Higher Non-hematologic Toxicity Research Articles

Efficacy and Safety of Reduced-Dose Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) in Patients over 80 with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)

Background: The standard treatment for newly diagnosed DLBCL has been R-CHOP for many years. Recently, Pola-R-CHP using polatuzumab vedotin has been reported to have superior efficacy to R-CHOP and is available as first-line treatment for DLBCL. However, the patients in the phase 3 POLARIX trial were under 80, and the efficacy and safety for patients over 80 are not established. To investigate the efficacy and safety of Pola-R-CHP in the elderly, we conducted this study. Patients and Methods: From September 2022 to March 2023, we retrospectively analyzed patients with newly diagnosed DLBCL treated with Pola-R-CHP at Anjo Kosei Hospital. Patients previously treated for hematologic malignancies were excluded. The dosages of polatuzumab vedotin and rituximab were not reduced, and the dosages of cyclophosphamide, doxorubicin, and prednisone or treatment schedules were determined by the treating physician. The primary endpoint was the rate of treatment continuation without early termination, and secondary endpoints were efficacy, progression free survival (PFS), and safety. Results: A total of 29 patients (younger group: under 80, n = 21; elderly group: over 80, n = 8) were consecutively enrolled. The median age in the younger group was 64 (range 42-78) and in the elderly group was 82.5 (range 80-94). Patient characteristics, including history of malignancy (24% vs 13%, p=0.50), lifestyle diseases (43% vs 50%, P = 0.73), and sanctuary lesions (10% vs 25%, P = 0.28), were comparable in both groups. However, advanced disease was significantly higher in the younger group (76% vs 38%, P = 0.05). The Revised IPI scores were similar in both groups (Very good: 5% vs 0 %, Good: 29% vs 50%, Poor: 67% vs 50%, P = 0.50). Cyclophosphamide, doxorubicin, and prednisone were administered at full dose in 71% of the younger group, but were reduced in all patients in the elderly group (P = 0.001). Peg-GCSF was administered during treatment in all cases in the elderly group. The median days to the 6th cycle were 111 (range 105-126) in the younger group and 114.5 (range 107-124) in the elderly group, with no significant difference (P = 0.37). The rate of treatment continuation until the 6th cycle was 86% in the younger group and 100% in the elderly group, with no significant difference (P = 0.27, Fig A). Three patients in the younger group discontinued treatment due to deterioration of comorbidities (n=1), early death due to infection (n=1), and insufficient treatment effect leading to regimen change (n = 1). In the positron emission tomography (PET) / computer tomography (CT)-based response evaluation after treatment, complete metabolic response was observed in 48% of the younger group and 50% of the elderly group, and partial metabolic response was observed in 19% and 13% respectively (P = 0.90, Fig B). The CT based response were evaluated during the treatment. After 2 cycles of treatment, partial response was achieved 86% of patients in younger group and 75% of those in elderly group (P = 0.50). In the elderly group, complete response was confirmed in 75% of the patients at the end of cycle 6. The 6-month PFS after treatment initiation was 95% in the younger group (95% confidence interval, 71-99%) and 100% in the elderly group (p = 0.54). The incidence of grade 3 or higher non-hematologic toxicity was 28% in the younger group and 48% in the elderly group (P = 0.27). The incidence of febrile neutropenia or grade 3 or higher infection was 76% in the younger group and 75% in the elderly group (P = 0.95), and one case of grade 5 sepsis was observed in the younger group. There were no cases of cytomegalovirus reactivation or infection. Peripheral neuropathy occurred in 3 cases (14%) in the younger group but not in the elderly group. Conclusion: Pola-R-CHP is a feasible and effective treatment in clinical practice for patients over 80 with newly diagnosed DLBCL, with efficacy equivalent to that in younger patients. Further confirmation of long-term treatment effects and safety is necessary, but reduced-dose Pola-R-CHP is a reasonable choice as a standard treatment for newly diagnosed DLBCL in the elderly.

Single Center Retrospective Study of Midostaurin Plus Intensive Chemotherapy for Older Patients with Newly Diagnosed FLT-3 Mutated Acute Myelogenous Leukemia

Background: Mutations in FLT3 (FLT3m), either internal tandem duplication (ITD) or tyrosine kinase domain (TKD) are found in approximately 25% of AML patients. The current standard of care for eligible patients is induction chemotherapy with 7 + 3 regimen with the addition of multikinase inhibitor midostaurin, based on CALGB 10603 which enrolled patients up to 59 years of age (Stone et al; NEJM 2017). Quizartinib recently demonstrated improved overall survival (OS) compared to placebo when combined with standard 7+3 induction in patients up to 75 years of age, although the benefit in patients 60 and above was less clear (Erba et al; Lancet Oncol 2023). We sought to review the clinical outcomes among patients 60 years of age or greater at our institution for who received midostaurin with 7+3 for newly diagnosed (ND) FLT3m AML. Methods: We retrospectively reviewed 20 patients, 60 years of age or older who received midostaurin in combination with 7+3 (7+3+Mido) for the treatment of ND-FLT3m AML. Response criteria of CR (complete remission) and CR without hematological recovery (CRi) were defined per standard International Working Group (IWG) AML response criteria. The primary endpoint was defined as composite CR rate (cCR: defined as patients achieving CR +CRi). Minimal residual disease (MRD) assessment was done on post-induction bone marrow aspirate using multiparametric flow cytometric assessment. The secondary endpoints were OS, leukemia-free survival (LFS) among patients with CR/Cri and proportion of patients who underwent subsequent allogeneic hematopoietic cell transplant (alloHCT). Results: Patients' demographic, cytogenetic and molecular features are summarized in Table 1, briefly, the median age was 64 (range 61-75), males (n=12, 60%), de novo AML (n=19, 95%), FLT3 ITD (n=13, 65%), FLT3 TKD (n=7, 35%). The most common consolidation regimen was high dose cytarabine (HiDAC) in combination with midostaurin (n=5, 25%). Grade 3 or higher hematologic toxicity was uniformly seen and the most common grade 3 or higher non-hematologic toxicities were neutropenic fever (19/20; 95%), cardiac disorders (3/20; 15%), and diarrhea (3/20; 15%). Dose reductions/interruption of midostaurin was required in 35% patients (n=7) and one patient died due to induction related mortality. 7+3+Mido yielded an overall response rate of 90% (18/20), with cCR noted in 75% (15/20) and MLFS seen in 15% (3/20) patients. MRD negative remission was documented in 40% (6/15) patients treated (table 2). The median follow up for the entire cohort was 9.3 months and overall survival at 6 months was 70% (14/20). The majority of patients, 70% (14/20) subsequently underwent alloHCT from matched or haploidentical donor. Reduced intensity conditioning (n=12/14; 86%) and GVHD prophylaxis with tacrolimus/ sirolimus prophylaxis (n=8; 57%) was commonly used in patients undergoing alloHCT. Six patients did not proceed to alloHCT due to death (n=4, one each due to sepsis, disease progression, infection, or intracranial bleed), comorbid conditions (n=1) or short follow up. The median OS for non HCT group was 2.3 months (range: 0.6-6.5). Detailed HCT outcomes data was available subset of patients at last data cut off (9/14; 65%). The Median age of patients undergoing HCT was 65 years (range: 62-76). The median KPS and HCT-CI for these patients was 90% (range :80-90%) and 1.5(range: 0-5) respectively. The majority of patients underwent alloHCT in CR-1(90%), all using PBSC graft from donor. The median duration of follow-up from transplant to last contact or death in the nine evaluable patients was 12.1 months. Median OS and leukemia free survival was not reached and 1-year GRFS was 50% (range:14-79%). Five patients (36%) patients received post-transplant FLT3 maintenance with the most common agents being midostaurin (n=2) and gilteritinib (n=2). Conclusion: The addition of midostaurin to intensive 7+3 chemotherapy induction for ND FLT3m AML is feasible and well tolerated in older AML patients. The combination results in high remission rates and the majority of patients are able to proceed to alloHCT.

