgen and estrogen receptor blockade warrants further study for efficacy in hormone-resistant prostate cancer. Clinical trial information: NCT01050842.