NCI CTCAE Grade Research Articles

New drugs to prevent oxaliplatin-induced peripheral neuropathy: A double-blind, randomized study.

3568 Background: Postoperative adjuvant chemotherapy for colorectal cancer reduces postoperative recurrence; however, it often causes undesirable adverse events. Oxaliplatin, the mainstay of postoperative adjuvant chemotherapy is particularly likely to cause chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSR) that may make it difficult to continue treatment. Various agents have been tested for prevention or treatment of CIPN caused by oxaliplatin, but none have proven effective. Reactive oxygen species contribute oxaliplatin-induced PN; therefore, super oxide dismutase (SOD) could potentially suppress them, but its very short serum half-life has made clinical application difficult. We developed a lecithinized human copper/zinc SOD (Cu/Zn-SOD) (PC-SOD) in which four phosphatidylcholine derivative molecules are bound covalently to each SOD dimer. Compared with SOD, PC-SOD enhanced stability in plasma and stronger tissue affinity, and exerts therapeutic effects in animal models of several diseases, including CIPN. Methods: This double-blind, randomized study included 90 patients with stage II/III colorectal cancer. All patients were slated to receive 12 cycles of mFOLFOX6. In each cycle, patients received PC-SOD or a placebo immediately before oxaliplatin. The primary endpoint of this study was the number of cycles before NCI-CTCAE Grade 2 (G2) CIPN occurred. One of the secondary endpoints was the number of cycles before DEB-NTC G2 PN occurred. Results: Forty-three patients received PC-SOD. No serious adverse events were observed that could be related to PC-SOD. The incidence of neutropenia, diarrhea, stomatitis, and malaise were lower in the study group, but the differences were not significant. Additionally, 3 patients (7.0%) in the study group and 11 (23.4%) in the placebo group had HSR. Although there was no difference in the number of cycles between the two groups until NCI-CTCAE G2 PN occurred, the study group had a significantly greater number of cycles before DEB-NTC G2 PN compared to the placebo group (P=0.08). The study group had a significantly greater number of cycles before NCI-CTC G1 PN (P=0.01) and HSR (P=0.03) compared to the placebo group. The number of cycles before HSR or NCI-CTCAE G2 PN occurred was greater in the study group , but the difference was not significant. The average total oxaliplatin dose was higher in the study group but the difference was not statistically significant. Conclusions: The primary endpoint did not occur; however, the study group had a significantly greater number of cycles before DEB-NTC G2 PN. Notably, the study group also had a significantly greater number of cycles before HSR. These results show that PC-SOD may suppress HSR as well as PN, both of which limit administration of oxaliplatin. Thus, this drug is expected to improve not only patient quality of life, but also the prognosis of patients. Clinical trial information: 2031210466.

PBP1510, a novel monoclonal antibody targeting pancreatic adenocarcinoma upregulated factor (PAUF): Phase 1/2a monotherapy and combination with gemcitabine in patients with advanced/metastatic pancreatic cancer.

e16296 Background: PAUF, a protein overexpressed in pancreatic cancer but not in non-cancerous tissues, plays a key role in cancer progression and metastasis. PBP1510 is a novel first-in-class humanized IgG1 monoclonal antibody that binds to and neutralizes PAUF with high specificity and affinity. PAUF-I (NCT05141149) is a first-in-human, multicenter, open-label study in patients with advanced/metastatic pancreatic cancer. Early Phase 1 results are presented here. Methods: Key eligibility criteria for Phase 1 include: locally advanced/metastatic pancreatic cancer; at least 1 previous line of chemotherapy; ECOG 0-1; and measurable disease by RECIST v1.1. A 3+3 dose escalation design is planned for 5 dose levels of intravenous PBP1510 (doses of 1, 3, 6, 10, and 15 mg/kg), either alone (monotherapy cohorts) or in combination with gemcitabine at a dose of 1000 mg/m2 (combination cohorts), in 28-day cycles. Tumor assessments are performed every 8 weeks from the first dose of PBP1510. Dose is escalated following a safety review committee meeting, if all patients in a cohort complete the dose-limiting toxicity (DLT) observation period (28 days from first dose) without any DLTs. Primary endpoints are safety parameters including treatment emergent adverse events (TEAEs) and laboratory findings. Results: As of January 2024, 6 patients (4 males, 2 females), aged 54-71 years, were enrolled. All patients had stage IV ductal adenocarcinoma and had received at least 2 prior lines of chemotherapy. Five patients received 2 cycles of PBP1510 each at 1 mg/kg or 3 mg/kg based on their cohort. One patient received 1 cycle of PBP1510 at 3 mg/kg. Seventeen TEAEs were assessed to be related to study treatment. The most frequently reported treatment-related TEAE was asthenia (n = 7). Most treatment-related TEAEs were NCI-CTCAE Grade 1 in severity (n = 14). Five serious TEAEs not related to study treatment were reported in 2 patients. There was 1 death reported due to disease progression. No patient discontinued treatment due to TEAEs. No clinically significant abnormalities in ECG, LVEF, and clinical laboratory assessments were reported during the DLT observation period. All patients in the first 2 monotherapy cohorts completed the DLT observation period without any DLTs. Conclusions: PBP1510 was well tolerated by all patients at 1 mg/kg or 3 mg/kg in the first 2 monotherapy cohorts. The next monotherapy (PBP1510, 6 mg/kg) and combination (PBP1510, 1 mg/kg; gemcitabine 1000 mg/m2) cohorts are open for recruitment. Clinical trial information: NCT05141149 .

Complication Avoidance of Reconstruction Implant Radiation Therapy (CARIT): A Retrospective Case-Cohort Analysis.

Patients are increasingly offered implant-based reconstruction prior to radiotherapy. However, it is unclear if the radiation treatment technique itself impacts upon toxicity. We performed this study to compare outcomes following implant-based reconstruction amongst breast cancer patients treated with a standard radiotherapy technique that irradiates the entire chest wall versus a novel technique which uses a smaller clinical target volume (CTV) to spare the implant. Need for corrective surgery, capsular contracture, and cosmetic outcomes were evaluated, with the hypothesis that the novel technique would result in fewer adverse outcomes and less need for corrective surgery. A retrospective case-cohort analysis of 57 patients who had post-mastectomy, implant-based reconstruction was conducted. Patients with invasive mammary carcinoma (IMC) or ductal carcinoma in-situ (DCIS) who were treated either with the novel radiotherapy technique (n = 26) or standard PMRT (n = 31) were included. Patient demographics such as age, BMI, TNM stage, implant size, hormone receptor status, and radiation course was collected. Primary endpoint was the need for corrective surgery within two years and cosmetic outcomes, measured using the Baker Classification Scale for capsular contracture and the Modified Harvard Harris Cosmetic Scale. Secondary endpoint was radiation-induced toxicity measured using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Cosmesis and toxicity were evaluated at 3 months post-radiation, 1 year, and after 13 months. Unpaired t-tests were used to compare need for corrective surgery, cosmesis (Baker Grade 2 or higher and Harvard Harris "Good" or worse), and toxicity (NCI CTCAE Grade 2 or higher). For the primary endpoint, need for corrective surgery, there was no significant difference between the novel and standard groups (two-sided p = 0.378, CI -0.38-0.14). The other primary endpoint of cosmesis, measured with the Baker scale and Harvard Harris, was also not significantly different (two-sided p = 0.147, CI -0.06-0.45), with the Harvard Harris cosmesis differences remaining insignificant across the 3 month, 1 year, and greater than 13 month periods (two-sided p = 0.854, 0.351, 0.468, respectively). The secondary endpoint, toxicity, was not significantly different between the novel and standard PMRT groups across 3 months and 1 year time periods (two-sided p = 0.328, 0.323, respectively). We will also be reporting the analysis for predictive factors related to toxicity, need for corrective surgery and cosmesis. Compared with standard PMRT, the novel technique was not significantly different in rates of reoperation, toxicity and cosmetic outcomes. Better understanding the factors involved in PMRT outcomes for breast cancer patients with implant-based reconstructions will aid in the development of standardized approaches to treating the breast cancer patient population.

