NCI-CTC Grade Research Articles

Thiotepa, Busulfan, and Cyclophosphamide and Busulfan, Cyclophosphamide, Etoposide As Autologous Stem Cell Transplantation Conditioning Regimen in Primary Central Nervous System Lymphoma

IntroductionPrimary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma and standard treatment is yet to be established. Induction therapy with methotrexate-based chemotherapy regimen and consolidation with high-dose chemotherapy followed-by autologous stem cell transplantation (ASCT) is a good treatment option with promising outcomes, but only few studies are available. Asan Medical Center had previously used busulfan, cyclophosphamide, and etoposide regimen (BuCyE) as standard high-dose chemotherapy in consolidation therapy until thiotepa, busulfan, and cyclophosphamide regimen (TBC) was introduced in December, 2012. The purpose of this study is to compare outcomes and toxicity profile of BuCyE and TBC as conditioning regimens for ASCT in consolidation therapy of PCNSL patients.MethodsThe registry data set of PCNSL, collected from March 1993 to May 2017 at a single institute, Asan Medical Center, was retrospectively reviewed and patients who had BuCyE or TBC as conditioning regimens were enrolled in analyses. BuCyE group had busulfan with dose of 3.2 mg/kg IV in day-7 to day-5, etoposide 200 mg/ IV in day-5 to day-4 and cyclophosphamide 50 mg/kg IV in day-3 to day-2. TBC group had thiotepa with dose of 250 mg/ IV in day-9 to day-7, busulfan 3.2 mg/kg IV in day-6 to day-4 and cyclophosphamide 60 mg/kg IV in day-3 to day-2. OS was defined as from beginning of high-dose chemotherapy conditioning to any cause of death, and PFS as from beginning of ASCT to disease progression or any cause of death. Analyses with chi-square test or Fisher's exact test were done to compare variables between two groups. Survival curves were estimated by Kaplan-Meier methods with log-rank tests and multivariate analyses were done with known prognostic factors. All statistical analyses were performed using IBM SPSS version 21.0.ResultsTotal 241 patients with diagnosis of PCNSL were identified and 73 patients who had ASCT as frontline or salvage setting with conditioning regimens of either TBC (45 patients) or BuCyE (28 patients) were enrolled in analyses. Median follow-up duration was 3.7 years [IQR 0.01-10.3], median OS was 6.1 years [95% CI 3.7-8.5], and median PFS was 6.5 [95% CI 1.4-11.7]. Median age was 54 years (range, 17-65), 27.4% of patients were 60 years or older and 54.8% of patients was male. Fifty three patients (72.6%) had upfront ASCT after induction therapy and 27.4% of patients had relapsed or refractory disease. ECOG performance status and infused dose of CD34 positive cells showed no statistical difference between two groups. Proportion of patient with refractory or relapsed disease was significantly higher in TBC group [TBC 37.8%, BuCyE 10.7%, p = 0.012]. Median OS of TBC group was not reached and median OS of BuCyE group was 4.5 years [95% CI 1.8-7.2] and TBC group showed better OS with log-rank test (p = 0.048). Median PFS of TBC group was not reached and median PFS of BuCyE group was 1.3 years [95% CI 0.00-2.7] and TBC group showed better PFS with log-rank test (p = 0.007). In multivariate analyses with age, ECOG performance status, CSF protein level, serum LD level, TBC group showed significantly better OS with HR of 0.20 [95% CI 0.04-0.97, p = 0.046] and better PFS with HR of 0.24 [95% CI 0.09-0.66, p = 0.006] compared to BuCyE group. Severe oral mucositis, nausea, vomiting (NCI CTC grade 3 or 4) was higher in TBC group. Median days to engraftment were 8 days (range, 3-19) in TBC group, and 9 days (range, 3-15) in BuCyE group. Median admission duration was 17 days (range, 4-42) in TBC group, and 18.5 days (range, 14-36) in BuCyE group. One case of treatment-related mortality was reported in TBC group due to septic shock.ConclusionTBC regimen showed better outcomes in both OS, PFS compared to BuCyE. Although TBC group showed more oral mucositis, nausea, vomiting, and diarrhea, it maybe tolerable regimen compared with BuCyE considering the fact that admission duration and days to engraftment was not inferior. Further long-term follow-up results with TBC regimen are warranted. DisclosuresNo relevant conflicts of interest to declare.

Abstract CT143: Phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers

Abstract Background: Preclinical experiments in-vitro show MEK inhibitors can cause upregulation of p-FAK in KRASM cells. The combination of a MEK and FAK inhibitor could overcome this in-vitro and in-vivo. Methods: We are conducting an open label phase I dose escalation with expansion study (NCT03875820). Dose escalation evaluated a twice a week schedule (Mon/Thurs) CH5126766/VS-6766 (CH) 3 weeks out of 4 with a twice a day dosing schedule of defactinib (Def) administered 3 weeks out of 4. The dose levels explored were cohort 1 (CH 3.2 mg, 200 mg Def), cohort 2a (CH 4 mg Def 200 mg) and cohort 2b (CH 3.2 mg and Def 400 mg). Pharmacokinetic data were collected at cycle 1 d15 when both drugs were administered. In a subset of patients consenting to multiple biopsies, 3 biopsies were performed (baseline, after a single dose of CH run in and after 8-15 days of the combination therapy). At the recommended phase 2 dose (R2PD), expansion cohorts in patients with low grade ovarian cancer (LGSOC, n=20), KRASM non-small cell lung cancer (NSCLC, n=20) and KRASM colorectal cancer (CRC, n=10) will be treated. Results: Forty two patients have been treated on the trial so far. There were no dose limiting toxicities (DLTs) in the first 3 patients in cohort 1 and thus patients were recruited to cohort 2a and 2b. The cohort 2b dose level was deemed intolerable because of 2/3 patients experiencing DLTs of grade 2 rash not allowing dosing of 75% of the planned dose. No DLTs were seen in the first 6 patients treated on schedule 2a. However, given chronic grade 2 toxicities in patients on treatment > 6 months, the RP2D was deemed to be cohort 1. The most common side effects in the study were rash, CK elevation, AST elevation, hyperbilirubinemia and nausea, most of which were NCI CTC grade 1-2. All changes were reversible. The mean AUC of CH and Def at R2PD was 6179 ng*hr/ml and 2071 ng*hr/ml, respectively, which is in the range of what was seen in the single agent dose escalation studies. Sequential biopsies were obtained in 7 patients and 6/7 showed an increase in p-FAK following single agent CH which was reduced in 5/7 with combined CH and Def therapy. The response rate was 67% (4/6) or 50% (4/8) in KRASM LGSOC or all LGSOC patients treated to date, respectively. A range of KRASM were found in tumors of LGSOC patients who responded (G12V, G12A and G12D). Of the 4 patients with LGSOC who have responded to treatment, 3 have had a prior MEK inhibitor and are currently are on study for a median of 20.5 months (range 7-23 months). Expansion cohorts in LGSOC and KRASM NSCLC and CRC are ongoing and will be presented. Conclusion: We report a novel intermittent schedule of the combination of a RAF-MEK and FAK inhibitor with very promising clinical activity in patients with KRASM LGSOC including those who had been previously treated with a MEK inhibitor. Citation Format: Rajiv Shinde, Angelika Terbuch, Martin Little, Reece Caldwell, Roopa Kurup, Ruth Riisnaes, Mateus Crespo, Ruth Ruddle, Bora Gurel, Adam Stewart, Jenny King, Mona Parmar, Alison Turner, Florence Raynaud, Muneeb Mahmud, Christina Yap, Jonathan A. Pachter, Gordon B. Mills, Anna Minchom, Juanita Lopez, Susana N. Banerjee, Johann S. de Bono, Matthew Krebs, Udai Banerji. Phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT143.