High-dose (60 Gy) intensity-modulated radiotherapy with concurrent weekly cisplatin followed by intracavitary radiation in locally advanced cervical cancer: A phase II prospective clinical trial

ObjectiveRadiotherapy dose-escalation using intensity-modulated radiotherapy (IMRT) has been necessary to improve treatment results in cervical cancer. MethodsThis was a phase II prospective clinical trial. 88 patients with FIGO II-IVa cervical cancer were enrolled in a single center. They received high-dose (60 Gy) IMRT with weekly cisplatin to the primary tumor and clinically positive nodes followed by intracavitary radiation. The primary endpoint was 30-month PFS rate (Target; 82%, an increase of 20% compared to GOG 120 trial using standard-dose radiotherapy). Secondary endpoints were tumor response, toxicity, recurrence, distant metastasis, and overall survival. ResultsProgression-free survival rate at 30 months was 82.8%. Overall survival, locoregional recurrence, distant metastasis, and para-aortic recurrence rates at 30 months were 93.6%, 8.2%, 9.2%, and 2.4%, respectively. Forty-five (51.1%) of 88 patients achieved downstaging on MRI during radiotherapy and 80 (90.9%) patients had clinically complete response at three months after high-dose IMRT and intracavitary radiotherapy. The 30-month recurrence-free survival (92.9% vs. 73.1%, P = 0.009) and overall survival (100% vs. 87.0%, P = 0.006) were significantly higher in the downstaged group than in the non-downstaged group during radiotherapy. Grade 3 or higher hematologic toxicity was found in 11 (12.5%) patients and grade 3 or higher non-hematologic toxicity was found in 3 (3.4%) patients. Fourteen had chronic urinary (8.0%), intestinal (5.7%) toxicity, pelvic insufficiency fracture (2.3%) or vesicovaginal fistula (2.3%). ConclusionHigh-dose (60 Gy) IMRT with concurrent weekly cisplatin in locally advanced cervical cancer yielded favorable progression-free survival outcome. Tumor response during radiotherapy can be a significant prognostic factor for PFS.Clinical trial information: This prospective trial is registered at ClinicalTrials.gov Identifier: NCT02993653.

A Prospective Study of Intensity-modulated Radiation Therapy Using a Standard Radiation Dose for High-grade Glioma.

We evaluated the treatment outcomes of intensity-modulated radiation therapy (IMRT) using a standard radiation dose in patients with high-grade glioma (HGG). We conducted a prospective, single-institutional, single-arm trial. Patients aged 20-75 years with histologically proven HGG were enrolled. Surgical procedures and chemotherapy regimens were not regulated. The prescribed dose of postoperative IMRT was 60 Gy in 30 fractions over six weeks. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), completion rate of IMRT, and Grade 3 or higher non-hematological toxicity. Between 2016 and 2019, 20 patients were enrolled. According to the World Health Organization 2016 Classification, glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma were present in nine, six, and five of the recruited patients, respectively. Gross total resection, partial resection, and biopsy were performed in four, nine, and seven patients, respectively. All patients received concurrent and adjuvant chemotherapy using temozolomide with or without bevacizumab. The completion rate of IMRT was 100%. The median follow-up period was 29 months (range=6-68 months). Median OS and PFS were 30 and 14 months, respectively. No patients experienced Grade 3 or higher non-hematological toxicity. The 2-year OS rates were 100%, 57%, and 33% in Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) classes I/II, IV, and V, respectively (p=0.002; log-rank test). IMRT using the standard radiation dose in patients with HGG can be carried out safely. RTOG-RPA class appears to be useful to estimate patient prognoses.

Phase I Dose Escalation Trial of 3-Day Total Marrow and Lymphoid Irradiation for Leukemia as Part of Myeloablative Conditioning in Unrelated Bone Marrow Transplantation

<h3>Purpose/Objective(s)</h3> Increasing the total body irradiation (TBI) dose during allogeneic hematopoietic stem cell transplantation (HSCT) has the potential to decrease relapse rates. However, higher doses of TBI increase toxicity and long-term morbidity. Total marrow and lymphoid irradiation (TMLI) allow for increased treatment intensity while avoiding dose escalation for at-risk organs. TMLI is expected to improve long-term survival outcomes of HSCT for hematologic malignancies. This prospective phase I trial aimed to determine the recommended dose of 3-day TMLI for a myeloablative conditioning regimen, by increasing the dose per fraction. <h3>Materials/Methods</h3> The eligibility criteria for this study were as follows, 1) diagnosed with hematologic malignancy, 2) planned HSCT with a myeloablative regimen, 3) with clinical remission status at pre-transplantation, and 4) with no evidence of extramedullary disease. The primary endpoint of this single-institution dose escalation study was the recommended TMLI dose, based on the frequency of dose-limiting toxicity (DLT) within 100 days after HSCT; a 3 + 3 design was used to evaluate the safety of TMLI. Three dose levels of TMLI (14/16/18 Gy in 6 fractions over 3 days) were set, and the treatment protocol began at 14 Gy. DLTs were defined as grade 3 or 4 non-hematological toxicities including those of cardiac, bladder, renal, pulmonary, hepatic, and central nervous system tissues, oral mucositis, gastrointestinal toxicities according to Bearman's criteria, and other grade 3 or higher non-hematological toxicities according to the Common Terminology Criteria for Adverse Events version 4.0. Grade 4 neutropenia (as per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) associated with fever or infection lasting beyond 3 weeks, or grade 4 neutropenia persisting for at least 28 days were also considered DLTs. <h3>Results</h3> The median follow-up period after HSCT was 453 (range, 131–915) days. Three patients were enrolled for each dose level. None of the patients exhibited DLT within 100 days of HSCT. Three patients experienced relapse, and no non-relapse mortality was documented during the observation period. One patient died 306 days after HSCT due to disease relapse. <h3>Conclusion</h3> The recommended dose of 3-day TMLI for a myeloablative conditioning regimen was 18 Gy in 6 fractions. The efficacy of this regimen is currently being planned in a phase II study.

