Toward Personalized Radiation Therapy of Liver Metastasis: Importance of Serial Blood Biomarkers

PURPOSE To assess the added value of serial blood biomarkers in liver metastasis stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS Eighty-nine patients were retrospectively included. Pre- and midtreatment blood samples were analyzed for potential biomarkers of the treatment response. Three biomarker classes were studied: gene mutation status, complete blood count, and inflammatory cytokine concentration in plasma. One-year local failure (LF) and 2-year overall survival (OS) were chosen as study end points. Multivariate logistic regression was used for response prediction. Added predictive benefit was assessed by quantifying the difference between the predictive performance of a baseline model (clinicopathologic and dosimetric predictors) and that of the biomarker-enhanced model, using three metrics: (1) likelihood ratio, (2) predictive variance, and (3) area under the receiver operating characteristic curve (AUC). RESULTS The most important predictors of LF were mutation in KRAS gene (hazard ratio [HR] = 2.92, 95% CI, [1.17 to 7.28], P = .02) and baseline and midtreatment concentration of plasma interleukin-6 (HR = 1.15 [1.04 to 1.26] and 1.06 [1.01 to 1.13], P = .01). Absolute lymphocyte count and platelet-to-lymphocyte ratio at baseline as well as neutrophil-to-lymphocyte ratio at baseline and before fraction 3 (HR = 1.33 [1.16 to 1.51] and 1.19 [1.09 to 1.30]) had the most significant association with OS ( P = .0003). Addition of baseline GEN and inflammatory plasma cytokine biomarkers in predicting LF, respectively, increased AUC by 0.06 (from 0.73 to 0.79) and 0.07 (from 0.77 to 0.84). In predicting OS, inclusion of midtreatment complete blood count biomarkers increased AUC from 0.72 to 0.80, along with significant boosts in likelihood ratio and predictive variance. CONCLUSION Inclusion of serial blood biomarkers leads to significant gain in predicting response to liver metastasis stereotactic body radiation therapy and can guide treatment personalization.

Abstract 123: Intra-arrest Delivery of Intra-muscular Magnesium Sulfate in a Rat Model of Cardiac Arrest

Introduction: Brain injury is the most common cause of death for patients resuscitated from cardiac arrest. Magnesium is an attractive neuroprotective therapy that has the potential to reduce neuronal calcium overload via NMDA receptor modulation and prevent mitochondrial permeability transition. Intramuscular (IM) delivery of MgSO4 during CPR has the potential to target these mechanisms within their presumed therapeutic window. Hypothesis: IM MgSO4 administrated during CPR will achieve therapeutic serum magnesium levels, which is ≥ 2 times of baseline, within 15 minutes after ROSC and improve neurologic outcomes. Methods: Male Long Evans rats were subjected to 8-minute asphyxial cardiac arrest. For the dose-finding study (n = 4/group), rats were block randomized to receive placebo, 107 mg/kg, 215 mg/kg, or 430 mg/kg MgSO4 IM at the onset of CPR. Serial blood samples were collected at baseline, 15 min, 30 minutes, 1 hour and 2 hours after return of spontaneous circulation (ROSC) and analyzed for serum magnesium concentration. For the long-term outcome study (n = 9/group), rats subjected to cardiac arrest were blindly block randomized to the same treatment groups with the addition of a sham-operated group. Post-cardiac arrest care included maintenance of normothermia (36.7 °C - 37.3 °C) for 72 hours. Serial blood samples were collected at baseline, 15 min and 1 hour after ROSC and neurologic function score (NFS) was performed daily for 10 days. Good neurologic function was predefined as NFS ≥ 450. Results: IM MgSO4 during CPR had no effect on ROSC rate (p > 0.05). The serum magnesium concentrations at 15 min after ROSC of 107 mg/kg group, 215 mg/kg group and 430 mg/kg group were 3.9 ± 0.9, 6.2 ± 1.8, and 7.6 ± 1.8 mg/dl, which were 2.0 fold, 3.1 fold and 4.2 fold of baseline respectively. IM MgSO4 had no statistically significant effect on 10-day survival or 10-day survival with good neurologic function. Conclusion: Single dose IM MgSO4 during CPR achieves up to 4-fold baseline magnesium levels within 15 min after ROSC in a rat model of asphyxia cardiac arrest. This treatment strategy did not improve survival or recovery of neurologic function. Future studies with repeated dosing or in combination with hypothermic targeted temperature management may be indicated.