Vefora, GETUG-AFU V06 study: Randomized multicenter phase II/III trial of fractionated cisplatin (CI)/gemcitabine (G) or carboplatin (CA)/g in patients (pts) with advanced urothelial cancer (UC) with impaired renal function (IRF)—Results of a planned interim analysis.

461 Background: Standard treatment for advanced UC is chemotherapy (CT) combining CI and G. 70% of pts with UC are over 65 and 40% of them are unfit for CI because of IRF or comorbidities. CA replaces frequently CI, when creatinine clearance (Cr Cl) is < 60 ml/min according to Cockroft and Gault formula (CGF). However, CA tends to show a lower efficacy than CI, due to decreased dose intensity of CT. Methods: We performed a multicentre randomized phase II/III study in order to compare the activity and safety of a CT regimen with fractionated CI or CA for advanced UC in 1st line setting among pts unfit for standard CT because of IRF (40 ≤ Cr Cl ≤ 60ml/min) according to CGF. We report here the results of the interim analysis of phase II. Treatment: Arm A: CA AUC4,5 D1+ G 1000 mg/m² D1, [D1 = D21]; Arm B: fractionated CI 35 mg/m² D1D8 + G 1000 mg/m² D1D8, [D1 = D21] The co-primary objectives of the phase II were to evaluate activity (non-progression (RECIST V1.1) at (D21 C6)) and safety defined by the absence during treatment of: IRF: Cr Cl <35 mL/min or deterioration of Cr Cl >20%; delayed CT (≥ 2 weeks); decrease twice G dose on day 1 for: NCI CTC grade III or IV non-hematologic toxicity; hematologic toxicity; A two-stage Bryant and Day design was used. Results: A planned first step analysis was performed after randomization of 25 and 21 pts from April 2015 to January 2018. 23 and 19 of them were evaluable (resp. Arm A/B). 8 failures were reported for safety reason in experimental arm B, 7 for renal toxicity. Conclusions: According to our pre planned first step analysis, the trial met criteria for excessive toxicity in experimental arm (fractionated CI), predominantly renal toxicity. The study was therefore definitely stopped. Survival results will be available at the meeting. Clinical trial information: NCT02240017 . [Table: see text]

Imatinib mesylate preoperative treatment for gastrointestinal stromal tumors: clinical analysis of 12 cases

Objective Evaluation of imatinib mesylate treatment of unresectable/marginally resectable gastric and duodenal stromal tumors,as well as its side effect and the toxicity.Methods Oral imatinib mesylate was prescribed at the dose of 400 mg/d for 12 cases of patients with unresectable/marginally resectable gastric and duodenal stromal tumors.The evaluation of the adverse reactions was in accordance with United States NCI-CTC grading standards (3rd edition).Choi standard was used to evaluate the patients at 3 and 6 month time points.Results For hematological toxicity,only 1 case of patient with Ⅲ° decreased white blood cell count,and the rest patients were with Ⅰ° to Ⅱ ° degree.For nou-hematological toxicity,the author observed cardiac toxicity,liver function damage,renal function damage,diarrhea,abdominal pain,nausea/vomiting,fatigue,anorexia,muscle pain,rash,hair loss,skin and mucosa edema.Among them,there was only 1 patient with Ⅲ° skin rash,and 1 patient with Ⅲ° edema,all the rest were with Ⅰ° to Ⅱ °.Eight and 11 cases of patients were evaluated as partial remission (PR) after 3 and 9 months of treatment respectively.Among them,nine patients were given R0 resection and 2 patients denied surgery due to old ages.One patient was stable (SD).Conclusions Preoperative treatment of patients with unresectable/marginally resectable gastrointestinal stromal tumors by imatinib mesylate will increase the resection rate.The related toxicity can be well-tolerated. Key words: Stomach neoplasms; Imatinib mesylate; Treatment, preoperative

A randomized, double-blind, placebo-controlled phase II study of maintenance therapy with tasquinimod in patients with metastatic castration-resistant prostate cancer responsive to or stabilized during first-line docetaxel chemotherapy