Radiation Therapy With Cyclin-Dependent Kinase 4/6 Inhibitors: A Multi-institutional Safety and Toxicity Study

Our purpose was to investigate radiation therapy (RT) toxicity when given with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) compared with RT alone. We conducted a retrospective cohort study of patients with hormonal receptor-positive and human epidermal growth factor-2 negative metastatic breast cancer treated with RT at 4 cancer centers in Alberta, Canada, between 2016 and 2020. Toxicity in patients treated with RT within 30 days of initiating to discontinuing CDK4/6i (RT+CDK4/6i) was compared with toxicity of RT in CDK4/6i-naïve patients (RT alone). The primary outcome was acute grade (G) 2 or higher, nonhematological toxicity within 30 days of RT. We also explored toxicity based on the timing of RT (prior, concurrent, post) in relation to CDK4/6i. Propensity score matching was applied to create comparable cohorts. A generalized linear mixed model was used to evaluate factors associated with acute toxicity. One hundred thirty-two patients (220 RT sites) in the RT+CDK4/6i and 53 patients (93 RT sites) in RT alone were eligible. The rate of acute G2 or higher nonhematological toxicity was 11.5% versus 7%, respectively (P=.439), and acute G3 or higher nonhematological toxicity was 3.7% versus 0%, respectively (P=.151). Acute toxicity in RT+CDK4/6i group was mainly observed when RT was given concurrently (67%), with most of the G3 toxicity recorded. After propensity score matching, the association of acute toxicity with RT+CDK4/6i versus RT alone was not significant on multivariable analysis (odds ratio, 3.13; 95% confidence interval, 0.74-13.2; P=.121). We did not observe a significant association between CDK4/6i use and acute G2 or higher nonhematological toxicity in women with metastatic breast cancer receiving palliative RT. Given the findings of G3 toxicity, caution is advised whenever CDK4/6i is given concurrently with RT.

Outcomes of anlotinib plus nab-paclitaxel/gemcitabine as first-line treatment for patients with advanced pancreatic adenocarcinoma: A retrospective analysis in China.

556 Background: Anlotinib, a novel small molecule multi-target tyrosine kinase inhibitor that can effectively inhibit VEGFR, PDGFR, FGFR, C-KIT et al, is proved to have anti-tumor angiogenesis and tumor growth inhibition effects. However, Anlotinib exploration on advanced pancreatic adenocarcinoma (PDAC) is still limited. The motivation of this work is to evaluate the efficacy and safety of anlotinib combined with nab-paclitaxel/gemcitabine in the first-line treatment of patients with advanced PDAC, and provide some evidence for the treatment regimens of advanced PDAC. Methods: This was a retrospective study in patients with advanced PDAC performed from Aug 17, 2019 to Apr 3, 2021. Patients who received anlotinib plus nab-paclitaxel/gemcitabine treatment were defined as Group 1, and patients who received nab-paclitaxel/gemcitabine as Group 2. The study was approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (P2021-13-21). The response to treatment was evaluated according to RECIST version 1.1. In addition, adverse events were evaluated by CTCAE v5.0. Results: In this work, 33 patients were included, with 17 cases in Group 1 and 16 cases in Group 2. The median PFS (mPFS) of Group 1 and Group 2 were 5.0 (95% Cl, 4.97-5.94) months and 2.7 (95% Cl, 2.4-3.3) months, respectively ( P = 0.0220). The median OS (mOS) of Group 1 and Group 2 were 9.0 (95% Cl, 6.55-11.45) months and 6.0 (95% Cl, 1.08-10.92) months, respectively ( P=0.006). The PFS rate in 3 and 6 months and the OS rate in 6 and 12 months of Group 1 were significantly higher than that of Group 2. The most common grade 3 treatment related AEs (trAEs) were hematological toxicity, with 35.29% in Group1 and 31.25% in Group 2. Non-hematological toxicity were hypertension, hand-foot syndrome and diarrhea. No grade 3 or higher non-hematologic toxicity was observed in all patients. Conclusions: Anlotinib plus nab-paclitaxel/gemcitabine as first-line treatment demonstrates encouraging efficacy and manageable AE in patients with advanced PDAC. Clinical outcomes are improved with longer PFS and OS in anlotinib plus chemotherapy group. More data are needed to confirm the long-term efficacy and safety of anlotinib plus nab-paclitaxel/gemcitabine in advanced PDAC patients.

Association between body composition and chemotherapy‐related toxicity in children with lymphoma and rhabdomyosarcoma

Body composition is associated with chemotherapy toxicity (chemotoxicity) in adults with cancer; this association remains unexplored in children with cancer. Using baseline computed tomography scans of 107 children with Hodgkin lymphoma (n = 45), non-Hodgkin lymphoma (n = 42), or rhabdomyosarcoma (n = 20), this study examined body composition (skeletal muscle index [SMI], skeletal muscle density [SMD], and height-adjusted total adipose tissue [hTAT]) to determine its association with chemotoxicity. Clinical characteristics and chemotoxicities were abstracted from medical records. Primary outcomes included grade 4 or higher hematologic toxicities and grade 3 or higher nonhematologic toxicities within 6 months of the diagnosis. Logistic regression models accounting for repeated measures were constructed to examine the association between body composition indices and chemotoxicities; adjustments were made for age at diagnosis, sex, race/ethnicity, cancer type, risk group, body mass index (measured as a percentile), or body surface area. The median SMI was 41.0 cm2 /m2 (range, 25.8-68.6 cm2 /m2 ), the median SMD was 54.1 HU (range, 35-69.4 HU), and the median hTAT was 19.5 cm2 /m2 (range, 0-226.7 cm2 /m2 ). Grade 4 or higher hematologic toxicities and grade 3 or higher nonhematologic toxicities were observed in 74.7% and 66.3% of the chemotherapy cycles, respectively. A higher SMD at diagnosis was associated with lower odds of grade 4 or higher hematologic toxicity (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.85-0.97; P = .004). SMI (OR, 0.99; 95% CI, 0.95-1.04; P = .7) and hTAT (OR, 1.00; 95% CI, 0.99-1.01; P = .9) were not associated with hematologic toxicities. Nonhematologic toxicities did not show any association with body composition. The association between low SMD and hematologic toxicities in children with lymphoma or rhabdomyosarcoma could be due to body composition-based biodistribution of chemotherapeutic agents and needs further investigation. Body composition at cancer diagnosis in children with lymphoma and rhabdomyosarcoma may provide information that could identify those at risk for serious side effects from chemotherapy. Routinely used measures such as body mass index and body surface area show poor correlations with body composition assessed via computed tomography scans.