A Phase 3 Double-Blind, Randomized, Placebo Controlled Study to Evaluate the Efficacy and Safety of AB-205 Plus Standard of Care (SOC) Versus Placebo Plus Standard of Care in Adults with Lymphoma Undergoing High-Dose Therapy and Autologous Hematopoietic Cell Transplantation (E-CELERATE) (NCT05181540) - Trials in Progress

Myeloablative conditioning or high-dose therapy followed by autologous hematopoietic cell transplantation (HDT-AHCT) is a standard of care (SOC) and potentially curative consolidation therapy for eligible patients diagnosed with aggressive lymphoma. Although effective in chemosensitive patients, HDT-AHCT is associated with severe regimen-related toxicities (SRRTs) that affect quality of life and may increase mortality risk (Olivieri et al., BBMT 2018). SRRTs occur due to the off-target cytotoxicity of HDT that involves damage to the microvasculature and the vascular stem cell niches of multiple organs. SRRTs predominantly affect organs with high cell turnover causing severe complications such as diffuse gastrointestinal (GI) mucositis (oral/GI SRRT) and delayed hematopoietic recovery. Rates and severity of toxicities increase with age, relevant to the demographics of the aging lymphoma population. Importantly, patients identify oral/GI SRRT as one of the most severe adverse effects experienced with HDT-AHCT (Stiff et al., BMT 2001). Notwithstanding, there are limited treatment strategies aimed at preventing SRRTs. AB-205 is an experimental, engineered cell therapy that consists of allogeneic, human umbilical vein endothelial cells transduced with the pro-survival E4ORF1+ gene (E-CEL® cells). The proposed mechanism of action is paracrine in nature consisting of cell expression of reparative angiocrine factors which are thought to accelerate the repair injuries from off-target cytotoxicity of myeloablative conditioning. In a previously presented Phase 1/2 study [NCT03925935] in HCT-eligible patients with lymphoma, AB-205 was well tolerated and resulted in a 9% incidence of early oral/GI SRRT [defined as Grade ≥3 mucositis (M), nausea (N), vomiting (V) or diarrhea (D) in systemic lymphoma subjects conditioned with BEAM and BEAM-alternates (Phase 1/2 data is locked and analysis is in progress). This oral/GI SRRT incidence compared highly favorably to an incidence rate of 41% resulting from a contemporary, retrospective observational study conducted at two phase 1/2 sites (done concurrently during the conduct of the phase 1/2 study). Accordingly, a phase 3, randomized, double-blind, placebo-controlled multi-center study (E-CELERATE) has been initiated to further investigate the efficacy and safety of AB-205 in reducing (preventing) severe toxicities and complications related to off-target cytotoxicity of myeloablative HDT. Approximately 140 patients will be enrolled across 25 sites in the United States. Key inclusion criteria: Age ≥ 40; diagnosis of Hodgkin or non-Hodgkin lymphoma who are candidates for HDT-AHCT with one of the following myeloablative conditioning regimens: carmustine, etoposide, cytarabine, melphalan (BEAM); bendamustine, etoposide, cytarabine, melphalan (BeEAM); achieved complete response (CR) or partial response (PR) prior to planned HDT; ECOG ≤ 2; serum bilirubin ≤ 2 mg/dL; AST, ALT, and alkaline phosphatase < 3 × ULN. Key exclusion criteria: Prior HCT; primary CNS lymphoma; systemic lymphoma with secondary CNS involvement at time of relapse prior to planned HDT-AHCT; active malignancy other than the one for which the subject is undergoing HDT-AHCT; subjects with a known history of HIV. Endpoints: The primary endpoint is complete response defined as the absence of oral/GI SRRT (NCI CTCAE Grade ≥ 3 M, N, V, or D from the time of HDT through Day +21 post-HCT). Secondary endpoints include the duration of oral/GI SRRT; patient-reported symptom burden per MD Anderson Symptom Inventory; duration of febrile neutropenia; time to neutrophil engraftment; incidence of Grade ≥ 3 non-hematologic treatment emergent AEs; absence of SRRT; and survival endpoints: non-relapse mortality, progression free survival and overall survival. Eligible patients will be randomized 1:1 to receive SOC supportive care prophylaxis + AB-205 or placebo intravenously (IV) given on Day 0 within 4 hours of AHCT. 20×106 cells/kg AB-205 IV or an analogous volume of placebo IV will be administered. Randomization will be stratified by lymphoma type (HL/NHL), hematopoietic cell transplantation-comorbidity index, disease status prior to HDT (CR/PR). Daily assessments of oral/GI SRRT will occur from start of HDT to Day +21 post AHCT (Figure 1). Current status: Active recruitment and enrollment ongoing [NCT05181540]. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

All-Trans-Retinoic Acid Plus Oxaliplatin/Fluorouracil/Leucovorin for Advanced Hepatocellular Carcinoma with Pulmonary Metastasis: A Multicenter Retrospective Study.

AimTo study the impact of All-trans-retinoic acid (ATRA) plus FOLFOX4 compared to FOLFOX4 alone in patients with advanced hepatocellular carcinoma (HCC) with pulmonary metastasis.MethodsThe data of patients with advanced HCC who underwent systemic chemotherapy using FOLFOX4 or ATRA plus FOLFOX4 at the Eastern Hepatobiliary Surgery Hospital, First Hospital of Jilin University, Zhejiang Sian International Hospital and Fujian Cancer Hospital were retrospectively analyzed. The survival outcomes in the 2 groups were compared.ResultsFrom May 2014 to July 2020, 66 patients were suitable to enter into this study. The median survival (14.0 vs 8.0 months, p=0.012), and the median time to progression in the ATRA plus FOLFOX4 group were both significantly longer than those in the FOLFOX4 group (8.7 vs 3.2 months, p=0.002). The 6 month-, 1 year- and 2 year- overall survival rates were also significantly better in the ATRA plus FOLFOX4 group (100.0%, 64.7% and 20.5%; respectively) than the FOLFOX4 group (59.4%, 21.9%, and 12.5%, respectively; p<0.001). Leukocytopenia, fatigue, anorexia, nausea, were the most common acute toxicities, but these were mostly NCI CTCAE Grade 1 or 2. There was no significant difference in adverse events between the two groups.ConclusionATRA plus FOLFOX4 significantly improved the survival outcomes in patients with advanced HCC with pulmonary metastasis.