BackgroundThis phase II study was conducted to assess clinical efficacy of tasquinimod maintenance therapy in patients with metastatic castrate-resistant prostate cancer not progressing during first-line docetaxel-based therapy. Patients and methodsPatients were randomly assigned (1:1) to receive tasquinimod (0.25–1.0mg/day orally) or placebo. The primary end point was radiologic progression-free survival (rPFS); secondary efficacy end points included: overall survival (OS); PFS on next-line therapy (PFS 2) and symptomatic PFS, assessed using the Brief Pain Inventory (BPI) questionnaire and analgesic use. Quality of life was measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and by the EuroQol-5 Dimension Quality of Life Instrument (EQ-5D). Adverse events were recorded. ResultsA total of 219 patients were screened and 144 patients randomized. The median duration of treatment was 18.7weeks (range 0.6–102.7weeks) for the tasquinimod arm and 19.2weeks (range 0.4–80.0weeks) for the placebo arm. Median (90% CI) rPFS was 31.7 (24.3–53.7) and 22.7 (16.1–25.9)weeks in the tasquinimod and placebo arms, respectively [HR (90% CI) 0.6 (0.4–0.9), P=0.0162]. The median OS was not reached because only 14 deaths occurred by the cut-off date. No statistically significant differences between treatment arms were noted for symptomatic PFS, PFS 2, BPI score, FACT-P score, or EQ-5D. The incidence of any treatment emergent adverse event (TEAE) was similar in the tasquinimod and placebo arms (97.2% versus 94.3%, respectively), whereas severe TEAEs (NCI-CTC Grade 3–5) incidence was higher in the tasquinimod group (50.7% versus 27.1%). ConclusionsRandomized trials testing new drugs as maintenance can be successfully conducted after chemotherapy in castrate-resistant prostate cancer. Maintenance tasquinimod therapy significantly reduced the risk of rPFS by 40%. ClinicalTrialsgov identifier NCT01732549.

First-in-man phase I study assessing the safety and pharmacokinetics of a 1-hour intravenous infusion of the doxorubicin prodrug DTS-201 every 3 weeks in patients with advanced or metastatic solid tumours

PurposeDTS-201 is a doxorubicin (Dox) prodrug that shows encouraging data in experimental models in terms of both efficacy and safety compared with conventional Dox. The purpose of this phase I study was to assess the safety profile, to establish the recommended dose (RD) for clinical phase II studies and to assess potential anticancer activity of the compound. Experimental designDTS-201 was administered as a 1-hour infusion every 3 weeks in eligible patients with advanced solid tumours according to common clinical phase I criteria. Dose escalation was performed according to a modified Fibonacci schema. ResultsTwenty-five patients with a median age of 58 years (range, 30–72) were enrolled in the study. The median number of treatment cycles was 2 (range, 1–8). DTS-201 was administered at four dose levels (DLs) ranging from 80 to 400 mg/m2, which is equivalent to 45–225 mg/m2 of conventional Dox. No dose-limiting toxicity (DLT) occurred at the first two DLs. Three DLTs were observed at DL3 and DL4 (diarrhoea for DL3, vomiting and neutropenia for DL4). DL4 (400 mg/m2) was considered the maximum tolerated dose. Myelosuppression was the main toxicity, and NCI-CTC grade III–IV neutropenia was common at RD. Non-haematological adverse reactions were mild to moderate and included nausea, anorexia, asthenia and alopecia. No treatment-related severe cardiac adverse events were observed. ConclusionsDTS-201 is well tolerated and safe in heavily pretreated solid tumour patients. A high equivalent dose of Dox could be delivered without severe drug-related cardiac events. DTS-201 showed evidence of clinical activity with a confirmed partial response in a patient with soft-tissue sarcoma. The recommended phase II dose is 400 mg/m2.

A randomized exploratory phase 2 study in patients with chemotherapy-related peripheral neuropathy evaluating whole-body vibration training as adjunct to an integrated program including massage, passive mobilization and physical exercises

BackgroundChemotherapy-induced polyneuropathy (CIPN) is a common toxicity after chemotherapy, immunomodulatory drugs or proteasome inhibitors, which is difficult to treat and may also have impact on quality of life. The objective of the study was to evaluate whole-body vibration (WBV) on the background of an integrated program (IP) including massage, passive mobilization and physical exercises on CIPN.Patients and methodsIn an exploratory phase-2 study patients with CIPN (NCI CTC grade 2/3) were randomized for WBV plus IP (experimental) to IP alone (standard). 15 training sessions within 15 weeks were intended. As primary endpoint we used chair-rising test (CRT) to assess physical fitness and coordination. In addition, locomotor and neurological tests and self-assessment tools were performed.ResultsA total 131 patients with CIPN were randomized (standard, n = 65; experimental, n = 66). The median age was 60 (range 24–71) years; 44 patients had haematological neoplasms and 87 solid tumors. At baseline, all patients presented with an abnormal CRT. Fifteen (standard) and 22 (experimental) patients left the program due to progression/relapse or concomitant disease. There was no significant difference in the proportion of patients with normal CRT (<10 s) at follow up between experimental (68%) and standard (56%) (p = 0.20). All patients experienced less symptoms and pain (p < 0.001) and had improved CRT (p < 0.001) over time. WBV was significantly associated with a higher reduction of time needed for CRT (p = 0.02) and significantly improved warm-detection-threshold comparing baseline to follow-up assessment (p = 0.02).ConclusionWhole-body vibration on the background of an IP may improve physical fitness and coordination in patients suffering from CIPN. Trial registration Retrospectively registered at http://www.iscrtn.com (ISRCTN 51361937) and http://www.clinicaltrials.gov (NCT02846844).

The Outcome of Low-Risk Childhood B-Cell Precursor ALL Treated with the Japan Association of Childhood Leukemia Study (JACLS) ALL-02 Trial