Prephase rituximab/prednisone therapy and aging-related, proinflammatory cytokine milieu in older, vulnerable patients with newly diagnosed diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) predominantly affects older adults with suboptimal therapeutic outcomes due to increased treatment-related mortality and toxicities in vulnerable patients, clinically defined by geriatric impairments such as functional limitation, multimorbidity, or cognitive deficits. In this prospective pilot study, we evaluated a rituximab/prednisone prephase treatment strategy in 33 older, vulnerable patients with newly diagnosed DLBCL, defined by either age ≥70 years or age 60-70 years with Karnofsky performance scale (KPS) <80. A single dose of rituximab 375 mg/m2 between 3-10 days and oral prednisone for at least 5 days prior to the first dose of chemoimmunotherapy was administered. All patients completed prephase treatment and all but one commenced anthracycline-based chemoimmunotherapy. Only one early cycle death occurred. Toxicity events, defined by either unplanned hospitalization, unplanned dose reduction/delay, or chemotherapy discontinuation, occurred in 22 patients (67%). Sixteen patients (48%) experienced grade 3 or higher non-hematologic toxicities and/or grade 4 or higher hematologic toxicities. With a median follow-up of 4.4 years, both 5-year progression-free survival and overall survival were at 81% (95% confidence interval: 69-96). Importantly, we found that phenotypic impairments in basic and instrumental activities of daily living, physical function, mobility, KPS, and Cancer and Aging Research Group chemotherapy toxicity risk score were significantly associated with senescence-associated, proinflammatory cytokine milieu which was readily reversed with prephase treatment, potentially explaining its clinical effectiveness. Prephase therapy with rituximab/prednisone should be considered for all older, vulnerable DLBCL patients prior to curative intent, anthracycline-based chemoimmunotherapy. This trial was registered as clinicaltrials gov. Identifier: NCT 89028394.

A Phase 2 Study Of Lenalidomide, Rituximab, Cyclophosphamide and Dexamethasone (LR-CD) For Untreated Low Grade Non-Hodgkin Lymphoma Requiring Therapy: Waldenström's Macroglobulinemia Cohort Results

BackgroundSingle agent therapy with the novel agent lenalidomide has shown efficacy in relapsed lymphomas, through anti-proliferative and immunomodulatory mechanisms, and may have a synergistic effect with rituximab. There is limited data on the efficacy and safety of lenalidomide in multidrug combinations in treatment naïve patients. We designed a phase II single arm trial of untreated low grade NHL patients with lenalidomide, rituximab, cyclophosphamide, and dexamethasone (LR-CD) to evaluate tumor response, toxicity (adverse events) and survival1. Initial analysis showed promising results in patients with lymphoplasmacytic lymphoma (WM), and the cohort was expanded for analysis. Lenalidomide has previously been studied with rituximab in this population but significant toxicity, mainly anemia (8/16 (50%) grade 2 and 1/16 (6%) grade 3), caused cessation of study enrollment2. We report here results of the Waldenström's macroglobulinemia cohort. MethodsEligibility: 18 years of age, untreated indolent NHL, ECOG PS ≤2, nodes ≥ 2cm by MRI or CT or IgM ≥ 400mg/dL, ANC >1400 mm³, platelet count ≥ 100,000/mm³, creatinine ≤ 2mg/dL. Treatment consisted of IV rituximab 375mg/m2 on day 1, oral lenalidomide 20mg days 1-21, cyclophosphamide 250mg/m2 days 1, 8, 15, and dexamethasone 40mg days 1, 8,15, 22, on a 28 day cycle. All patients received aspirin 325 mg daily. Treatment continued 2 cycles beyond best response up to a maximum of 12 cycles. Toxicity was assessed using NCI CTCAE v3.0. ResultsSixteen patients with lymphoplasmacytic lymphoma, with monoclonal IgM present at baseline, have enrolled at Mayo Clinic with 15 evaluated for toxicity and response (1 withdrew before treatment). Four patients are still receiving treatment. Patient characteristics: median age 69 (47-83), 87% male, 100% Caucasian, median IgM 4480 (1740-7890). At baseline 4/15 (27%) patients had grade 2 anemia and 2/15 (13%) had grade 3. Median number of cycles administered was 8, and 73% completed the study per protocol. Overall best response rate was 80%, 1 patient with CR and 11 with PR. The most common grade 3 or 4 adverse events were neutropenia (13% grade 3 and 33% grade 4), anemia (27% grade 3, 13% grade 4), and leukopenia (grade 3, 13%, grade 4, 20%). Six patients had grade 3 or higher nonhematologic toxicity. At a median follow up of 17 months (0.9-38.3), 11 patients had not progressed and 4 progressed. The median PFS is 24.9 months, and the OS at 2 years is 86%. One death secondary to relapsed disease occurred 7.7 months after completing 12 cycles of treatment. ConclusionsLR-CD can be safely administered in newly diagnosed symptomatic Waldenström's macroglobulinemia. The main toxicities are anemia and neutropenia, with more anemia (≥gr3 40% vs. 14%) than seen in other low grade histologies treated with LR-CD1. A prior study of lenalidomide and rituximab in WM was stopped due to the development of anemia suggesting that lenalidomide was not a safe or efficacious drug in this disease. However, while we did see anemia develop during therapy with LR-CD, 6/15 patients had grade≥2 anemia at baseline. Compared to historical results this highly active regimen deserves study in a randomized trial.1 Blood (ASH Annual Meeting Abstracts), Nov 2012; 120: 27412 Clin Cancer Res 2009; 355 15(1) January 1, 2009This trial is sponsored by Celgene Disclosures:Off Label Use: lenalidomide is not approved for treatment of waldenstrom macroglobulinemia. Nowakowski:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stewart:Onyx: Consultancy, Research Funding; Millenium: Honoraria, Research Funding; Celgene: Honoraria; BMS: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Fonseca:millennium: Consultancy; amgen: Consultancy; Binding site: Consultancy; onyx: Consultancy; medtronic: Consultancy; Genzyme: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; lilly: Consultancy; Onyx: Research Funding; cylene: Research Funding. Tiedemann:Celgene: Honoraria; Janssen: Honoraria. Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.

Phase 2 Study of Nimotuzumab in Combination With Concurrent Chemoradiotherapy in Patients With Locally Advanced Non–Small-Cell Lung Cancer

BackgroundWe evaluated the tolerability and efficacy of nimotuzumab, a humanized IgG1 monoclonal anti–epidermal growth factor receptor antibody, with concurrent chemoradiotherapy in patients with unresectable locally advanced non–small-cell lung cancer. Patients and MethodsIn this multicenter, single-arm, open-label, phase 2 trial conducted in Japan (JapicCTI-090825), patients received thoracic radiotherapy (60 Gy, 2 Gy per fraction, 6 weeks) and four 4-week cycles of chemotherapy (day 1, cisplatin 80 mg/m2; days 1 and 8, vinorelbine 20 mg/m2). Nimotuzumab 200 mg was administrated weekly for 16 weeks. The primary endpoint was treatment completion rate, defined as the percentage of patients completing 60 Gy of radiotherapy within 8 weeks, 2 cycles of chemotherapy, and at least 75% of the required nimotuzumab dose during the initial 2-cycle concurrent chemoradiotherapy period. ResultsOf 40 patients enrolled, 39 received the study treatment, which was well tolerated, with a completion rate of 87.2%. Thirty-eight patients completed 60 Gy of radiotherapy within 8 weeks. Infusion reaction, grade 3 or higher rash, grade 3 or higher radiation pneumonitis, or grade 4 or higher nonhematologic toxicity were not observed. The objective response rate was 69.2%. The median progression-free survival (PFS) and 5-year PFS rate were 508 days and 29.0%, respectively. The 5-year PFS rate in patients with non–squamous cell carcinoma (n = 23) was 13.7% and in patients with squamous cell carcinoma (n = 16) was 50.0%. The 5-year overall survival rate was 58.4%. ConclusionAddition of nimotuzumab to the concurrent chemoradiotherapy regimen was well tolerated and showed potential for treating patients with locally advanced non–small-cell lung cancer, particularly squamous cell carcinoma.

