Citations

TPS3161 Background: VV1 is an oncolytic vesicular stomatitis virus engineered to express human IFNβ to enhance cellular anti-tumor immune responses and tumor selectivity, and the human sodium iodide symporter (NIS) for virus tracking by SPECT imaging. Cancer cells are often hyporesponsive to IFNβ, enabling the efficient spread of VV1 and resulting in increased oncolysis. Differently from other oncolytic viruses, VV1 is suitable for both intra-tumoral (IT) and/or intra-venous (IV) administration. Despite considerable anti-tumor activity with checkpoint inhibitors (CPI) among some malignancies, long term survival and overall cures remain elusive. Prior Ph 1 studies have shown significant anti-tumor activity among several malignancies when VV1 was administered either as monotherapy or in combination with a CPI, despite progression on prior CPI monotherapy. Furthermore, pre- and post-treatment biopsy evaluations after VV1 treatment have demonstrated T cell infiltration and inflammation in both IT injected and non-injected lesions. Among IV treated patients (pts), IFNβ was detectable in the serum correlating with viral replication, making it an effective biomarker. C is a high-affinity potent human IgG4 anti-PD-1 monoclonal antibody. Though approved for use in cutaneous squamous cell carcinoma, C has shown anti-tumor activity, similar to other CPI, in several other indications. Therefore, VV1 and C could be an attractive combination for the immunotherapy for several solid tumors. This study represents the first clinical evaluation of VV1 in combination with C in pts with advanced solid tumors. Methods: The Ph 2 Simon 2 stage five-arm study of IV administration VV1 in combination with IV C will enroll pts with advanced NSCLC, HCC, melanoma & endometrial cancer. Enrolled pts with NSCLC & melanoma will be recent CPI-progressors, whereas enrolled HCC & endometrial cancer will be CPI-naïve. The study’s objectives include assessment of preliminary anti-tumor activity, safety, & immuno-regulatory activity of the combination. Pts will receive IV VV1 once on D1 and IV C once every 3 weeks until confirmed disease progression or intolerable toxicity. Pts enrolled in one melanoma cohort will also receive IT VV1 administered to palpable lesions. Response will be assessed every 9 weeks per RECIST v1.1. The null hypothesis of each cohort’s ORR will be tested versus a one-sided alternative yielding a Type I error rate of 5% and power of 80%. Cohorts will be expanded based on signal of activity. Clinical trial information: NCT .

3090 Background: VV1 (Voyager V1) is derived from VSV, an RNA virus with low human seroprevalence, engineered to replicate selectively in and kill human cancer cells. In Part 1 of this study, we demonstrated the safety of intratumoral VV1 and dose-response, using serum IFNβ as a biomarker; we observed viral replication in tumor and concomitant lymphocyte/neutrophil trafficking (SITC 2018). 2 other studies suggested greater efficacy and higher IFNβ levels with IV administration. Longer infusion durations were reported to mitigate infusion reactions (IRRs) for another oncolytic. Methods: We studied 3 different infusion durations of VV1 monotherapy at the recommended phase 2 IV dose (1.7 x 1010 TCID50) in patients with advanced solid tumors. Endpoints included safety, preliminary anti-tumor activity, viral titers, IFNβ PD and shedding. Patients received IV VV1 once on D1 and were monitored for DLT over 21 days with efficacy assessments every 6 weeks. IRRs were classified using Lee 2014 criteria for CRS as either constitutional symptoms only (G1) or involving hypotension (G2). Results: 18 patients were treated at 30, 60 and 180-minute durations (n = 7, 5 and 6, respectively). No DLTs, deaths or G3-4 related IRR AEs were observed. Most pts were female (67%), white (100%), with ECOG PS 0 (61%) and median 4 lines of prior systemic therapy (range 1-14) for colorectal (CRC; 56%), squamous cell carcinoma (11%), pheochromocytoma (11%), sarcoma (11%) or other (11%) cancers. The table shows results (number of patients) by infusion duration. Conclusions: There was no difference in safety between the 3 infusion durations, while efficacy and PD markers suggested better anti-tumor effect with 30-minute infusion. VV1 is safe for caregivers, with no viral shedding. Part 3 of this study will now treat CRC patients with VV1 in combination with a checkpoint inhibitor (avelumab). A 5-arm phase 2 basket study in combination with cemiplimab is proceeding with 30-minute infusions. Clinical trial information: NCT02923466 . [Table: see text]