Background: It is important to establish proper intensity of chemotherapeutic regimen for low risk group of childhood B-precursor ALL (BCP-ALL) to avoid late effects. For this purpose, in Japan Association of Childhood Leukemia study (JACLS) ALL-02 clinical trial, we defined standard risk (SR) group as the patients ranged from 1 to 10 years showing white blood cell (WBC) count of less than 10,000/μL at the diagnosis without predonisolone poor responder, t(4;11), t(1;19) and CNS3 to treat with less intensive chemotherapy (JACLS ALL02 SR protocol). Herein, we report the outcome of JACLS ALL02 SR protocol and analyzed prognostic factors to identify super low risk group which is curable by less intensive chemotherapy.Patientss and treatment: JACLS ALL02 SR protocol consisted of early phase therapies for total 4 months including an induction therapy using vincristine (VCR), steroids, pirarubicin (THP-ADR), and L-asparaginase (L-asp) for 4 weeks, a consolidation therapy using cyclophosphamide and a combined administration of cytarabine and dexamethasone (DEX) or 6-mercaptopurine (6-MP), a sanctuary therapy with only two cycles of high-dose methotrexate (MTX) of 3g/m2, one course of 4 drugs re-induction therapy and maintenance phase with 6-MP and oral MTX combined with VCR and PSL every 5 weeks by the end of the second year. In addition, total of 12 times of triple intrathecal therapy were administered by the end of the first year. Estimation of event free survival (EFS) and overall survival (OS) was performed using the Kaplan-Meier method and the differences were compared using the log-rank test. Multivariate analysis was performed using a Cox regression model.Results: 1252 newly diagnosed ALL patients were enrolled from April 2002 to May 2008 in JACLS ALL02 clinical trial, which include 388 patients (192 males and 196 females) in SR group (31.0%). The median age at diagnosis was 4.2 years (range, 1.0 to 9.9 years) and the median WBC count was 3,700/μL (range, 370 to 9,984 /μL). The median follow-up time was 6 year and 5 months. 4y / 8y EFS and OS (±SE) of the SR group are 91.5±1.4% / 89.4±1.7% and 97.9±0.7% / 95.2±1.2%, respectively. 4y / 8y EFS of the patients of 1 to 5 years old (n=300) and 6 to 9 years old (n=88) are 93.5±1.4% / 93.0±1.5% and 84.9±3.9% / 75.8±5.8%, respectively (log rank p=0.0003). 4y / 8y EFS of the patients with day 15 M1 marrow (n=287 ) was 92.8±1.6% / 91.6±1.8%, while those of the patients with day 15 M2 marrow (n=101) was 88.0±3.3% / 83.7±3.9% (log rank p=0.0446). When 388 patients were further classified into 4 subgroups based on genetic abnormalities, such as ETV6-RUNX1 (n=89, 22.9%), high hyperdiploid (HHD) (n=97, 25%), normal karyotype (n=147, 37.9%), and others (n=55, 14.2%), 4y-EFS/OS of each group was 97.6±5.9 /100% (ETV6-RUNX1), 91.5±2.9 /100% (HHD), 89.6±2.5 /95.1±1.8% (normal karyotype), and 86.9±4.6 /98.2±1.8% (others), suggesting poor EFS of B-others group. When HHD subgroup was divided into two groups, such as triple trisomy (TT; n=35) (trisomy of chromosome 4,10,17) and non-TT (n=62), 4y-EFS of each sub-group was 100% and 84.5±4.5%, respectively (log rank p=0.0161). Interestingly, day 15 M2 marrow was associated with poor 4y/8y EFS only in the normal karyotype subgroup (day 15 M1 vs M2 92.0±2.6% / 90.2±3.1% vs, 81.3±6.9% / 77.2±7.7%, log rank p=0.0497). The rates for NCI-CTC grade 4 infection, allergy, increase of transaminase were 1.80%, 0.26%, and 22.9%, respectively. Multivariate analysis identifies the patients of 6 to 9 years old (HR=3.178, p=<0.001) as a predictor of poor prognosis in EFS and day 15 M2 marrow (HR=3.273, p=0.027) and B-others subgroup (HR=11.1, p=0.0017) as predictors of poor prognosis in OS.Discussion: Although JACLS ALL-02 SR protocol was less intensive chemotherapeutic regimen compared to the contemporary protocols used for NCI-SR patients, good outcome of the 4y EFS and OS (91.5±1.4 % and 97.9±0.7 %) was achieved with good feasibility. Because the specific genetic subgroups such as B-others and HHD without TT were associated with relatively poor outcome, those patients should be treated with more intensive chemotherapy, especially for the patients showing initial poor response (day 15 M2). On the other hand, ETV6-RNUX1 and TT subgroups showed excellent outcome. Thus, appropriate reduction of therapy should be explored for these subgroups. DisclosuresNo relevant conflicts of interest to declare.

FAST: An international, multicenter, randomized, phase II trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without IMAB362, a first-in-class anti-CLDN18.2 antibody, as first-line therapy in patients with advanced CLDN18.2+ gastric and gastroesophageal junction (GEJ) adenocarcinoma.

LBA4001 Background: Claudin18.2 (CLDN18.2) is a tight junction protein expressed by several cancers including gastric and GEJ adenocarcinoma. IMAB362 is a chimeric monoclonal antibody that mediates specific killing of CLDN18.2-positive cancer cells by activation of immune effector mechanisms. IMAB362 has demonstrated single-agent activity and was safe and tolerable in patients (pts) with pretreated gastric cancer. Methods: Pts with advanced/recurrent gastric and GEJ cancer were centrally evaluated for CLDN18.2 expression by IHC (validated CLAUDETECT18.2 Kit). Eligible pts had a CLDN18.2 expression of ≥ 2+ in ≥ 40% tumor cells, an ECOG PS of 0–1 and were not eligible for trastuzumab. Pts were randomized 1:1 to first-line EOX (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 d1, and capecitabine 625 mg/m2 bid, d1–21; qd22) with or without IMAB362 (loading dose 800 mg/m2, then 600 mg/m2 d1, qd21). The study was extended by an exploratory Arm3 (N = 85) to investigate a high dose IMAB362 (1000 mg/m2) plus EOX, (not subject here). The primary study endpoint was PFS (Arm 1 v 2, 70% power, HR 0.72, 1-sided p = 0.1). Results: 730 pts were consented, of whom 352 pts (48%) were tested CLDN18.2+ per protocol criteria. Of those, 161 pts (median age, 58 yrs; male 64%; gastric, 80%; GEJ, 16%; esophageal, 4%) were randomized into Arms1 and 2. The study met its endpoints. IMAB362 plus EOX improved PFS (median 5.7 v 7.9 mon; HR 0.5; 95% CI 0.35–0.78, 1-sided p = 0.001) and OS (median 8.7 v 12.5 mon; HR 0.5, 95% CI 0.28–0.73) compared to EOX alone. In the subpopulation with very high CLDN18.2 expression ( ≥ 2+ intensity in ≥ 70% tumor cells), efficacy was more pronounced (PFS, 6.1 vs 9.1 mon; HR 0.46; OS, 9.3 v 16.6 mon; HR 0.44). Most common IMAB362-related adverse events included vomiting, neutropenia, and anemia, which were mostly of NCI-CTC grade 1/2. Grade 3/4 events were not significantly increased by IMAB362. Conclusions: IMAB362 combined with first-line chemotherapy exhibited a clinically relevant benefit in PFS and OS and a favorable risk/benefit profile. Clinical trial information: NCT01630083.