A Pilot Study of Weekly Brentuximab Vedotin in Patients with CD30+ Malignancies Resistant to Every 3 Week Brentuximab Vedotin

Background:Brentuximab vedotin (BV) is effective in treating of relapsed/refractory CD30 positive malignancies, such as classical Hodgkin lymphoma (CHL) and systemic anaplastic large cell lymphoma (ALCL). BV combines an anti-CD30 monoclonal antibody with a potent anti-microtubule agent, Monomethyl auristatin E (MMAE), disrupting the cell cycle of CD30 positive cells. Patients (pts) with relapsed/refractory CHL and systemic ALCL have shown promising overall response rates (ORR) with BV, but most patients will eventually suffer progressive disease (PD). The mechanism of resistance to BV remains unclear, however, most lymphomas with PD following BV still demonstrate CD30 expression suggesting that it may remain a viable target. Prior clinical data indicate that weekly BV dosing given on Days 1, 8 and 15 of a 28 day cycle was tolerable, had an ORR of 59% and a higher complete remission rate than was seen in a similar phase I trial of 21-day dosing of BV. We, thus, hypothesized that patients with CD30-positive lymphomas who progressed on standard BV dosing may still respond to weekly BV dosing and tested this in a prospective phase II trial. We also quantified CD30 expression to evaluate the impact of BV on CD30 expression and the impact of CD30 on response to BV, and assessed T and NK cell infiltrates for correlation with response.Methods:Eligible pts were age >18 or older with relapsed or refractory CD30 positive lymphoma who had progressed during or achieved less than a partial response following a minimum of 2 cycles of BV. Key inclusion criteria included documented expression of CD30 on tumor cells following the last dose of prior BV, as well as adequate marrow, hepatic and renal function and no major infections. Key exclusion criteria were ECOG > 2, prior transplant within 100 days, radioimmunotherapy within 12 weeks, active CNS involvement, and pre-existing neuropathy > NCI-CTCAE Grade 2 (or > Grade 1 if secondary to prior BV). Each cycle consisted of BV at 1.2 mg/kg (capped at 120mg) given over 30 minutes on Days 1, 8 and 15 every 28 days. Patients with stable disease or better could remain on therapy for up to 4 cycles. CD30 expression was quantified using multiparameter flow cytometry to identify the Hodgkin-Reed-Sternberg (HRS) cells.Results:Eight (8) pts enrolled in the study. The median age was 42 (27-68). The pts were heavily pretreated (median 6 prior lines of treatment) and 63% had undergone autologous transplant (Table 1). Histologies included CHL (7) and ALK-negative systemic ALCL (1). Pts received between 2 to 16 (median 5) prior cycles of Q3 week BV prior to enrolling in the study. All patients suffered eventual progressive disease (PD) on Q3 week BV, though 3 had a transient prior partial response (PR). Weekly BV was well tolerated with only one grade 3 event (hypokalemia). Neuropathy was seen in 5 (63%) pts: 3 Grade 1, 2 Grade 2 resulting in one treatment discontinuation. Two pts completed all 4 BV cycles on study; both had progressive disease after the 4th cycle. Of the 6 pts who terminated the study early, the majority (67%) did so due to progressive disease. One pt had a partial response to BV after 3 cycles (with a 50% decrease in size of target nodes compared to baseline). Reduction in target lesions were seen in 5/7 (71%) response-evaluable patients (Figure 1). The overall response rate (ORR) of 13% triggered the protocol-defined early stopping rule. None of the screened patients were found to have lost CD30 expression following prior BV, however expression only ranged from dim to intermediate by IHC. CD30 surface density was quantified in paired pre and post BV samples from 3 patients and did not show a significant change or correlation with response. NK and T cell infiltrates were not correlated with response.Conclusions:Pts with BV-refractory CD30 positive malignancies can safely receive weekly BV at 1.2 mg/kg dosing given on Days 1, 8 and 15 of a 28-day cycle. Even though a majority demonstrated reduction in target lesions, the response rate was low. Alterations in CD30 density on HRS cells was not observed following BV when quantified by flow cytometry. Elucidation of tumor- and immune-related mechanisms of BV resistance is needed, as BV is poised for increased use earlier in the course of therapy for HL and ALCL. [Display omitted] DisclosuresSmith:Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Sharp: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Dohme Corp: Research Funding; Merck: Research Funding. Gopal:Seattle Genetics: Consultancy, Research Funding.

Incidence and Predictors of Adverse Respiratory Events during Induction Therapy in Children with Acute Myeloid Leukemia

Background: Mortality in pediatric acute myeloid leukemia (AML) has plateaued between 30-40%, with 5-15% of these deaths occurring during initial induction. While pulmonary complications contribute to the early morbidity and mortality in pediatric AML, our knowledge of the incidence, risk factors, and patterns of respiratory adverse events (AEs) is lacking. Hypothesized risk factors for respiratory AEs during induction include hyperleukocytosis, fluid overload, coagulopathy, and infection. Our objective was to characterize the incidence, categories, and risk factors of respiratory AEs in de novo pediatric AML patients during induction chemotherapy.Methods: We conducted a single institution retrospective longitudinal study from presentation to Day 42 or initiation of the next chemotherapy cycle in de novo pediatric AML patients (age 0-21 years) presenting between January 1, 2001 and December 31, 2016. Patients were identified through the institutional cancer registry. Exclusion criteria included: relapsed AML, induction at another institution, and failure to treat with conventional protocols. Outcomes of interest included development of an NCI CTCAE (v4.0) grade 2-5 respiratory AE or death from another cause. Data was abstracted in regards to demographic and disease characteristics at presentation. Supportive care measures included fluid status, with fluid overload defined as a ≥ 10% increase from body weight at presentation or the use of ≥ 3 doses of furosemide during the follow up period. Respiratory AE was attributed to infection in cases with a positive bacterial or fungal blood culture, respiratory viral panel, endotracheal tube aspirate, or a chest imaging report explicitly suggesting a pulmonary infectious process. A single rater assigned the most specific, best fitting CTCAE category and grade for each incident event at its maximal severity. Time to event distribution curves were created and descriptive statistics using two-sample T-test, Chi square test for independence, or Fisher's exact test as appropriate were calculated (SAS v X, Cary, NC).Results: To date we have reviewed the induction course on 63 of 245 eligible patients with de novo AML. Median age at diagnosis was 8.0 years (range, 0-21 years), 58.7% were female (n = 37), and 42.9% non-Hispanic White (n = 28). During the follow up period, 3 patients died (4.8% induction death at days 5, 25, 73). The deaths at days 25 and 73 were due to pulmonary fungal infection and the death at day 5 from an intracranial bleed. During the first 42 days, 52.4% (n = 33) patients experienced 34 discrete respiratory AEs: CTCAE grade 2 in 2.9% (n = 1), grade 3 in 64.7% (n = 22), grade 4 in 26.5% (n = 9) and grade 5 in 5.9% (n = 2). Among the respiratory AEs, 44.1% required BiPAP/CPAP (n = 4) or mechanical ventilation (n = 11). As shown in Table 1, those with and without respiratory AEs differed significantly in regards to median age at diagnosis (p = .003), coagulopathy at diagnosis (PT (p = .019), D-dimer (p = .012)), and fluid overload status (p < .0001). Those with respiratory AEs did not differ by sex (p = .08), development of infection (p = .65), or WBC at diagnosis (p = .08). A bimodal distribution of time to event was (Figure 1) with 67.7% (n = 23) of AEs occurring between presentation and day 7 and classified as “early.” As seen in Table 2, there were statistically significant differences between the early and late AE groups for WBC at diagnosis (p = .007), PT at diagnosis (p = .012), and fluid overload (p = .026). While a larger proportion of the late AEs experienced infection (45.5% vs 30.4%), this did not significantly differ from the early AEs (p = .39).Conclusion: We note a high incidence of grade 2-5 respiratory AEs in pediatric patients during AML initial induction [52.4%]. Fluid overload appears to be a significant factor in early AEs. Documented infection occurred in a higher proportion of late AE cases, although this did not reach statistical significance. Future analyses will examine the role of cytogenetic factors and morphology. Pulmonology and oncology raters will independently characterize and validate the category of each respiratory AE (e.g. atelectasis, pulmonary edema, pulmonary leukostasis, pneumonia) through a standardized process for the full eligible cohort. Identifying modifiable risk factors will enable design of supportive care interventions to decrease the risk of respiratory AEs and their associated morbidities during induction. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Phase 2, International, Multicenter, Prospective Clinical Trial of Subcutaneous Tbo-Filgrastim in Pediatric Patients with Solid Tumors Undergoing Chemotherapy