514 Background: The 21- gene Breast Recurrence Score predicts benefit from adjuvant chemotherapy in estrogen receptor positive (ER+), HER-2 negative (-) breast cancer (BC). We aimed to examine whether the 21-gene assay predicts response to neoadjuvant chemotherapy (NAC). Methods: We identified patients with stage I-III ER+/HER2− BC treated with NAC from the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with BC at age ≤ 40 years. The 21-gene assay was performed on tumor specimens removed prior to NAC either as part of clinical care or retrospectively for research. Pathologic complete response (pCR) was defined as no residual invasive tumor (ypT0/is ypN0). The relationship between Recurrence Score result (RS) and pCR was evaluated using logistic regression modeling. Results: 76 women in the cohort had undergone NAC for ER+, HER2- BC and were eligible for this analysis: 5 had undergone clinical 21-gene assay testing, 71 had banked specimens retrospectively tested. Median age at diagnosis was 36.7 (24.3-40). Most tumors were of ductal histology (78%), high grade (51%), progesterone receptor (PgR) positive (86%), ≥T2 (88%), clinically node positive (74%), and anthracycline and taxane containing protocols were administered in 86% of cases. RS ranged between 5-75 with 50% > 25 and only 4 < 11. Mean RS was significantly higher among tumors achieving pCR vs. non-pCR response (51.9 vs. 26.6, pwilcoxon= 0.0005). pCR rate in patients with RS > 25 was 21% (8/38) vs. 5% in patients with RS < 25 (2/38), with both pCRs in the <25 group in patients with RS 21-25. In univariable analysis, PgR negativity (odds ratio (OR) 5.62, 95% confidence interval (CI) 1.27-24.89, p = 0.02), high grade (OR 9.03, 95%CI 1.07-76.32, p = 0.04) and higher RS as a continuous variable (OR 1.08, 95%CI 1.04-1.13, p = 0.0003) were associated with a greater likelihood of pCR. In multivariable analysis only RS remained significantly associated with pCR (OR: 1.07, 95%CI 1.01-1.12, p = 0.01): a 7% increase in the odds of pCR for every 1-point increase in RS. Conclusions: In young women with ER+, HER2- BC who received NAC, higher pretreatment RS was associated with an increased likelihood of pCR. Genomic expression profiling assays may have a role in decision-making in young women in need of neoadjuvant therapy. For women with low likelihood of benefiting from NAC, alternative approaches are clearly warranted. Given the demonstrated efficacy of neoadjuvant endocrine therapy in post-menopausal women, further evaluation in young women should be pursued.

Background. Despite demonstrated efficacy, patient decision aids (DAs) are rarely used in clinical practice in the absence of coverage mandates. Deciding whether to pursue a left ventricular assist device (LVAD) is a major, preference-sensitive decision—ideal for exploring implementation of a DA. Methods. We conducted a type II effectiveness-implementation hybrid trial at 6 LVAD programs using a stepped-wedge cluster-randomized design. Using the RE-AIM framework, we collected both quantitative and qualitative outcomes, including a checklist collected by study staff for each enrolled patient regarding DA use and interviews with LVAD program clinicians preintervention, 6 months postintervention, and at the conclusion of the study. Results. From June 2015 to January 2017, 248 patients and their caregivers were enrolled. A total of 69 interviews were conducted with 48 clinicians at 3 time points. The DA reached 95% of eligible patients. Adoption was 100%, as all sites approached agreed to participate in the trial. Interviews revealed several themes related to the implementation of the DA: clinicians had a strong desire to ensure patients were informed and embraced the DA. Despite this, they reported communication challenges among their team that impeded implementation. Five of the 6 sites have maintained use of the DA following the trial; 1 site reported concerns about decreased procedural volume with use of the DA as a reason for discontinuation. Conclusions. In this hybrid trial, a DA for patients considering LVADs and their caregivers demonstrated high reach. Adoption and implementation were facilitated by a strong desire to ensure that patients were well informed. Future dissemination research and practice should attend to concerns about procedure volume and coverage mandates and facilitate ongoing communication at sites using the DA.