LBA-06 IMAB362: a novel immunotherapeutic antibody targeting the tight-junction protein component CLAUDIN18.2 in gastric cancer

Background: Claudin18.2 (CLDN18.2) is a tight junction protein expressed by several cancers including gastric and GEJ adenocarcinoma. IMAB362 is a chimeric monoclonal antibody that mediates specific killing of CLDN18.2-positive cancer cells by activation of immune effector mechanisms. Methods: Patients (pts) with advanced/recurrent gastric and GEJ cancer were centrally evaluated for CLDN18.2 expression by IHC (validated CLAUDETECT18.2 Kit). Eligible pts had a CLDN18.2 expression of≥2+ in≥40% tumor cells, an ECOG PS of 0–1 and were not eligible for trastuzumab. Pts were randomized 1:1 to first-line EOX (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 d1, and capecitabine 625 mg/m2 bid, d1–21; qd22) with or without IMAB362 (loading dose 800 mg/m2, then 600 mg/m2 d1, qd21). The study was extended by an exploratory Arm3 (N=85) to investigate a high dose IMAB362 (1000 mg/m2) plus EOX, (not subject here). The primary study endpoint was PFS. Results: 730 pts were consented, of whom 352 pts (48%) were tested CLDN18.2+ per protocol criteria. Of those, 161 pts (median age, 58 yrs; male 64%; gastric, 80%; GEJ, 16%; esophageal, 4%) were randomized into Arms1 and 2. IMAB362 plus EOX improved PFS (mPFS 4.8 v 7.9 mon; HR 0.47; p<.001) and OS (mOS 8.4 vs. 13.2 mon; HR 0.51; p<.001) compared to EOX alone. In the subpopulation with very high CLDN18.2 expression (≥ 2+ intensity in≥70% tumor cells), efficacy was more pronounced (mOS mOS 9 vs. 16.7 mo; HR 0.45; p<.001). Most common IMAB362-related adverse events included vomiting, neutropenia, and anemia, which were mostly of NCI-CTC grade 1/2. Grade 3/4 events were not significantly increased by IMAB362. Conclusions: IMAB362 combined with first-line chemotherapy exhibited a clinically relevant benefit in PFS and OS and a favorable risk/benefit profile. Clinical trial information: NCT01630083.

Irinotecan Plus Gemcitabine and Fluorouracil in Advanced Biliary Tract Cancer: A Retrospective Study

Background: Since 2010, combination therapy with gemcitabine and cisplatin is the standard treatment for patients with biliary tract cancer (BTC) based on the ABC-02 trial. However, treatment after first-line progression is less clearly defined. We therefore retrospectively analyzed the efficacy of a 3-drug chemotherapy regimen in patients with advanced BTC. Methods: Patients with advanced BTC treated with palliative chemotherapy between April 2000 and October 2005 at Regensburg University Hospital were reviewed retrospectively. We analyzed the efficacy and safety of an institutional standard 3-drug regimen consisting of irinotecan, gemcitabine and 5-FU (IGF). One cycle, lasting 21 days, included applications on days 1 and 8 consisting of 75 mg/m² irinotecan i.v. for 90 min, 1,000 mg/m² gemcitabine i.v. for 30 min and 2,000 mg/m² fluorouracil (5-FU) for 24 h. Results: A total of 12 histologically confirmed cases with gallbladder cancer and intrahepatic BTC were reviewed. Fifty percent of the patients (6/12) had been pretreated with other chemotherapies. Median progression-free survival was 9.4 months (1.5-21.5) and median overall survival was 17.2 months (2.5-24.3). Only neutropenia (8%) was observed as an NCI-CTC grade 3 toxicity. Anemia and leucopenia grades 1 and 2 were the most common side effects. Conclusions: The combination of IGF shows a promising survival benefit with manageable toxicity in patients with advanced BTC. Therefore, this regimen seems to be a feasible second-line treatment option for patients with rapid progression under first-line therapy with gemcitabine and cisplatin and with a good performance status.

Abstract P5-18-06: Trastuzumab can be safely administered concurrently with anthracycline for adjuvant treatment of HER2-positive breast cancer

Abstract Background Anthracycline and trastuzumab are the preferential choices in the treatment of HER2-positive breast cancer. Due to the unacceptably high rates of cardiotoxicity observed in the metastatic breast cancer, concurrent administration of anthracycline and trastuzumab (A+H) is contraindicated. However, in the neoadjuvant setting, A+H has shown high rates of pathological complete response and very low cardiotoxicity. So far, all the large adjuvant trials have only evaluated the sequential strategy of administration anthracycline and trastuzumab (A-H), whereas the safety and efficacy of A+H has never been evaluated prospectively. Thus, we conducted a prospective study to evaluate the cardiac safety and efficacy of A+H regimen in the adjuvant treatment of HER2-positive breast cancer. Methods This is a prospective, randomized and controlled trial. Participants, with HER2-positive, operable breast cancer, but without previous neoadjuvant treatment, were randomized to receive adjuvant A+H or A-H. If anthracycline was administered alone or sequentially to taxane, the dose of doxorubicin and epirubicin was 60mg/m2 and 90-100mg/m2, respectively. If anthracycline was given concurrently with taxane, the dose of doxorubicin and epirubicin was 50mg/m2 and 75mg/m2, respectively. Trastuzumab was given every 3 weeks (loading dose of 8mg/kg, followed by 6mg/kg) for one year. Left ventricular ejection fraction (LVEF) was monitored by echocardiogram (ECHO) at baseline (before chemotherapy) and 3, 6, 9, 12 and 24 months after the initial dose of trastuzumab. The primary endpoint was cardiac safety. The second endpoints were disease-free survival (DFS) and overall survival. ClinicalTrials.gov ID: NCT01413828. Results Between August 2011 and March 2014, 196 HER2-postive breast cancer patients (98 in the A+H group and 98 in the A-H group) were enrolled and randomized. Women in the two groups had similar baseline characteristics including age, tumor stage, hormonal receptor status, chemotherapy regimen, radiation therapy and endocrine therapy. Trastuzumab was well-tolerated in both groups and the primary cardiac event was asymptomatic decrease in LVEF. In the A+H group, there were 11 (11.2%) patients showed more than 10% but less than 20% reduction in LVEF (NCI-CTC Grade I). In the A-H group, there were 14 (14.3%) patients showed NCI-CTC Grade I LVEF reduction and 1 (1.0%) patient showed more than 20% reduction in LVEF (NCI-CTC Grade II). There was no case of congestive heart failure. The difference of the rates of cardiac events between the two groups was not significant (P=0.400). The mean LVEF of the baseline and 3, 6, 9, 12 and 24 months after initial dose of trastuzumab also showed no difference between the two groups. Patients in both groups had excellent disease control at a median follow up of 16 months. There were numerically more DFS events in the A-H group (6/98, 6.1%) than the A+H group (10/98, 10.2%), but the difference of DFS did not reach the statistical significance (P=0.485). There was no death in both groups. Conclusions Trastuzumab administered concurrently with anthracycline is a safe adjuvant regimen and might improve the survival of patients with HER2-positvie breast cancer. Citation Format: Songjie Shen, Qiang Sun, Ying Xu, Yidong Zhou, Jinghong Guan, Feng Mao, Yan Lin, Xuejing Wang. Trastuzumab can be safely administered concurrently with anthracycline for adjuvant treatment of HER2-positive 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 P5-18-06.