72 Endocrine and ovarian responses to combined estradiol benzoate-sulpiride in anestrous mares treated with kisspeptin

The objective of this study was to determine if incorporation of kisspeptin 10 (Kp10) into an estradiol benzoate (EB)-sulpiride treatment would result in greater endocrine responses, and a greater number of mares ovulating within 28 days of treatment compared to EB-sulpiride alone. Eighteen anestrous mares were blocked by horse type (light horse and pony crosses), body condition, and age, then randomly assigned to treatment or control. On day 0, all mares received 50 mg EB. On day 1, mini osmotic pumps containing saline (n = 9) or Kp10 (50 mg/hour; n = 9) were inserted subcutaneously in the neck and remained for 7 days. Serial blood sampling occurred for 24 hours after pump placement. On day 2, all mares received 3 g sulpiride. Serial blood sampling continued for 36 hours and daily for 28 days. Transrectal ultrasounds were performed regularly for detection of ovulation. Plasma was assayed for prolactin, luteinizing hormone (LH) and progesterone. Data were analyzed by ANOVA with repeated measures. Plasma prolactin increased (P < .001) in response to sulpiride in all mares and remained stimulated for 7 days. Prolactin responses tended to be greater (P = .09) in Kp10- treated mares compared to controls. No differences were detected in plasma LH during the first 24 hours after pump placement; however, LH increased in all mares beginning 5 days after sulpiride and were greater (P < .05) in Kp10-mares from day 7 to day 21. Eleven of 18 (61%) mares ovulated within 18 days of sulpiride treatment; however, no differences in ovulation dates were detected between Kp10 treated- and control- mares. No differences were detected in plasma progesterone during the first 5 days post ovulation. In conclusion, incorporation of Kp10 potentiated the prolactin and LH responses to EB-sulpiride, but did not further advance first ovulation in treated-mares.

388 Preliminary results from KEYNOTE-A36, a study of GB1275, a first-in-class oral CD11b modulator, alone and with pembrolizumab or chemotherapy in specified advanced solid tumors

BackgroundGB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs), repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. Preclinical anti-tumor activity was observed with single-agent therapy and in combination with chemotherapy or immuno-oncology therapies.1 We report results from the dose escalation portion of an ongoing, first-in-human study of GB1275 monotherapy and combined with pembrolizumab in patients with specific advanced solid tumors. (NCT04060342)MethodsThis study comprises phase 1 dose escalation followed by phase 2 expansion in specific tumor types. In phase 1, cohorts of 3 to 6 patients with histologically confirmed, locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, metastatic castrate-resistant prostate cancer, or triple negative breast cancer are sequentially assigned to one of the ascending dose levels of GB1275 orally twice daily (BID) in 1 of 3 regimens: A (GB1275 monotherapy); B (GB1275 + pembrolizumab) commenced after completion of two cohorts of A; and C (GB1275 + nab-paclitaxel + gemcitabine) will be initiated after A. Patients in Regimens A and B had previously exhausted standard of care treatment options. Dose escalation was based on safety, including dose-limiting toxicity (DLT). Serial blood samples were collected for pharmacokinetic (PK) and biomarker analyses; tumor tissue was also collected for biomarker analysis.ResultsAs of July 28, 2020, 36 patients were treated, 23 in Regimen A (GB1275 100 mg to 1200 mg BID) and 13 in Regimen B (GB1275 100 mg to 800 mg BID + pembrolizumab). No DLTs or adverse events requiring steroid treatment were reported. GB1275-related adverse events were reported in 19 (52.8%) patients; most were Grade 1 and most frequent events (≥10%) were dysesthesia (13.9%) and photosensitivity reaction (11.1%). Stable disease was reported in 4 (17%) patients in Regimen A and 6 (46%) in Regimen B with a median (range) exposure of 84 days (35–172). A dose-dependent increase in GB1275 exposure was observed. An increase in tumor infiltrating lymphocyte (TIL) counts was noted in both Regimens A and B. Other biomarker analyses in serial blood and tumor tissue are ongoing.ConclusionsDose escalation of GB1275, up to 1200 mg and 800 mg BID in Regimens A and B, respectively, demonstrated tolerability as monotherapy and combined with pembrolizumab. The maximum tolerated dose has not been reached. Preliminary observation of an increase in TILs after treatment is encouraging.Ethics ApprovalThis ongoing study is being conducted in accordance with the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study was approved by the Ethics Boards of the University of Colorado Hospital, Washington University School of Medicine - Siteman Cancer Center, Memorial Sloan Kettering Cancer Center, The Sarah Cannon Research Institute/Tennessee Oncology, South Texas Accelerated Research Therapeutics, and The Royal Marsden NHS Foundation Trust.ReferencePanni RZ, Herndon JM, Zuo C, et al. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med 2019 Jul 3;11(499).