Augmentation of Therapy for Combined Loss of Heterozygosity 1p and 16q in Favorable Histology Wilms Tumor: A Children's Oncology Group AREN0532 and AREN0533 Study Report.

In National Wilms Tumor Study 5 (NWTS-5), tumor-specific combined loss of heterozygosity of chromosomes 1p and 16q (LOH1p/16q) was associated with adverse outcomes in patients with favorable histology Wilms tumor. The AREN0533/AREN0532 studies assessed whether augmenting therapy improved event-free survival (EFS) for these patients. Patients with stage I/II disease received regimen DD4A (vincristine, dactinomycin and doxorubicin) but no radiation therapy. Patients with stage III/IV disease received regimen M (vincristine, dactinomycin, and doxorubicin alternating with cyclophosphamide and etoposide) and radiation therapy. Patients were enrolled through the AREN03B2 Biology study between October 2006 and October 2013; all underwent central review of pathology, surgical reports, and imaging. Tumors were evaluated for LOH1p/16q by microsatellite testing. EFS and overall survival were compared using the log-rank test between NWTS-5 and current studies. LOH1p/16q was detected in 49 of 1,147 evaluable patients with stage I/II disease (4.27%) enrolled in AREN03B2; 32 enrolled in AREN0532. LOH1p/16q was detected in 82 of 1,364 evaluable patients with stage III/IV disease (6.01%) in AREN03B2; 51 enrolled in AREN0533. Median follow-up for 83 eligible patients enrolled in AREN0532/0533 was 5.73 years (range, 2.84 to 9.63 years). The 4-year EFS for patients with stage I/II and stage III/IV disease with LOH1p/16 was 87.3% (95% CI, 75.1% to 99.5%) and 90.2% (95% CI, 81.8% to 98.6%), respectively. These results are improved compared with the NWTS-5 updated 4-year EFS of 68.8% for patients with stage I/II disease (P = .042), and 61.3% for patients with stage III/IV disease (P = .001), with trends toward improved 4-year overall survival. The most common grade 3 or higher nonhematologic toxicities with regimen M were febrile neutropenia (39.2%) and infections (21.6%). Augmentation of therapy improved EFS for patients with favorable histology Wilms tumor and LOH1p/16q compared with the historical NWTS-5 comparison group, with an expected toxicity profile.

Dynamic BH3 Profiling Predicts for Clinical Response to Lenalidomide Plus Chemotherapy in Relapsed Acute Myeloid Leukemia

Background: Early prediction of response to novel chemotherapy combinations for patients diagnosed with relapsed or refractory acute myeloid leukemia (R/R AML) may have clinical utility. We conducted a phase 1 clinical trial (NCT01904643) of lenalidomide (LEN) given prior to MEC (Mitoxantrone + Etoposide + Cytarabine) salvage chemotherapy (LEN+MEC) for patients with R/R AML. Although the clinical trial was terminated due to administrative reasons, we explored the utility of FACS-based BH3 and dynamic BH3 profiling (DBP) assays to predict for response. Standard BH3 profiling is a functional assay that uses synthetic peptides derived from the BH3 domains of pro-apoptotic BCL-2 family members to measure mitochondrial “priming” (a cell's readiness for apoptosis) (Ni Chonghaile, Science, 2011). DBP measures whether short term incubation with drug enhances priming (Montero J, Cell, 2015).Methods: Primary objective was to assess the safety/toxicity profile (DLTs and MTD) of LEN+MEC. LEN was administered 5-7 days prior to MEC and dose was escalated using an mTPI design with a target toxicity level of 30%. Dose levels (DL) included LEN given at doses of 15mgx5d (DL1), 15mgx7d (DL2), 25 mgx5d (DL3), 25mgx7d (DL4), 50mgx5d (DL5), and 50 mgx7d (DL6). Dose-escalation decisions were made based on DLTs that occurred during induction chemotherapy. DLT was defined as persistent cytopenias in absence of disease, gr 3 or higher non-hematologic toxicity not due to underlying disease or intolerable gr 2 toxicities attributable to LEN. Blood/bone marrow samples were collected at pre-treatment, post LEN only, and post LEN+MEC therapy. Clinical response was defined per ELN guidelines. For correlative studies, standard BH3 and DBP assays were used to measure overall mitochondrial priming and individual anti-apoptotic protein dependencies. DBP was performed after overnight (~16h) treatment with LEN at various concentrations on pretreatment leukemic blasts. Delta priming, utilized as a readout, represents the change in mitochondrial outer membrane depolarization after LEN treatment as measured by cytochrome C release following exposure to BH3 peptides. Data analysis was performed blinded to clinical response. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off level for respective clinical end points.Results: 17 total patients with R/R AML received LEN+MEC. Median age was 55 years (range: 22-72) with 12% Fav, 47% Int and 41% Adv risk by ELN risk stratification. 60% were heavily pre-treated. DLTs were observed in DL2 (n=1, gr 4 sepsis due to bacteremia), DL3 (n=1, gr 5 septic shock), and DL5 (n=1, gr3 bacteremia). MTD was not yet reached due to early study termination (although patients were treated at all 6 dose levels). No GVHD was observed among post-transplant patients. Composite remission rate among the 17 patients (CR + PR) was 35% (5 CR and 1 PR). Of the 5 patients who achieved CR, 3 of them eventually progressed. Median PFS and OS for the entire cohort was 2.30 (90% CI 1.84-3.47) and 4.60 (90% CI 2.84-22.10) months, respectively.To assess whether mitochondrial priming might correlate with clinical response, we first performed standard BH3 profiling with a series of peptides on 16 pretreatment bone marrow samples. Mitochondrial cytochrome c release in response to BIM-BH3 correlated weakly with clinical response. DBP on pretreatment myeloblasts in response to BIM (activator) or PUMA (sensitizer) peptides were able to stratify responders based on an increase in mitochondrial priming caused by ex vivo LEN treatment (P<0.01 and P<0.0005, respectively). Using ROC curve analysis, it was determined that BIM and PUMA peptides served as binary predictors of achievement of CR, with AUC 0.95 and 1.0, respectively.Conclusions: LEN+MEC was tolerable and had modest efficacy in this small study. Correlative studies showed that leukemic blasts briefly treated ex vivo with LEN which then underwent DBP were predictive of in vivo response among a heterogeneous patient population to LEN+MEC treatment. This study is an example of how a powerful biomarker can potentially identify those who are more likely to respond to novel therapies to avoid undesirable toxicity in those who would otherwise have less chance to benefit. Further validation is required to confirm the utility of DBP as a predictive biomarker to targeted agents given with chemotherapy. [Display omitted] DisclosuresGarcia:Celgene: Consultancy. Letai:AbbVie: Consultancy, Other: Lab research report; Vivid Biosciences: Equity Ownership; Flash Therapeutics: Equity Ownership; AstraZeneca: Consultancy, Other: Lab research report; Novartis: Consultancy, Other: Lab research report. Medeiros:Genentech: Employment; Celgene: Consultancy, Research Funding.