Absence of Liver Toxicity in Perampanel-Treated Subjects: Pooled results from partial seizure phase III perampanel clinical studies

The liver plays a major role in the metabolism and elimination of many antiepileptic drugs (AEDs), including perampanel. Some of the metabolites identified for perampanel are likely formed via reactive intermediates, which have the potential to covalently bind to protein and cause idiosyncratic toxicities, including hepatotoxicity. The approved AED perampanel is a selective, noncompetitive AMPA receptor antagonist. The safety and tolerability of perampanel have been well documented in 3 double-blind, randomized, placebo-controlled, phase III studies. Here we report the effects of perampanel on liver function in patients from the phase III studies to assess the potential for liver toxicity. Following 6-week baseline, patients (≥12 years old) with drug-resistant partial seizures were randomized to once-daily double-blind treatment (6-week titration, 13-week maintenance) with 2, 4, 8, or 12mg perampanel (n=1038) or with placebo (n=442). Clinical laboratory tests for hepatobiliary laboratory parameters were evaluated at baseline and at end of treatment. These included alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and total bilirubin. Treatment-emergent markedly abnormal values (an increase in NCI-CTC grade relative to baseline and a grade ≥2) and treatment-emergent adverse events (TEAEs) related to hepatobiliary parameters were also recorded. Mean hepatobiliary values were within normal ranges at baseline and end of treatment for all perampanel groups and placebo. Mean changes from baseline to end of treatment were small. The incidence of markedly abnormal results was very low for perampanel and placebo. TEAEs related to hepatobiliary parameters occurred in 0.4% of perampanel patients and 0% of placebo patients. Hepatobiliary disorders included cholelithiasis (n=3 in perampanel) and abnormal hepatic function (n=1 in perampanel). None of the events were serious or led to perampanel discontinuation. No subject had values that met the criteria for Hy's Law. Hepatobiliary laboratory data and related TEAEs were not notably different between perampanel and placebo treatment groups, and no dose-related trends were observed. Based on the laboratory results from the 3 Phase III studies, perampanel (2, 4, 8, and 12mg) demonstrated no clinically important effects on liver function tests, indicating perampanel is an AED with a low potential for drug-induced liver toxicity.

A prospective study to evaluate the usefulness of the clanging tuning fork test and the nerve conduction velocity test for oxaliplatin-induced peripheral neuropathy.

544 Background: Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Cumulative sensory peripheral neurotoxicity results in discontinuation of chemotherapy for cancer and impairs neurological function irreversibly. To develop new strategies to continue chemotherapy according to the treatment plan without more severe neurotoxicity, objective assessment tools for oxaliplatin-induced peripheral neuropathy (OIPN) are needed. The clanging tuning fork test (CTFT) and the nerve conduction velocity test (NCVT) are widely used forbenign neuropathies. However, little is known about their clinical usefulness for OIPN. Methods: Colorectal cancer patients were prospectively monitored at baseline and during chemotherapy with modified FOLFOX6. The incidence and severity of OIPN were recorded using NCI-CTC grading (ver. 4.0). CTFT was conducted every 2 weeks and NCVT every 8 weeks. A generalized estimating equation model was used to examine the correlations between NCI-CTC grade and CTFT/NCVT. The accuracy of the assessment was evaluated using receiver operating characteristic (ROC) curve analysis. Results: Twenty-one patients without peripheral sensory neuropathy (PSN) were enrolled. Mean CTFT values were 13.4 ± 0.7 sec at baseline, 14.1 ± 0.4 sec with grade 0 PSN, 14.0 ± 0.4 sec with grade 1 PSN, 12.5 ± 0.7 sec with grade 2 PSN, and 7.5 ± 0.9 sec with grade 3 PSN. The mean CTFT value with grade 3 PSN was significantly shorter than with the other grades (p&lt;.001, all). ROC curve analysis showed that variation in CTFT provides a high-accuracy assessment of grade 3 PSN (AUC=0.898, 95% CI: 0.764-1.000, p=.004), and its optimal cut-off value was -3.5 sec (sensitivity and specificity for grade 3 PSN were 86% and 79%, respectively). Unlike CTFT, NCVT showed little association with OIPN. Conclusions: CTFT was found to be very effective for assessing grade 3 OIPN. The present results suggest that CTFT, a simple, quick, and non-invasive examination, is a promising assessment tool for OIPN. Clinical trial information: 000004305.