Abstract Up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with an accumulation of chronic conditions, frailty, and/or cognitive impairments resulting from cancer and its treatment. Thus, survivors often show an accelerated development of multiple geriatric syndromes and need therapeutic interventions. To advance progress in this area, the National Cancer Institute convened the second of 2 think tanks under the auspices of the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative. Experts assembled to share evidence of promising strategies to prevent, slow, or reverse the aging consequences of cancer and its treatment. The meeting identified research and resource needs, including geroscience-guided clinical trials; comprehensive assessments of functional, cognitive, and psychosocial vulnerabilities to assess and predict age-related outcomes; preclinical and clinical research to determine the optimal dosing for behavioral (eg, diet, exercise) and pharmacologic (eg, senolytic) therapies; health-care delivery research to evaluate the efficacy of integrated cancer care delivery models; optimization of intervention implementation, delivery, and uptake; and patient and provider education on cancer and treatment-related late and long-term adverse effects. Addressing these needs will expand knowledge of aging-related consequences of cancer and cancer treatment and inform strategies to promote healthy aging of cancer survivors.

Abstract Introduction: The immunoglobulin free light chain (FLC) is the precursor protein of amyloid in primary systemic amyloidosis (AL). Historically, the ability to monitor the amyloid protein precursor has been crude. There is now a test that reproducibly measures serum levels of FLC. We evaluated the utility of this assay in patients with AL undergoing peripheral blood stem cell transplant (PBSCT). Methods: Between March 1, 1996 and July 31, 2004, 98 patients with AL undergoing PBSCT had serial FLC measurements performed either prospectively or on stored sera. Patients who died before their 100 day evaluation were excluded because response could not be estimated. FLC levels were performed using Freelite™ reagents on a Dade-Behring Nephelometer. In order to pool the data of the monoclonal kappa and lambda patients, the clonal free light chain was considered the involved] immunoglobulin free light chain for the purpose of these analyses and is henceforth referred to as FLC. The prognostic effects of the initial concentration and the extent of reduction of monoclonal FLC on survival were evaluated. Results: Pre-transplant, 94% of patients had an abnormal FLC ratio, with a median involved FLC of 152 mg/L [15.2 mg/dL]. Only 14% of 98 patients had a “measurable” serum M-spike (i.e. ≥ 10 g/L [1 g/dL]) on electrophoresis with a median of 1 g/L [0.1 g/dL]. Ten patients have died of their disease during a median follow-up time of 19.5 months, range 3.3 to 103 months. The 2- year and 4-year estimated survivals are 92% and 76%, respectively. Using the 75th percentile value of pre-PBSCT FLC (382 mg/L [38.2 g/dL]) as a grouping variable, there was a significantly higher risk of death 5.4 (95% confidence interval 1.5–19.3) in the patient quartile with the highest baseline FLC. Baseline FLC correlated with serum cardiac troponin T levels (rho 0.51, p&lt;0.0001), suggesting that high FLC levels are associated with more advanced disease. After PBSCT, the median percent reduction of FLC was 81%. The percent FLC reduction did not predict for survival, but the absolute level of FLC achieved after therapy did. The hazard ratio for death for not achieving a post-transplant FLC of 20 mg/L [2 mg/dL] post-transplant was 5.1 (95% confidence interval 1.1–24.1). Of 91 patients evaluable for complete response by EBMT criteria, 45 had a complete hematological response. Sixty-five percent of the patients achieving a FLC level of less than 20 mg/L [2 mg/dL] also had a complete hematologic response. Free light chain response as defined by a post transplant FLC level 20mg/L [2 mg/dL] or lower was a more powerful predictor of survival than complete hematologic response, as defined by the EBMT multiple myeloma criteria. Post-PBSCT FLC level only weakly predicted for organ response, but median follow-up for surviving patients is relatively short at 19.6 months. Conclusion: FLC measurements both pre- and post-PBSCT are important predictors of patient outcome.