Background: Chemotherapy (CT)-induced neutropenia is a common complication from chemotherapy, limiting optimal dosing and treatment. Tbo-filgrastim (GRANIX®) is a non-glycosylated recombinant methionyl human granulocyte colony-stimulating growth factor manufactured by recombinant DNA technology. It is indicated to reduce the duration of severe neutropenia (SN) in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia (FN). It is approved under a biologic license application in the United States. This phase 2, multicenter, open-label study investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and immunogenicity of tbo-filgrastim in pediatric patients receiving at least 1 cycle of myelosuppressive CT.Methods: Patients ages 1 mo to <16 y with solid tumors without bone marrow involvement were administered tbo-filgrastim 5 µg/kg/body weight once daily subcutaneously. Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last CT treatment. Daily dosing with tbo-filgrastim continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 109/L but not longer than 14 consecutive days. Patients were stratified into three age groups: infants (1 mo to <2 y), children (2 to <12 y), and adolescents (12 to <16 y). The CT regimens included at least one of the following: etoposide, doxorubicin, ifosfamide, or cyclophosphamide. The primary endpoint was the safety of tbo-filgrastim; secondary objectives were to assess the PK, PD (incidence and duration of SN, defined as absolute neutrophil count <0.5x109/L), and efficacy (incidence of FN). Immunogenicity was also assessed.Results: Fifty patients (2 infants, 30 children, and 18 adolescents) were administered a single daily dose of tbo-filgrastim. The most common cancers were rhabdomyosarcoma (14%), neuroblastoma (14%), Ewing tumors (12%), and osteosarcoma (12%). The mean (SD) number of doses administered were 9.2 (2.83) in children and 7.3 (1.88) in adolescents. Twelve and 14 doses, respectively, were administered to each infant. Serious treatment-emergent adverse events (TEAEs) were reported in 24% of patients (Table). The most common serious TEAEs were FN (12%, 4 children, 2 adolescents), anemia (8%, 4 children) and thrombocytopenia (8%, 2 children, 2 adolescents), increased alanine aminotransferase (ALT) and increased aspartate aminotransferase (AST) (6% each). The majority of grade 3 and 4 events, per Common Terminology Criteria for Adverse Events (NCI CTCAE), were in the hematologic system organ class. Nine patients (18%) experienced treatment-related TEAEs. The most common treatment-related TEAEs were musculoskeletal and connective tissue disorders (4/50, 8%) and were of NCI CTCAE grade 1 severity. Two patients (2/50, 4%) had increases in liver function enzymes considered to be related to tbo-filgrastim and CT by the investigator. No clinical symptoms were observed with these events, which resolved by the end of the study. No deaths or study withdrawal occurred during the study. PK parameters of exposure were comparable between age groups as shown by the overlap of tbo-filgrastim serum concentrations (Figure). The incidence of SN was 52% (26/50; 95% CI 0.374-0.663). The mean (SD) duration of SN was 1.8 (2.21) d. The incidence of FN was 26% (13/50; 95% CI 0.146-0.403). Immunogenicity assessments found that none of the patients had an antidrug antibody response after tbo-filgrastim treatment.Conclusion: A daily dose of tbo-filgrastim 5 μg/kg/body weight administered to pediatric patients with solid tumors without bone marrow involvement demonstrated a safety profile consistent with the safety profile in adult patients. No immunogenic response was observed in this population. The increases in liver function enzymes were considered related to both tbo-filgrastim and CT by the investigator. The sponsor assessed these events to be related to CT and concomitant medications and not related to tbo-filgrastim. The incidence of FN was on the lower end of the range in the literature. PD variables of the incidence and duration of SN provide supportive results of the efficacy of tbo-filgrastim in pediatric cancer patients. [Display omitted] DisclosuresBias:Teva ratiopharm: Employment, Equity Ownership. Lammerich:Teva ratiopharm: Employment, Equity Ownership. Roth-Ben Arie:Teva Pharmaceuticals Industries: Employment. Zou:Teva Pharmaceuticals: Employment, Equity Ownership. Buchner:Teva ratiopharm: Employment, Equity Ownership.

Programmed cell death-1 inhibitor combined with rituximab in refractory or relapsed diffuse large B-cell lymphoma: a preliminary efficacy and safety analysis