Efficacy of Herbal Medicine, TJ-14 (Hangeshashinto) for Acute Radiation Induced Enteritis: A Multi-Institutional Prospective Phase II Trial

Acute radiation-induced enteritis (ARE) is a major burden on patients receiving whole pelvic radiotherapy, but the standard treatment has not been established yet. TJ-14 (Hangeshashinto) is a herbal medicine traditionally used in East Asia. It consists of 12 kinds of herbs, and an anti-imframatory effect has been reported in a murine model. We hypothesized that this agent might be effective for ARE. In this multi-institutional phase II study (UMIN000022110), the efficacy of TJ-14 for ARE was investigated. Patients receiving radiotherapy for pelvic cancer were registered before start of irradiation. When ARE occurred during the radiation treatment period, TJ-14 (7.5 g/ day) was administered orally. ARE was defined as 1) watery bowel movement, 2) more frequent stools than baseline plus 2 per day, and 3) symptom duration of 2 or more days. ARE symptoms were evaluated weekly according to diarrhea grading scale during the pelvic radiotherapy. The primary endpoint was TJ-14 efficacy for ARE at 1 week. The secondary endpoints were: 1) the efficacy of TJ-14 at 2 and 3 weeks after administration, 2) quality of life score (FACT-G) at 1, 2, and 3 weeks after administration, and 3) adverse events during the treatment. Diarrhea grading scale worsening was defined as treatment failure and when the treatment failure was absent, TJ-14 was considered effective. Assuming that the proportion of TJ-14 effective cases was 45% compared to 20% of a control group, the target number of patients was 21. If the TJ-14 efficacy had been only seen in 8 or less, TJ-14 efficacy would have been rejected. Initially, 40 patients receiving pelvic radiotherapy were enrolled. Of these, 22 developed ARE and received TJ-14. Among these, 19 had cervical cancer and 9 received chemo-radiotherapy. In 17 of the 22 patients, efficacy of TJ-14 was shown (77%). The stool frequency per day at 1 week decreased significantly (4.9 ± 2.1 vs. 3.7 ± 1.9, p= 0.02). The effect continued at 2 weeks (2.2 ± 1.4, p= 0.004) and 3 weeks (2.1 ± 0.9, p= 0.05). Finally, 13 of the 22 patients (59%) continued TJ-14 until the radiotherapy finished. Before radiation treatment, the FACT-G score was 81.8 ± 15.1. The score aggravated at the time of ARE (72.5 ± 14.3, p= 0.009), while no further worsening was observed after TJ-14 administration. Regarding adverse events, 3 patients developed grade 2 or 3 leucopenia and 1 developed grade 2 anemia. However, these patients received chemotherapy for cervical cancer, so it might not have been a toxicity of TJ-14. Grade 1 hypokalemia was observed in 4 patients, and grade 1 constipation in 3. No Grade 2 or higher non-hematologic toxicity was observed. This study showed that as a specific medicine for ARE during pelvic radiotherapy, TJ-14 is promising enough to be examined in a phase III trial. A randomized controlled trial will start soon.

Long-term Results of a Phase I/II Trial of Nelfinavir with Concurrent Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer

The objective of this Phase I/II trial was to determine the response rate by RECIST and the median overall survival (OS) of concurrent chemoradiation (CT-RT) in combination with the radiosensitizer nelfinavir in locally advanced non-small cell lung cancer (LA-NSCLC) compared to historical controls. Nelfinavir (Dose Level (DL) 1: 625 mg PO BID, DL2:1250 mg PO BID) was administered for 7 to 14 days prior to and during concurrent CT-RT to patients (pts) with biopsy confirmed unresectable IIIA and IIIB NSCLC. 23 patients (65.7%) had stage IIIA disease; 11 patients (31.4%) had stage IIIB disease; 1 patient (2.9%) had a mediastinal recurrence after resection of early stage disease. Median age was 60 years for all patients. Nineteen patients (54.2%) were male, 16 (45.7%) were female. Ten patients (28.6%) had adenocarcinoma, 16 patients (45.7%) had squamous cell carcinoma; 9 patients (25.7%) had poorly differentiated carcinoma. Patients were treated with concurrent CT-RT to a dose of 66.6/1.8Gy and cisplatinum and etoposide. DLTs were defined as any treatment related Grade 4 hematologic toxicity requiring a break in therapy or non-hematologic Grade ≥ 3 toxicity except esophagitis and pneumonitis. Protocol specified criteria for compliance included receiving greater than 80% of the prescribed RT treatments and 70% of the prescribed nelfinavir doses. Thirty-five patients were enrolled and met protocol-specified criteria for compliance, 5 at DL1 and 30 at DL2. Two patients were enrolled and did not meet protocol-specified compliance criteria are excluded from this analysis. No DLTs were observed. The recommended phase II dose of nelfinavir was 1250 mg PO BID. Median follow-up for all patients was 6.8 years and minimum follow-up for survivors was 5 years. No Grade 4 or higher non-hematologic toxicities were observed. Of the non-hematologic toxicities: 10 patients (28%) experienced Grade 3 esophagitis/dysphagia/dehydration; 4 patients (11.4%) experienced Grade 3 nausea; 3 patients (8.5%) experienced Grade 3 anorexia; 3 patients (8.5%) experienced Grade 3 fatigue; and 1 patient (3%) experienced grade 3 diarrhea and 1 patient (3%) experienced grade 3 dyspnea. 33 of the 35 patients had evaluable post-treatment CT with RECIST response rate of 94% and (31/33) stable disease rate of 6% (2/33). The cumulative incidence of local failure as site of first failure was 20%, with the median time to failure not reached (NR). The cumulative incidence of distant failure as site of first failure was 51%, with the median time to distant failure of 15.8 months. The median progression-free survival was 12 months. The median OS for all patients was 40 months; 5 year OS was 37%. Nelfinavir administered with concurrent CT-RT is associated with acceptable toxicity and very promising local control, overall response rate, and survival in unresectable LA-NSCLC. These data suggest that nelfinavir may enhance the efficacy of chemo-RT in this disease.