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. For selected patients high dose chemotherapy with peripheral blood stem cell support is effective, but even in those patients, only 50% derive organ responses. Other patients are too sick to undergo that therapy. Thalidomide has limited utility in this disease, largely because of its toxicity profile in patients with AL. Lenalidomide, Celgene’s lead clinical compound in a new group of drugs called IMiDs®, is highly active in patients with multiple myeloma, especially in conjunction with dexamethasone. We sought to determine the toxicity and efficacy of lenalidomide in patients with AL. Methods: Patients with symptomatic AL who had a measurable plasma cell disorder (defined as serum M-spike ≥ g/dL urine M-spike &gt;200 mg/24 hours; or involved immunoglobulin free light chain (FLC) ≥10 mg/dL and an abnormal FLC ratio) and adequate organ reserve defined as a creatinine ≤3 mg/dL, absolute neutrophil count ≥1000, platelet count ≥75000, and a hemoglobin ≥8 g/dL were eligible. Patients were started on lenalidomide 25 mg/day for 21 days followed by a 7 day rest (1 cycle). Dose modifications were made based on toxicity. If there was evidence of progression before 3 months or no evidence of hematologic response after 3 cycles, dexamethasone 40 mg p.o. days 1–4 and 15–18 was added. Results: Twenty-three patients were enrolled between 10/28/04 and 4/7/05; 14 were previously treated. Patient characteristics are shown in Table. Organ involvement was as follows: cardiac (61%); renal (70%), hepatic (22%); nerve (13%). Nine patients withdrew from study before completing 3 months of therapy. The reasons were: cancel (1); death (4); adverse events (2); and progression (2). At the time of our preliminary analysis in July 2005, an additional 3 patients have withdrawn from study: death (1) and patient refusal (2). Of the 5 patients who died, 4 had severe cardiac involvement and at least 3 organs involved by amyloid. The median follow-up for the eleven patients remaining on study is 6.2 months. Of the 12 patients who have crossed the 3 month treatment landmark, there are 7 hematologic partial responses (4 confirmed and 3 unconfirmed), two renal responses and one liver response. Of these same 12 patients, all but one has had dexamethasone added to their treatment program. The most common grade 3–4 adverse advents at least possibly attributable to lenalidomide were neutropenia (43%), thrombocytopenia (26%), rash (17%), dyspnea (9%), fatigue (9%), and edema (4%). Expansion of the trial is planned to accrue an additional 10 evaluable patients. Conclusions: Early results suggest that lenalidomide ± dexamethasone has activity in patients with primary systemic amyloidosis. Supported in part by the Caliguiri Fund for Amyloidosis Research, Robert A. Kyle Hematologic Malignancies Program, and Celgene. Patient Characteristics Median Range Age 64 44–88 Major Organs 2 0–3 Involved FLC, mg/dl 23 4.1–278 Serum alb, g/dl 2.8 1.2–3.7 Urine protein, g/24 hrs 3.7 0.02–14.3 Creatinine, mg/dl 1.3 0.7–2.6 Alkaline phos IU/l (nml &lt;115) 99 57–1729 NY Heart Class 1 1–3 Troponin T, mcg/l 0.03 0.01–0.55 NT-proBNP, ng/l 1419 109–42844 LV Septum, mm 13 9–24 LV EF, % 63 22–72

Abstract Effective cancer therapy with a minimum of undesired side effects in multiple myeloma (MM) requires specifity of the therapeutic agent against the neoplastic cells. One approach to reach this aim is virotherapy using oncolytic measles virus. Attenuated replication-competent Edmonston lineage strains of measles virus (MV-Edm) have proven anti-tumor activity against xenograft models of human multiple myeloma, ovarian cancer, lymphoma and glioma. The virus is selectively oncolytic, causing extensive lethal cell to cell fusion via CD46, which is more highly expressed on tumor cells than on normal cells. However, MV-Edm retains the capacity to infect a variety of nontransformed cell types via its native receptors, CD46 and SLAM which are present on many different cell types. One approach to avoid this risk is to engineer the viral attachment protein to ablate its natural tropisms and at the same time, redirect its specificity to interact with alternative tumor specific receptors. The native measles Hemagglutinin (H) protein recognizes CD46 or SLAM resulting in membrane fusion and syncytia formation of cells. In this work the H protein was engineered to restrict and retarget membrane fusion through the display of a single-chain antibody (scFv) recognizing the Wue-1-antigen known to be highly specific for MM cells and abrogation of native measles binding domains for CD46 and SLAM by mutation. This modified H protein (chimeric H) was cloned in a full-length viral backbone including EGFP enabling to detect infected cells and syncytia formation under the UV light emitting green fluorescence (EGFP). On the basis of the parental measles virus expressing EGFP (MV-GFP) two different viruses were generated: non-ablated virus expressing the chimeric H protein including the scFv Wue-1 still competent to infect cells expressing CD46 and SLAM (MV-W1) with the chimeric H protein but ablated for the interactions with CD46 and SLAM (MV-W2). The genetically modified viruses propagated as recently described (Nat. Biotech., Vol.23, Nr.2, Feb.2005, pp.209–214.). To determine if the fully retargeted MV-Edm would be able to infect MM cell lines selectively a first array of infection assays was performed using the MM cell lines RPMI 8226 and ARH-77 expressing the Wue-1 antigen as expected targets and K562 and healthy CD40L activated CD19 positive B cells as controls. 24 to 96 hours after infection with MV-GFP, MV-W1 and MV-W2 we observed syncytia formation and expression of EGFP with MV-GFP and MV-W1 in all cells indicating that the modification of the virus with the scFv-Wue-1 doesn’t alter the potential to infect and kill cells compared to the parental virus. In contrast MV-W2 was able to form only EGFP positive plaques with the Wue-1 antigen positive cells RPMI 8226 and ARH-77 but did not infect K562 or CD19 positve B cells both negative for Wue-1 antigen. These results indicate that the measles virus vaccine strain Edmonston B can be modified to express a scFv recognizing the Wue-1 antigen. In addition the native H protein can be mutated resulting in ablation of the natural tropism towards CD46 and SLAM positive cells. Viruses with these modifications can be rescued and propagated in vitro and selectively infected Multiple Myeloma cells without causing damage to normal B-cell progenitors.

Abstract Background: As the first radiolabled monoclonal antibody approved for the treatment for the treatment of cancer, yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) achieves both high response rates and durable remissions in patients with relapsed or refractory, low-grade, follicular, or transformed B-cell NHL. Because of the stability of 90Y ibritumomab tiuxetan and its favorable pharmacokinetic profile (ie, predictable urinary clearance and absence of dehalogenation), dosing is based on patient weight and platelet counts. Yttrium 90 ibritumomab tiuxetan is typically delivered at a dose of 0.4 mCi/kg (in patients with platelets &gt;150,000/mm3) or 0.3 mCi/kg (in patients with platelets ≤150,000/mm3) to a maximum recommended dose (MRD) of 32 mCi. However, patients &gt;80 kg with platelet counts exceeding 150,000/mm3 may receive a lower drug concentration (ie, &lt;0.4 mCi/kg 90Y) as a result of dose capping. We evaluated whether the 32 mCi dose cap influences the safety or efficacy of ibritumomab tiuxetan therapy in patients &gt;80 kg. Methods: Efficacy and safety data were collected for patients from 3 registrational trials that received either 0.4 mCi/kg 90Y (patients ≤80 kg) or 32 mCi 90Y (patients &gt;80 kg). Results: Clinical responses in 170 patients were evaluated. Patients ≤80 kg (n = 103) had a median weight of 70 kg (range, 45–80 kg) versus a median weight of 95 kg (range, 81–159) for patients &gt;80 kg (n = 67). Gender (41% M vs 73% M, respectively; P &lt;.01) was the only significantly different baseline characteristic between the ≤80 kg and &gt;80 kg groups. Similar efficacy and safety results were reported for both subsets of patients. Overall response rates of 79% and 70% were observed for patients ≤80 kg and &gt;80 kg, respectively (P =.27); and no significant differences were seen in complete response rates (28% vs 34%, respectively; P =.40). Median TTP (8.9 months vs 9.5 months; P =.53) and median DR (8.5 months vs 11.5 months; P =.34) were equivalent between the 2 weight-based groups. In addition, there were no statistically significant differences in safety measures including grade 3/4 nonhematologic adverse events, neutropenia, thrombocytopenia, or anemia. Conclusions: As a consequence of dose capping at an MRD of 32 mCi, 39% of patients received a lower dose/kg of 90Y ibritumomab tiuxetan. However, despite the difference in dose administered on a unit of body weight basis, the efficacy and safety results were similar between patients ≤80 kg and &gt;80 kg. We conclude that the 32 mCi dose cap does not influence the efficacy or safety profile of 90Y ibritumomab tiuxetan for patients &gt;80 kg.