Objective: To investigate the efficacy and safety of programmed cell death protein-1 (PD-1) inhibitor combined with rituximab in the treatment of refractory or relapsed diffuse large B-cell lymphoma (rrDLBCL) patients. Methods: The efficacy and safety of rrDLBCL patients treated with PD-1 inhibitor combined with rituximab as salvage therapeutic regimen after initially treated with rituximab, cyclophosphamide, anthracycline, vincristine and prednisone (R-CHOP) regimen in Cancer Hospital, Chinese Academy of Medical Science & Peking Union Medical College from October 2018 to Janurary 2020 were retrospectively analyzed.Patient who received at least one dose of PD-1 inhibitor combined with rituximab treatment and obtained the efficacy and safety evaluation were included. Results: A total of 22 patients were enrolled in this study. The median age was 51.5 years and the median number of prior treatment regimen was 2. The median time to progression (TTP) for the initial R-CHOP treatment was 9.3 months and the median interval time of rituximab administrations between the previous and the research regimen was 5.5 months. Patients were classified as germinal center B cell (GCB) origin (n=8), non-GCB origin (n=9) and primary mediastinal large B cell lymphoma (PMBCL, n=5). Four patients were double-expression lymphoma, one patient were triple-hit lymphoma. Nine patients had PD-L1 immunohistochemical staining and the proportion of PD-L1 positive tumor cells were 1%-90% for eight patients and negative for one patient.The objective response rate (ORR) and complete response rate (CR) were 72.7% (16/22) and 13.6% (3/22), respectively. The median progression free survival (PFS) was 8.0 (95%CI: 7.0-14.5) months, and overall survival (OS) was not reached. For the 17 patients of non-specific DLBCL, the ORR was 64.7% (11/17), the estimated median PFS was 4.0 (95%CI: 0-8.8) months, the 1-year PFS and OS rates were 39.2% (95%CI: 19.4%-43.4%)and 81.3% (95%CI: 71.4%-91.1%), respectively. All of 5 PMBCL cases achieved ORR, among them, one case was CR and 4 cases were partial responase (PR), and their PFS were 16.4, 9.3, 8.3, 7.9and 3.0 months, respectively. One patient had National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 grade 3 hypophysitis and one patient had NCI CTCAE grade 3 interstitial pneumonia. Conclusion: For rrDLBCL patients who have underwent rituximab treatment previously, PD-1 inhibitor combined with rituximab regimen shows a promising efficacy and tolerability, which can be a potential treatment option.

Association of CEP72 rs924607 with vincristine-induced peripheral neuropathy (PN) in patients with diffuse large B-cell lymphoma on CALGB 50303 (Alliance).

e13535 Background: Pediatric patients (pts) receiving long-term vincristine treatment for acute lymphoblastic leukemia (ALL) who carry two variant alleles of CEP72 rs924607 experience more severe peripheral neuropathy (PN) at lower cumulative vincristine doses. The objective of this retrospective pharmacogenetic analysis was to determine if pts homozygous for rs924607 have increased PN risk when receiving short-term vincristine treatment for diffuse large B-cell lymphoma (DLBCL). Methods: Caucasian pts with DLBCL randomized to either of two vincristine-containing regimens (R-CHOP or DA-EPOCH-R) on the CALGB 50303 (Alliance) trial were genotyped for germline rs924607 via TaqMan. Vincristine was administered intravenously 1.4 mg/m2 (2 mg cap) on day 1 of each R-CHOP cycle (1.4 mg/m2/cycle) or 0.4 mg/m2/day (no cap) on days 1-4 of each DA-EPOCH-R cycle (1.6 mg/m2/cycle). Dosing was repeated every 21 days for 6 treatment cycles, for a maximum cumulative vincristine dose of 8.4 (R-CHOP) or 9.6 (DA-EPOCH-R) mg/m2 over 18 weeks. The primary analysis compared risk of NCI CTCAE grade 3 or higher PN in rs924607 homozygous variant pts versus wild-type allele carriers using multivariable Cox proportional hazards regression adjusted for treatment received (R-CHOP vs. DA-EPOCH-R), age (continuous), and sex (male vs. female). A secondary analysis was conducted only in pts assigned to the DA-EPOCH-R arm. Results: Of 307 pts included in the analysis, 32 (10.4%) experienced grade 3+ PN. PN occurrence was nominally lower in homozygous pts (5/59 = 8.5%) than wild-type carriers (27/248 = 10.9%). In the primary analysis, homozygous pts did not experience PN earlier in treatment (Hazard ratio (HR) = 1.04, (95% confidence interval: 0.39-2.75), one-sided p-value = 0.47). There was no significant difference between groups in dose-at-PN occurrence (homozygous (n = 5): 8.81 mg/m2 vs. wild-type carrier (n = 27):6.74 mg/m2, p &gt; 0.05). The secondary analysis in pts on the DA-EPOCH-R arm (n = 147), in which the majority of PN events occurred (n = 27/32 = 84%), homozygous pts (n = 26) did not have significantly increased PN risk (HR = 1.30, p = 0.56). Conclusions: This retrospective analysis of the prospective CALGB 50303 trial did not find that pts homozygous for CEP72 rs924607 had increased PN risk during short-term vincristine treatment for DLBCL. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org . ClinicalTrials.gov Id: NCT00118209.

Impact of fluid overload and infection on respiratory adverse event development during induction therapy for childhood acute myeloid leukemia.

Treatment-related morbidity and mortality occur frequently in childhood acute myeloid leukemia (AML) induction. Yet the contributions of respiratory adverse events (AEs) within this population are poorly understood. Furthermore, the roles of fluid overload (FO) and infection in AML pulmonary complications have been inadequately examined. To describe the incidence, categories, and grades of respiratory AEs and to assess the associations of FO and infection on respiratory AE development in childhood AML induction. We retrospectively examined the induction courses of a cohort of de novo pediatric AML patients for any NCI CTCAE grade 2 to 5 respiratory AE, FO, and systemic/pulmonary infection occurrence. Demographic, disease, and treatment-related data were abstracted. Descriptive, univariate, survival, and multivariable analyses were conducted. Among 105 eligible subjects from 2009 to 2016, 49.5% (n=52) experienced 63 discrete respiratory AEs. FO occurred in 28.6% of subjects (n=30), with half occurring within 24hours of hospitalization. Positive FO status<10 days (aHR 5.5, 95% CI 2.3-12.8), ≥ 10 days (aHR 13, 95% CI 4.1-41.8), and positive infection status ≥ 10 days into treatment (aHR 14.9, 5.4-41.6) were each independently associated with AE development. We describe a higher incidence of respiratory AEs during childhood AML induction than previously illustrated. FO occurs frequently and early in this course. Late infections and FO at any time frame were strongly associated with AE development. Interventions focused on the prevention and management of FO and infectious respiratory complications could be instrumental in reducing preventable treatment-related morbidity and mortality.

Referral pathways and outcome of patients with colorectal peritoneal metastasis (CRPM)

IntroductionTraditionally patients with colorectal peritoneal metastases (CRPM) were offered palliative chemotherapy and best supportive care. With the introduction of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), patients in the UK have been referred to nationally approved centres. This study describes the pattern of referral and outcomes of patients managed through one UK centre. Methodsand Methods: A prospective register recorded referrals, demographics, prior treatment pathways, and specialist multidisciplinary team (MDT) decisions (2002-2015). Peritoneal cancer index (PCI) was recorded intra-operatively; complete cytoreduction was deemed when a CC0/1 was achieved. Complications were classified using NCI CTCAE. v.4. Median overall survivals (OS) were described for those treated by CRS/HIPEC and in derived estimates for patients with isolated peritoneal metastases treated by chemotherapy alone in the ARCAD trials consortium. ResultsTwo-hundred-eighty-six patients with CRPM were referred. Despite increasing numbers of referrals annually, the proportion of patients selected for CRS/HIPEC decreased from 64.5%, to 40%, and to 37.1% for 2002–09, 2010–12, and 2013–15, respectively (p < 0.017). CRS/HIPEC was undertaken in 117 patients with a median PCI of 7 and CC0/1 achieved in 86.3%. NCI CTCAE grade 3/4 complication rates were 9.4%; 30-day mortality was 0.85%. Median OS following CRS/HIPEC was 46.0 months: that for patients not receiving CRS/HIPEC was 13.2 months. ConclusionThe evolution of the national peritoneal treatment centre over 14 years has been associated with increased referral numbers, refinement of selection for major surgery, matched with achievements of low complication rates and survival advantages in selected patients compared with traditional non-surgical treatments.