A phase II study of irinotecan and pegylated liposomal doxorubicin in platinum-resistant recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 104 study)

PurposeWe report a phase II clinical study of the combination of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in platinum- and taxane-resistant recurrent ovarian cancer, based on the recommended doses determined in a phase I trial.MethodsPLD was administered intravenously at a dose of 30 mg/m2 on day 3. CPT-11 was administered intravenously at a dose of 80 mg/m2 on days 1 and 15, according to the recommendations of the phase I study. A single course of chemotherapy lasted 28 days, and patients underwent at least 2 courses until disease progression. The primary endpoint was antitumor efficacy, and the secondary endpoints were adverse events, progression-free survival (PFS), and overall survival (OS).ResultsThe response rate was 32.3% and the disease control rate was 64.5%. Grade 3 and 4 neutropenia, anemia, and a decrease in platelet count were observed in 17 (54.9%), 3 (9.7%), and 1 patient (3.2%), respectively. In terms of grade 3 or higher non-hematologic toxicities, grade 3 nausea occurred in 1 patient (3.2%), vomiting in 3 patients (9.7%), and grade 3 diarrhea and fatigue in 1 patient (3.2%). The median PFS and OS rates were 2 months and not reached, respectively. Of the 11 patients with a treatment-free interval (TFI) of ≥3 months, the response rate was 63.3%, and the median PFS was 7 months.ConclusionsThe treatment outcomes for the 31 patients enrolled in this study were unsatisfactory. However, sub-analysis suggested that patients with a TFI of ≥3 months had a good response rate and PFS. This suggests that CPT-11/PLD combination therapy may be a chemotherapy option for platinum-resistant recurrent ovarian cancer.

Multicenter, Open-Label Phase I Clinical Study of Oral Rigosertib in Japanese Patients with Recurrent/Relapsed or Refractory Myelodysplastic Syndromes: Tolerability, Efficacy, and Pharmacokinetic Profiles

Background:Rigosertib is a novel phosphoinositide 3 kinase pathway inhibitor that induces G2/M arrest leading to the apoptosis of cancer cells and myeloblasts and causes minimal damage to normal cells. A Phase I study in the U.S. showed the safety and good tolerability of oral rigosertib in patients (pts) with low, intermediate-1, intermediate-2, or high risk myelodysplastic syndromes (MDS).Methods:A multicenter, open-label Phase I clinical study was conducted to examine the tolerability of oral rigosertib in Japanese pts with recurrent/relapsed or refractory MDS, and to determine the recommended dose for a Phase II clinical study. The key eligibility criteria were as follows: patients with recurrent/relapsed or refractory MDS, aged 20 years or older, ECOG PS of 0 to 2, and no major organ dysfunctions. Rigosertib (280 and 560 mg BID) was administered orally in one 21-day cycle that consisted of the 14-day, twice-daily, oral administration term, followed by the 7-day monitoring term. In principle, oral rigosertib was administered in up to cycle 6. The primary endpoint was the dose-limiting toxicity (DLT) in each dose group. The secondary endpoints were as follows: 1) safety as assessed with adverse events (AEs) and laboratory results; 2) efficacy as assessed according to the International Working Group 2006 criteria; and 3) pharmacokinetics.Results: Between March 2013 and November 2014, 10 patients were enrolled at 7 medical institutions in Japan. However, 1 of them did not receive rigosertib because of a tendency for PS deterioration. Six pts were male, the median age was 70 years (range 52 to 80 years), and ECOG PS was 0 in 7 pts and was 1 in 2 pts. Consequently, 3 and 6 pts were eventually assigned to the 280 and 560 mg dose groups, respectively. According to the FAB classification, 4, 2, 2, and 1 pts were categorized to RAEB, RARS, RA, and RAEB-t, respectively. The prognostic factor according to IPSS was Int-1 risk in 4 pts (1 and 3 pts in the 280 and 560 mg dose groups, respectively) and was Int-2 in 5 pts (2 and 3 pts in the 280 and 560 mg dose groups, respectively). In the 280 mg dose group, 2 of 3 pts completed cycle 6, and the median relative dose intensity (RDI) was 86% (77 to 92%). In the 560 mg dose group, the maximum number of cycles delivered was 4, and the median RDI was 85% (68 to 93%). A total of 57 AEs developed. In the 280 mg dose group, grade 3 or higher nonhematologic toxicities, grade 3 type 2 diabetes mellitus, and grade 4 delirium (1/3, 33.3%) developed. In the 560 mg dose group, grade 3 AEs: cholecystitis, periodontitis, pneumonia, soft tissue infection, increased alanine aminotransferase, increased aspartate aminotransferase, and prolonged QT interval, as well as grade 5 urinary tract infection (1/6, 16.7%) developed. DLTs (all of which were grade 3 or higher nonhematologic toxicities) were observed with 1 of 3 pts in the 280 mg dose group (type 2 diabetes mellitus and delirium) and with 2 of 6 pts in the 560 mg dose group (urinary tract infection and prolonged QT interval). Serious AEs were 2 events in 1 of 3 pts in the 280 mg dose group (type 2 diabetes mellitus and delirium) and were 6 events in 3 of 6 pts in the 560 mg dose group (soft tissue infection, periodontitis, cholecystitis, and pneumonia in 1 pt, hematuria in 1 pt, and urinary tract infection in 1 pt). One pt in the 560 mg dose group died of septic shock that had been caused by a urinary tract infection during the study period. The hematological remission rate was 11.1% (1 marrow CR; 1/9 pts), and the hematological improvement rate was 11.1% (1 HI-P; 1/9 pts); however, cytogenetic response was not found. Plasma concentrations of rigosertib increased rapidly after each oral administration. Among the PK parameters, intersubject variability was observed in the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC). However, changes suggesting the accumulation of rigosertib during repeated oral administration (e.g., consistent increases in the Cmax and AUC) were not found. The urinary excretion rates of rigosertib on day 1 were 1.6 ± 1.0% and 11.0 ± 6.6% (mean ± SD) in the 280 and 560 mg dose groups, respectively.Conclusions: The present chemotherapy regimen of oral rigosertib was well tolerated. Our study indicates that the recommended dose for a Phase II clinical study is 560 mg BID in Japanese patients with recurrent/relapsed or refractory MDS. DisclosuresIshizawa:SymBio Pharmaceuticals: Research Funding. Usuki:Nippon Shinyaku: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Honoraria; Kyouwa-Kirin: Honoraria; Novartis: Honoraria; Bristol-Myer-Squibb: Honoraria; SymBio Pharmaceuticals: Research Funding. Ando:SymBio Pharmaceuticals: Research Funding. Ueda:SymBio Pharmaceuticals: Research Funding. Uike:SymBio Pharmaceuticals: Research Funding. Onishi:SymBio Pharmaceuticals: Research Funding. Iida:SymBio Pharmaceuticals: Research Funding.

Phase II study of the early start of chemotherapy after excision of primary colorectal cancer with distant metastases (Pearl Star 02).