Phase I/II Trial of Weekly Escalated Dose Bortezomib Combined with Lenalidomide and Dexamethasone in Patients in First Relapse or Primary Refractory Disease after First Line Therapy for Multiple Myeloma

Background Both Bortezomib and Lenalidomide monotherapy, as well as in combination with dexamethasone and chemotherapy, have shown high overall response rates (ORR) in relapsed and refractory multiple myeloma (RRMM). Recently, the combination of Bortezomib (1.0 mg/m2), Lenalidomide (15 mg) and Dexamethasone was reported to show efficacy in RRMM. (Richardson, Blood 2014) Here, we report the long-time follow-up results of a multicenter, dose-escalating phase I-II trial, HOVON86, which evaluated the effect of weekly escalated dose Bortezomib combined with Lenalidomide and Dexamethasone as reinduction treatment followed by Lenalidomide monotherapy for maintenance treatment in patients with RRMM after first line therapy. (Trial EudraCTnr 2007-002533-37)Methods In the dose escalation part of the study, the maximum tolerated dose (MTD) and recommended dose level (RDL) of weekly Bortezomib and Lenalidomide with Dexamethasone were determined according to a ‘3 + 3′ dose-escalation scheme. A maximum of 4 dose levels were planned. Bortezomib was administered once weekly by rapid intravenous administration on days 1, 8, and 15, at a starting dose of 1.3 mg/m2 and planned to be escalated to 1.6 mg/m2, Lenalidomide was administered days 1-21 followed by a one-week interval at a starting dose of 10 mg/day and planned to be increased to 15 mg at dose level 3 and 4. Low dose Dexamethasone was added at a fixed dose of 20 mg days 1,2,8,9,15, and 16. Cycles were repeated at 28 days for a maximum of 8 cycles. The MTD was defined as the level with 2 dose-limiting toxicities (DLT) minus 1 level. A phase II part of the study was performed at the MTD level. All patients received Lenalidomide maintenance at a dose of 10 mg/day, days 1-21 in 28 day cycles until relapse or progression. Patients received valaciclovir prophylaxis with Bortezomib and prophylactic salicylic acid throughout treatment.Results 81 patients with a first RRMM were enrolled, 4 patients were non-eligible based on not having measurable disease. The median age of all 77 evaluable patients at enrollment was 66 years (range, 46–84), 64% male, and 26%/5% of patients had ISS II/III disease. In the Phase 1 part, 15 patients received Bortezomib/Lenalidomide/Dexamethasone according to dose level 1: 1.3 mg/m2/10mg/20mg (n=3), dose level 2: 1.6 mg/m2/10mg/20mg (n=6) or dose level 3: 1.6 mg/m2/15mg/20mg (n=6). The DLT was reached at the 3rd dose level, due to two grade 3 non-hematological DLT’s. There were no DLT’s in dose level 1 or 2. Therefore, the RDL for the phase 2 part was established at Bortezomib 1.6 mg/m2, Lenalidomide 10 mg, Dexamethasone 20 mg.In the Phase 2 part of the study, the ORR after induction in 70 patients at the RDL of Phase I (n=6) and in Phase II (n=64), was 89%, with 64% CR +VGPR, table 1. The median number of cycles to achieve ≥PR was 1, while the median number of cycles to maximum response was 2. The median duration of response was 28 months. The median progression free survival (PFS) and overall survival (OS) were 19 and 42 months, respectively, Figure 1. The median time to progression was 27 months; the median time to next treatment was 19 months.Prognostic factors associated with PFS included complex karyotype, defined as showing 3 or more abnormalities; no prognostic factors were identified in association with OS.Hematologic toxicity NCI-CTC grade 1-4 occurred in 33/70 (47%) of patients, including 30% grade 3-4. Infectious complications concerned grade 2 in 29% and grade 3 in 16% of patients. Thrombo-embolic events (VTE) occurred in 2 patients (3%). 41/70 (59%) patients developed polyneuropathy (PN) grade ≥ 1; of these 41 patients, 18 patients experienced sensory PN, 2 patients had motor PN, and in 21 cases the type of PN was not further specified. 29 (41%) patients had grade 1-2, and the remaining 12 (17%) patients had grade 3-4 PN. 12/29 (41%) patients received a dose reduction upon development of PN grade 1-2, 11/12 (92%) patients upon development of grade 3-4 PN. 19/29 (66%) patients with grade 1-2 PN showed a complete recovery as compared to 6/12 (50%) patients with grade 3-4 PN.Conclusion Weekly Bortezomib 1.6 mg/m2 plus Lenalidomide 10 mg/day, combined with low-dose Dexamethason is a feasible, effective treatment for relapsed, refractory patients with manageable toxicity.Table 1Phase 1: n(%)Phase 2: n(%)Total: n(%)Total66470CR+VGPRNo3(50%)2(34%)25(36%)Yes3(50%)42(66%)45(64%)ORR: ≥PRNo1(17%)7(11%)8(11%)Yes5(83%)57(89%)62(89%) [Display omitted] [Display omitted] DisclosuresKersten:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees. Vellenga:Janssen: Research Funding. Bos:celgene: Research Funding. Lokhorst:Genmab: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees. Sonneveld:Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Combined Analysis of V20, VS5, Pulmonary Fibrosis Score on Baseline Computed Tomography, and Patient Age Improves Prediction of Severe Radiation Pneumonitis After Concurrent Chemoradiotherapy for Locally Advanced Non–Small-Cell Lung Cancer

We aimed to develop a more accurate model for predicting severe radiation pneumonitis (RP) after concurrent chemoradiotherapy for non-small-cell lung cancer. We retrospectively analyzed data from 122 patients with locally advanced non-small-cell lung cancer treated with concurrent chemoradiotherapy. Several dose-volume histogram metrics including absolute lung volume spared from a 5 Gy dose (VS5) were analyzed for an association with RP above NCI-CTC grade 3 (RP ≥ G3). Clinical factors including pulmonary fibrosis score (PFS) and pulmonary emphysema score on baseline chest computed tomography (CT) were also analyzed. Fourteen patients (11.4%) developed RP greater than or equal to G3. On univariate analysis, all dose-volume histogram metrics, sex, and PFS on baseline CT were significantly (p < 0.05) associated with occurrence of RP greater than or equal to G3. Multivariate analysis revealed that V20 greater than or equal to 26%, VS5 less than 1500 cc, age greater than or equal to 68 years, and PFS on baseline CT greater than or equal to 2 were significant risk factors. Thus, we defined a new predictive risk score (PRS) that combines these factors. The cumulative incidence of RP greater than or equal to G3 at 12 months were 0%, 7.8%, 26.6%, and 71.4% when the PRS was 0, 3-5, 6-8, and 9-14, respectively (p < 0.001). This PRS was superior at predicting RP than both V20 and VS5 combined, or V20 alone by receiver operating characteristic analysis (area under the curve, 0.888 versus 0.779 versus 0.678). V20, VS5, age, and PFS on baseline CT are independent and significant risk factors for occurrence of severe RP. Combining these factors may improve the predictability of severe RP.