Biomodulatory therapy approach with lenalidomide in combination with pioglitazone, dexamethasone, and metronomic low-dose chemotherapy with treosulfan in patients with relapsed/refractory multiple myeloma &gt; second-line.

8037 Background: Nowadays, therapy for relapsed or refractory multiple myeloma (rrMM) usually consists of multi-targeted combination regimens for achieving complete remission. In this context, resistance resembles a therapeutic challenge that may be overcome by novel biomodulatory therapies communicatively reprogramming dysregulated cellular and intercellular homeostasis in neoplasia. Methods: The present, prospective phase II, one-arm, one-stage multi-center, open label trial, following phase I, focused on reprogramming myeloma and adjacent stroma cells in order to control rrMM beyond &gt; 2nd-line treatment and following lenalidomide resistance in prior line. Adults with rrMM were eligible for receiving continuously, oral, daily dexamethasone 1mg, pioglitazone 45mg, low-dose treosulfan as metronomic chemotherapy ( 250mg bid) and lenalidomide 15mg, respectively, until disease progression. Results: Thirty-nine patients (mean time since diagnosis, 5.7 years; 66.7% with age &gt; 60 years) had received a median of 5.5 (range 2 to 10) prior treatments. 89.5% of the patients were refractory to last therapy (all IMiD resistant), and 48.7% had received autologous stem-cell transplants. The overall response rate (CR, VGPR) was 17.9%. Eighteen patients (46.2%) had partial response or better; ten patients (25.6%) had stable disease. The disease control rate (DCR) was 71.8%. Time-to-progression was not significantly different between IMiD refractory patients and those relapsing following prior IMiD therapy or between high-risk versus non-high-risk cytogenetics. The median progression-free survival (PFS) and overall survival was 5.6 months (95% confidence interval [CI], 3.8 to 8.5) and 17.6 months (95% [CI], 14.9 to 39.2), respectively. The major AE (NCI-CTCAE grade) with grade ≥ 3 and relation to study drugs was hematologic toxicity (N = 31, 67.4%). Due to scheduled dose reductions, this was associated with only 7 (15.2%) grade ≥ 3 infections. Conclusions: The favorable safety profile, encouraging efficacy and equivalent median PFS between biomodulatory and modern targeted therapy in a historic comparison reveal a proof of concept of combined biomodulatory therapy in patients with heavily pretreated and IMiD-resistant rrMM, which should be further evaluated. Clinical trial information: NCT001010243.

Chemotherapy-induced peripheral neuropathy-patient-reported outcomes compared with NCI-CTCAE grade.

Patient-reported outcomes (PRO) are becoming increasingly recognised as essential to comprehensively collect chemotherapy-induced peripheral neuropathy (CIPN) symptom information. This study aimed to evaluate the utility and feasibility of CIPN PRO assessment tools in a real-world clinical setting through investigation of the correlation of PRO with NCI-CTCAE assessments particularly in relation to cumulative dose of chemotherapy. Patients receiving oxaliplatin or paclitaxel chemotherapy in Sydney, Australia, completed a questionnaire containing standardised CIPN PRO assessments (EORTC CIPN-20, PRO-CTCAE) via tablet device. PRO assessment scores were correlated with NCI-CTCAE grade determined by nursing assessment and analysed with respect to cumulative dose of chemotherapy. There were 87 patients who completed a total of 145 questionnaires, 68 in patients receiving oxaliplatin and 77 in patients receiving paclitaxel. CIPN PRO scores were associated with NCI-CTCAE grade, for EORTC CIPN-20 (r2 = 0.19, p < 0.01) and PRO-CTCAE (r2 = 0.41, p < 0.01), although individual patient correlation was poor. PRO assessments, however, identified higher grade symptoms, in particular symptoms causing functional impairment, at lower doses of cumulative chemotherapy compared to NCI-CTCAE. This study demonstrated that CIPN PRO may provide complementary information to nursing assessed NCI-CTCAE grade, particularly in earlier stages of chemotherapy and can be considered an important component in the comprehensive assessment of neuropathy.

Oxaliplatin desensitization after hypersensitivity reaction: A single-center experience on more than 300 procedures.

610 Background: Oxaliplatin is an essential drug in gastrointestinal oncology. Hypersensitivity reactions (HSR) occur frequently (incidence varying from 10% to 25%), leading to permanent treatment discontinuation. The present study aimed to report our experience of oxaliplatin desensitization in patients with history of HSR to oxaliplatin. Methods: We retrospectively reviewed all patients who received at least one infusion of oxaliplatin according to a desensitization protocol after prior history of HSR to oxaliplatin, from June 2011 until June 2017. HSRs were classified from NCI CTC-AE grade 1 (transient rash, fever &lt; 38°C) to grade 4 (anaphylaxis). We applied in all cases a desensitization protocol in which the oxaliplatin infusion rate is gradually increased from 1mL/hr. to 150mL/hr., on an inpatient basis. Intravenous or hepatic arterial infusion was used depending on clinical setting. Results: Overall, 54 patients were included in this study, in whom HSR to oxaliplatin occurred after a median of 9 infusions (range, 1-31). The severity of HSRs was grade 1-2 in 33 patients (61%) and grade 3-4 in 21 patients (39%). A total of 305 oxaliplatin infusions according to a desensitization protocol were performed in these 54 patients (median, 5 infusions; range, 1-20). These infusions were by intravenous route in 42 patients (78%), by hepatic arterial route in 11 patients (18%), and both in 2 patients (4%). Infusions were well tolerated in 41 patients (76%), without new HSR. The remaining 13 patients (24%) experienced HSR recurrence (grade 2, 9 patients [69%]; grade 3, 4 patients [31%]). No anaphylaxis or oxaliplatin-related death occurred. In the 21 patients with a prior history of severe (grade 3-4) HSR, oxaliplatin desensitization procedure was effective and sustained in 16 patients (79%). Among 32 evaluable patients, 23 (72%) experienced disease control (14 partial responses, 9 stable diseases). Conclusions: Rechallenging Oxaliplatin desensitization procedure was successful in three out of four patients with prior history of HSR to oxaliplatin. Our retrospective study confirms that oxaliplatin desensitization is safe, and allows patients who developed HSR to continue an effective treatment.