746 Background: The start of chemotherapy usually requires a delay of about 4 weeks after surgical resection of colorectal cancer. However, there is no evidence for the required length of this delay interval. In addition, there is a chance that a patient may die because postoperative chemotherapy was not started soon enough and a metastatic tumor was able to develop rapidly. We have previously reported the first pilot study to determine the safety and feasibility of an early start of chemotherapy after resection of primary colorectal cancer with distant metastases. We therefore conducted a next study to determine the safety and efficacy of the early start of chemotherapy after the resection of colorectal cancer with distant metastases. Methods: The Pearl Star 02 study was a prospective and single-arm trial. They received XELOX therapy (130 mg/m2 of oxaliplatin on day 1 plus 1,000 mg/m2 of capecitabine twice daily on days 1–14) on the 7th postoperative day and XELOX+bevacizumab (7.5 mg/kg of bevacizumab on day 1) after the 2nd cycle of chemotherapy. Results: A total of 20 patients were enrolled from September 2011 to June 2015. Baseline characteristics included a median age of 64 years (range: 43-72) for 15 men and 5 women. The procedures included right hemicolectomy in 6 patients, sigmoidectomy in 3 patients, high anterior resection in 3 patients, low anterior resection in 2 patients, and Hartmann procedure in 6 patients. All patients started chemotherapy on postoperative day 7. Grade 3 or higher hemotoxicity and grade 3 or higher non-hematological toxicity was noted in 5.0 % and 25.0 % of patients, respectively. Postoperative complications were observed in 2 patients (superficial incisional surgical site infection and Ileus). Median progression-free survival was 14.9 months. Overall response rate was 75%. Conclusions: An early start of chemotherapy after surgery is safe and effective. These findings suggest possible changes in the start time of chemotherapy after surgery in the future. However, further studies are certainly needed to confirm these findings. Clinical trial information: UMIN000006310.

Abstract P5-19-22: A phase I clinical trial of entinostat and lapatinib in patients with trastuzumab refractory HER2-positive metastatic breast cancer

Abstract Background: Our preclinical data show that entinostat enhances the efficacy of lapatinib in HER2 positive (HER2+) breast cancer cell lines via FOX-03-mediated Bim1 expression. In-vitro and in- vivo, the combination of entinostat and lapatinib enhanced apoptosis in lapatinib-resistant cells. We conducted a phase I study with the primary objective to determine the RP2D of entinostat plus lapatinib in patients with HER2+ metastatic breast cancer with progressive disease (PD) after trastuzumab treatment. Methods: This was a single-center, open-label study to evaluate the dose limiting toxicity (DLT) and determine the MTD of every-other-week entinostat plus daily lapatinib in 28-day cycles. Patients with locally recurrent or metastatic breast cancer in whom trastuzumab had failed were enrolled. DLT was defined as: any toxicity resulting in 14 or more days of treatment delay, febrile neutropenia (NTP), grade 4 NTP for over 7 days, any grade 3 or higher non-hematologic toxicity, grade 3 nausea, vomiting, diarrhea or electrolyte imbalance lasting over 48 hours despite adequate supportive care, or a platelet count less than 10,000. Grading was assigned according to common toxicity criteria (CTC 4). A standard 3+3 dose escalation design was used. Entinostat was given at 10 mg (level 0), 12 mg (level 1), or 15 mg (level 2) by mouth every 14 days. Lapatinib was given at 1250 mg by mouth daily. Toxicity was evaluated on day 15 and day 28 for C1 and C2, and at the end of each cycle thereafter. Results: Fifteen patients with HER2+ metastatic breast cancer were enrolled. Median age was 52 years (range 26-69), median of all prior systemic treatment was 4 (range 1- 12), and median prior trastuzumab-based regimens was 2 (range 1-6). Eight patients had prior lapatinib exposure. Seven patients had ER+/HER2+ tumors. Median number of cycles completed was 2 (range 1-13). DLT was observed in 0 of 3 patients at level 0, 1 of 6 at level 1, and 1 of 6 at level 2. 3 patients at level 1 had lapatinib dose reductions because of grade 3 rash (n=2) or grade 3 dyspnea (n=1) or grade 3 abdominal pain (n=1). 2 patients at level 2 had entinostat dose reductions because of grade 4 NTP in cycle 1 (n=1) or grade 3 NTP in cycle 5 and grade 4 neutropenia in cycle 6 (n=1). Five patients had SD (defined per 2009 RECIST guidelines): two at dose level 1 for 6 months and 13 months, three at level 2 for 3, 4, and 8 months. Median time to progression was 2 months (range 1-13). The most common treatment related adverse events were fatigue (n=15), myalgia (n=14), nausea (n=14), diarrhea (n=13), anemia (n=11), and rash (n=11). Conclusion: MTD was not reached. Cumulative toxicity of entinostat plus lapatinib was fairly well tolerated. The combination therapy suggests there was clinical activity in at-least 5 patients who had SD in this cohort of heavily pretreated trastuzumab-resistant MBC. Data from the EG104900 clinical trial showed that lapatinib plus trastuzumab significantly improved median overall survival compared with lapatinib alone. Therefore, this study was modified after 15 patients to add trastuzumab to the combination. We are currently conducting a phase 1b trial to determine the MTD of entinostat, trastuzumab and lapatinib. Citation Format: Jie Willey, Ricardo H Alvarez, Daniel J Booser, Sharon H Giordano, Ana M Gonzalez-Angulo, James L Murray, Vincente Valero, Jangsoon Lee, Naoto T Ueno, Summer A Jackson, Fahad A Faruqi. A phase I clinical trial of entinostat and lapatinib in patients with trastuzumab refractory HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-22.

A validation study of preventing oxaliplatin-induced hypersensitivity reactions by dexamethasone: The AVOID trial.

727 Background: Patients treated with oxaliplatin are at risk for hypersensitivity reactions. The incidence of hypersensitivity reactions in clinical practice is estimated to be 12% to 20%. Prescribing information says that oxaliplatin is incompatible in solution with alkaline medications or media and must not be mixed these or administered simultaneously through the same infusion line. Because steroid is alkaline, the coinfusion of steroids and oxaliplatin can make oxaliplatin unstable due to the elevation of pH; further, the effectiveness of steroid in this therapy is unknown. Therefore, dexamethasone is routinely given to patients before they receive chemotherapy. However, we have reported that the pH after the addition of DEX (6.6 mg) to oxaliplatin was less than 7.4, and there is possibility that hypersensitivity reactions to oxaliplatin could have been prevented by coinfusion of dexamethasone (DEX) (Yoshida et al.2012 ASCO-GI) but just in a retrospective study. This prospective study was undertaken to evaluate the effectiveness of coinfusion of DEX to oxaliplatin for controlling hypersensitivity reactions caused by oxaliplatin. Methods: The AVOID trial is a prospective, multicenter, open-label, single-arm, phase II trial investigating hypersensitivity reactions to oxaliplatin could have been prevented by coinfusion of DEX. The study included 73 patients who received XELOX or XELOX +bevacizumab therapy for colorectal cancer. In all the patients, oxaliplatin (130mg/m²) was administered in combination with DEX (6.6 mg). Results: Hypersensitivity reactions developed in 3 patients (4.1%). Respiratory symptoms, ocular symptoms and anaphylaxis were not observed in 73 patients. The three patients experienced cutaneous reaction (erythema: grade1). Grade 3 or higher hemotoxicity was noted in 13.7% of the patients, and grade 3 or higher nonhematological toxicity was noted in 13.7%. The response rate was 58.1%. Conclusions: This trial supports coinfusion of dexamethasone and oxaliplatin reduced oxaliplatin-related hypersensitivity reactions. This effective approach should be considered for all patients who receive oxaliplatin, allowing treatment to be completed as planned. Clinical trial information: UMIN000009742.