Definitive External Beam Radiation Therapy With Stereotactic Body Radiation Therapy Boost for FIGO Stage IB-IIB Cancer of the Cervix: Minimum 4-Year Disease Control, Toxicity, and Quality of Life Outcomes from a Phase 2 Trial

SBRT for gynecologic cancers may offer practical advantages over brachytherapy at similar radiobiologic dosing. Dose-fractionation SBRT schedules may be selected to approximate those of HDR, and SBRT eliminates the needs of optimal applicator placement and sedation. Herein, we report health-related quality of life (HRQOL), toxicity, and disease control outcomes of a prospective, phase II trial of SBRT for primary cervical cancers. Eligible patients included those with (1) pathologically confirmed cervical squamous cell carcinoma or adenocarcinoma; (2) FIGO stage IB, IIA or IIB disease; (3) technical or medical contraindication to brachytherapy; and (4) primary GTV < 125 cc following induction therapy. Induction therapy consisted of external beam radiotherapy (EBRT) to a minimum dose of 45.0 Gy encompassing primary tumor and regional pelvic lymphatics. All patients received cisplatin-based chemotherapy concurrent to EBRT. SBRT boost treatment planning then followed, and GTV delineation was aided by co-registration of the boost planning CT set to a pre-EBRT FDG PET/CT scan and post-EBRT MRI. A boost dose of 40.0 Gy was prescribed to the primary tumor and delivered over a 10-day schedule of 5 fractions of 8.0 Gy each. Assessments included (1) disease response was determined pathologically by 3-month post-therapy biopsy and radiographically by biannual PET/CT imaging for 2 years; (2) acute and chronic toxicities were assessed using the National Cancer Institute's CTCAE v3 toxicity scales; and (3) quality-of-life was scored using FACT-G measurements. Thirty-five patients with FIGO stage IB - IIB cervical cancer have been treated since June 2007 and have been followed for a median of 66.0 months and a minimum of 48.0 months. Stage distribution was as follows: 4/35 FIGO stage IB1, 9/35 FIGO stage IB2, 3/35 FIGO stage IIA1, 3/35 FIGO stage IIA2 and 16/35 FIGO stage IIB. Post-SBRT biopsy at 3 months was negative for 32 of 35 patients, or 91.4%, for all patients. At 5 years, estimated local control by combined pathologic and radiographic (i.e., PET SUVmax < 2.5) criteria at the SBRT treatment site is 88.5 % for all patients. No NCI CTCAE grade 3 or greater urinary or bowel toxicities have been observed to date. Post-treatment FACT-G scores were statistically superior compared to pre-treatment assessments for the following studied domains: physical, emotional, and functional well-being. At a minimum follow-up of 4 years, SBRT offers an effective and well-tolerated boost modality for selected FIGO stage IB - IIB cervix cancer patients otherwise contraindicated for brachytherapy. To our knowledge, this prospective phase 2 study reports the largest cohort of cervical cancer cases treated with curative intent using boost SBRT.

A Phase 1 Study of Total Marrow Irradiation Combined with High-Dose Melphalan for Patients with Relapsed/ Refractory Multiple Myeloma

High dose melphalan at 200mg/m2(Mel200) followed by autologous stem cell transplant (ASCT) prolongs the survival of patients with multiple myeloma (MM) although it does not prevent relapse. Enhancing the anti-myeloma effect of pre-transplant conditioning without increasing toxicity is an important goal. To this purpose, intensity modulated radiation therapy (IMRT) can be used to deliver radiation to the marrow (total marrow irradiation, TMI) while sparing other organs. Here we tested the safety of combining linear accelerator based TMI to Mel200 in a phase 1, 3+3 trial.Twelve patients with MM who relapsed after at least one line of therapy were enrolled in 3 dose cohorts (3Gy, 6Gy and 9Gy). Prior ASCT was permitted. All patients received Mel200 over 2 days. In addition, 1.5Gy TMI was administered twice daily for 1, 2 or 3 days depending on dose cohort. Dose-limiting toxicity was defined as the occurrence of any NCI-CTCAE grade 4/5 non-hematologic toxicity or failure to engraft prior to day 30 after ASCT. Quality of life (QoL) was assessed using the FACT-BMT scale at baseline and 90-100 days after ASCT. Three groups of patients were enrolled and received 3Gy (n=3), 6Gy (n=3) or 9Gy (n=6). Median age at time of transplant was 66 years (range 40-71). Three patients had high risk FISH/ karyotype as defined by IMWG criteria. Median lines of prior therapy was 2 (range 1-4). Five patients (42%) had undergone prior autologous transplant. Of eleven patients (92%) who received prior lenalidomide, 7 (58%) were considered lenalidomide refractory. Similarly, of 11 (92%) patients previously treated with bortezomib, 6 (50%) were considered refractory. Eleven patients had a pre-transplant PET scan performed with 8 (73%) having skeletal PET avidity.All patients received TMI as scheduled. The mean reduction in dose to organs at risk (lens, oral cavity, kidneys, liver, bowels, lung) ranged from 25-63%. Median time to neutrophil (greater than 0.5x109/L) and platelet (greater than 20x109/L) engraftment were 10 (range 9-15) and 13 (range 9-17) days respectively. There were no dose limiting toxicities. Five patients experienced a total of 7 NCI CTCAE grade 3 toxicities including: diarrhea, n=2; mucositis, n=3; and nausea, n=2. Four of 6 patients who received 9Gy did not experience any toxicity greater than grade 2. Using the FACT-BMT scale, we observed that there was no significant difference in QoL between baseline and day 90 assessments. At day 100 overall response rate was 82% with 5 patients (45%) achieving a complete response. Four of 6 patients in the 9Gy cohort achieved at least a very good partial response. With a median follow up of 314 days, all patients were alive and only 4 patients (33%) relapsed.In this phase 1 trial we showed that TMI at 9Gy can be safely added to Mel200 without an increase in transplant related toxicities. Initial promising clinical results, even in high risk MM patients, will be further tested in a phase 2 study. DisclosuresNo relevant conflicts of interest to declare.

A Phase 1B Study of CC-122 in Combination with Obinutuzumab (GA101) in Relapsed or Refractory Diffuse Large B-Cell Lymphoma and Indolent Non-Hodgkin Lymphoma

A Phase 1B Study of CC-122 in Combination with Obinutuzumab (GA101) in Relapsed or Refractory Diffuse Large B-Cell Lymphoma and Indolent Non-Hodgkin Lymphoma

Safety and Activity of Brentuximab Vedotin (BV) Plus Ifosfamide, Carboplatin, and Etoposide (ICE) for Relapsed/Refractory (Rel/Ref) Classical Hodgkin Lymphoma (cHL): Initial Results of a Phase I/II Trial

Background: When initial therapy for cHL fails, the standard approach is multiagent salvage chemotherapy followed by autologous stem cell transplant (ASCT). The success of ASCT can be predicted by achievement of complete remission (CR) by fluorodeoxyglucose positron emission tomography (PET) following salvage chemotherapy (Moskowitz, et al. Blood 2012;119:1665-70). Unfortunately, about half of patients (pts) are unable to achieve CR with first salvage. The anti-CD30 antibody-drug conjugate BV is effective as a single agent in rel/ref cHL (Younes, et al. JCO 2012;30:2183-9). Pre-ASCT salvage chemotherapy combinations with BV have been explored (LaCasce, et al. ASH 2015, #293; Garcia-Sanz, et al. ASH 2015, #582), as has a PET-adapted sequential approach with BV then ICE (Moskowitz, et al. Lancet Oncol 2015;16:284-92). We hypothesized that concurrent therapy with BV and ICE would be safe and produce high CR rates. We also sought to explore inflammatory microenvironment prognostic factors. (ClinicalTrials.gov #NCT02227199)Methods: Pts ≥ 18 years old with first relapse or primary refractory CD30+ cHL were eligible. Key inclusion criteria were ≥ 1 FDG-avid site of disease ≥ 1 cm; adequate marrow, hepatic, and renal function; and HIV-. Key exclusions were any prior BV; chemotherapy ≤ 3 weeks of enrollment; and pre-existing neuropathy > NCI-CTCAE Grade 1. All pts signed IRB-approved informed consent forms. Treatment included BV on Days 1 and 8, ifosfamide and mesna 5 g/m2 each on Day 2, carboplatin AUC 5 (capped at 800 mg) on Day 2, and etoposide 100 mg/m2daily on Days 1-3. A 3+3 dose-escalation schema for BV was used to determine the maximum tolerated dose (MTD) with ICE: starting dose was 1.2 mg/kg on Days 1 and 8, escalated to 1.5 mg/kg on Days 1 and 8 or de-escalated to 1.2 mg/kg on Day 1 only, based on rate of dose-limiting toxicity (DLT). Once MTD of BV was established, subsequent pts received this dose. 2 21-day cycles were given with G-CSF support. PET was performed after Cycle 2, with response assigned per Cheson 2007. Stem cells were collected after Cycle 2 at discretion of treating investigator. Peripheral blood (PB) pre- and post-treatment, stem cell (PBSC) product, and (when available) archived formalin-fixed paraffin-embedded tissue from presentation and relapse were collected for correlative studies. Pre-treatment PB PD-L1 levels were measured by ELISA.Results: To date, 16 pts have enrolled and completed study treatment. Median age was 32 (range, 23-60). All received ABVD-based initial chemotherapy, and 5 (31%) received radiation. 11 (69%) did not obtain CR with initial therapy. Grade 3-4 neutropenia, lymphopenia, and anemia was seen in 2 (12%) pts each; thrombocytopenia in 4 (25%) pts. 6 (38%) pts experienced Grade 3-4 non-heme toxicity, but no single toxicity occurred in > 1 pt. Neuropathy was seen in 5 (31%) pts: 4 Grade 1, and 1 Grade 3. 1 DLT (sepsis) was observed in the 9 pts treated in the dose-escalation phase, defining 1.5 mg/kg on Days 1 and 8 as the MTD of BV with ICE.Overall response rate for all enrolled patients was 94% (n=14), with 88% (n=14) and 69% (n=11) achieving CR by investigator and central independent radiographic review, respectively. 15 (94%) pts underwent PBSC collection, all of which were successful. 12 (75%) pts proceeded to ASCT immediately following this treatment. With a median follow-up of 6.5 (range, 2-20) months, there have been 3 (19%) relapses (2 were in CR after BV-ICE) and no deaths.Counts of CD68+ macrophages (15%, 14%), granzyme+ cytotoxic cells (6.2%, 8.7%), and CD20+ B cells (24%, 14%) by immunohistochemistry were not significantly different between presentation and relapse (respectively). Levels of PD-L1 were below the limit of detection (500 pg/mL) in all pts.Conclusions: Pts with rel/ref cHL can safely receive BV up to 1.5mg/kg on Days 1 and 8 per cycle of ICE. Apart from generally-mild neuropathy, adding BV does not appreciably change the toxicity profile of ICE. Observed response rates by PET are very encouraging. Inflammatory cell composition appears similar at presentation and relapse. Without more sensitive testing, circulating levels of PD-L1 are unlikely to be of use in this setting. Enrollment is ongoing, and updated clinical and correlative data, including the use of next-generation sequencing-based detection of lymphoma-specific DNA sequence as a novel method of response assessment, will be presented at the meeting. DisclosuresGopal:Seattle Genetics: Research Funding.

Abstract P5-12-02: Effect of 5 vs 2.5 mg/day letrozole on residual estrogen levels in post-menopausal women with high BMI - A prospective crossover study

Abstract Background: Some studies have suggested that women with high BMI have less benefit from aromatase inhibitors (AI) vs. tamoxifen as adjuvant treatment for early breast cancer. One possible mechanism for this observation is that complete suppression of estrogen is not achieved in these women with the standard flat dose of AI. We evaluated whether a doubling of letrozole to 5 mg/day for 4 weeks affected residual estrogen levels in this population. Methods: Post-menopausal women with early breast cancer and BMI&amp;gt;25 already taking adjuvant letrozole for at least 3 months were recruited from medical oncology clinics at 4 sites in Toronto, Canada. Fasting blood samples were collected 24 hours following the last dose at baseline (routine use of own letrozole), after 28 days of monitored adherence to a provided supply of letrozole (Femara) 2.5 mg/day (Part A), and after an additional 28 days of letrozole (Femara) 5 mg/day (Part B). Symptom/quality of life questionnaires were completed at the same timepoints. Estradiol and estrone were measured using a high sensitivity liquid chromatography-tandem mass spectrometry assay. One interim analysis for futility and efficacy was planned after 31 eligible patients had completed the study, using estradiol and O'Brien-Fleming boundaries with an inner wedge. Results: 36 patients were enrolled and started on study, and 31 eligible patients completed Parts A and B. The 5 non-completers withdrew because of adverse events (n=4, unlikely related to drug) or withdrawal of consent (n=1). Median age was 62 (range 48 to 77) and BMI 28.3 kg/m2 (Range 25.2 to 42.2 kg/m2). One patient had non-postmenopausal estrogen levels at Day 29 and Day 57 and one patient's blood assay was unsuccessful; both were excluded from further analyses. The predetermined stopping rule for futility was met. Estradiol levels (mean±standard deviation) changed from 2.68±0.40 pg/mL at baseline to 2.67±0.59 pg/mL at Day 29 to 2.70±0.53 pg/mL at Day 57. Mean change from Day 29 to Day 57 was 0.03±0.48 pg/mL (95% confidence interval -0.15 to 0.21 pg/mL). Four patients reported new or increased arthralgias (to NCI CTCAE Grade 2 or 3) while taking letrozole 5 mg/day in Part B. There was no association between changes in estradiol levels and either study non-completion or the development of arthralgias. Estrone results were similar. Conclusion: Increasing letrozole from 2.5 to 5 mg/day did not further suppress estrogen levels in women with BMI&amp;gt;25. It is unlikely that letrozole dosing tailored to body size would improve clinical outcomes. The letrozole 5 mg/day intervention was terminated based on the results of the interim analysis for futility. Citation Format: Cescon DW, Ennis M, Pritchard KI, Townsley C, Warr D, Elser C, Rao L, Stambolic V, Sridhar S, Goodwin PJ. Effect of 5 vs 2.5 mg/day letrozole on residual estrogen levels in post-menopausal women with high BMI - A prospective crossover study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-02.