1:39 PM; Abstract No. 185 - Y90 radioembolization planning with MAA shunt study: predictors of high shunt fraction

TU ES D A Y: S ci en ti fic S es si on s Purpose: The most common serious complication of Y90 radioembolotherapy (Y90 RE) is gastrointestinal ulceration secondary to extrahepatic microsphere deposition. The conventional method to prevent extrahepatic deposition of Y90 microspheres is the coil occlusion of the origins of hepatoenteric arteries. However, this method of exclusion is not possible in all cases. Redirection of blood flow towards the liver (hepatopetal) within hepatoenteric arteries during Y90 RE delivery could achieve the identical intention of prevention of gastrointestinal microsphere deposition. We present the utility of the creating hepatopetal flow within hepatoenteric arteries with use of the balloon occlusion technique at our institution for Y90 RE. Materials and Methods: Between September 2010December 2012, 62 patients with diagnostic or treatment angiograms with attempted use of the balloon occlusion technique were catalogued. Tumor types included colorectal (18), hepatocellular (22), neuroendocine (17) or other (5). Temporary balloon catheter occlusion of the common hepatic artery was used to transiently create hepatopetal flow within hepatoenteric arteries during both the diagnostic Tc99m MAA (47 patients) and therapeutic Y90 RE (48 patients) delivery. Planar & SPECT nuclear scintigraphy was performed after delivery of the radionuclides. Whole liver, right lobe, left lobe Y90 RE treatments were performed in 40,8 and 2 sessions respectively. Clinical and laboratory follow up at 1, 3 and 6 months and imaging follow up at 3 and 6 months were performed. Results: 50 Y90 RE treatment sessions were performed with use of the balloon technique with either glass (20) or resin (30) microspheres. Post Y90 RE scintigraphy confirmed hepatic only activity. Greater than 80% administration of the prescribed dose of resin microspheres was possible in 22/30 sessions and in 19/20 sessions of glass microspheres. One NCI-CTC grade 2 gastrointestinal ulcer was present at 90 day follow up. Conclusion: Transient common hepatic artery ballooncatheter occlusion provided a reasonably safe, reliable, and reproducible alternative to conventional fibered coil occlusion of patent hepatoenteric arteries to facilitate Tc99m MAA & Y90 RE delivery.

Feasibility of docetaxel-prednisone (DP) in frail elderly (age 75 and older) patients with castration-resistant metastatic prostate cancer (CRMPC): GERICO10-GETUG P03 trial led by Unicancer.

152 Background: Chemotherapy with docetaxel-prednisone (DP) is one of the standard treatment of castration-resistant metastatic prostate cancer (CRMPC). However little is known about feasibility of DP in frail elderly patients seen in daily practice. Methods: Randomized phase II study evaluating prospectively the feasibility of DP administered either q3w (Arm A: 60 mg/m² cycle one then 70 mg/m²) or weekly (Arm B: 35 mg/m² D1 D8 q3w) in patients age 75 or older, assessed through comprehensive geriatric assessment (CGA) and classified according to the International Society of Geriatric Oncology (SIOG) as vulnerable (SIOG group 2) or frail (SIOG group 3). Failure was defined as: (1) stop or delay of chemotherapy more than 2 weeks, (2) need for dose reduction more than 25%, (3) febrile neutropenia or NCI CTC grade 3 non-haematological toxicity (excluding alopecia), and (4) decrease of activities of daily living (ADL) scoring two or more points. The study was based on a Simon’s optimum two-stage design for each group (α = 5%, 1-β = 90 %, p0 = 0.70 and p1 = 0.90). An interim analysis was planned after enrolment of 15 patients per arm, with continuation of the program if at least 12 patients met the feasibility criteria. Results: From December 2010 to August 2012, 21 centers have included 66 CRMPC patients, 45 and 21 in SIOG groups 2 and 3 respectively, based on investigators evaluation. The planned interim analysis primary endpoint is based on group allocation by a steering committee (per-protocol [PP] population). The enrolment in group 3 was prematurely closed on October 2012 after inclusion of 19 PP patients (Arm A/B, n=9/10) on recommendation of a safety committee due to an excess of toxic deaths. In this group, only four patients completed six cycles of DP in each arm. In group 2, the planned interim analysis was performed after inclusion of 30 PP patients (Arm A/B n=15/15): 11 and 10 patients in Arm A and B did not meet the predefined criteria for feasibility (73.3%; 95%CI=[44.9; 92.2] and 66.6%; 95%CI=[38.4; 88.2], respectively, and only nine and seven respectively completed six cycles of DP. Conclusions: Chemotherapy with DP given q3w or weekly is not feasible in CRMPC patients age 75 and older classified in SIOG group 2 and 3, according to our study criteria. Patients age 75 and older shouldn’t be offered DP without a CGA. Clinical trial information: NCT01254513.

Phase II Randomized Trial Of Radiation-Free Central Nervous System (CNS) Prophylaxis Comparing Intrathecal Triple Therapy With Liposomal Cytarabine (DepoCyte®) In Adult Acute Lymphoblastic Leukemia (ALL)

Phase II Randomized Trial Of Radiation-Free Central Nervous System (CNS) Prophylaxis Comparing Intrathecal Triple Therapy With Liposomal Cytarabine (DepoCyte®) In Adult Acute Lymphoblastic Leukemia (ALL)

A Phase 2a, Open-Label, Dose-Finding Study To Determine The Safety and Tolerability Of Sotatercept (ACE-011) In Adults With Beta (β)-Thalassemia: Interim Results

BackgroundBeta (β)-thalassemia is characterized by ineffective erythropoiesis leading to anemia, bone marrow erythroid hyperplasia, iron overload, and organ failure. Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor (ActRIIA) fusion protein that increases the release of mature erythrocytes into circulation by acting mainly on late-stage erythropoiesis (Carrancio S, et al. Blood. 2012;120:abstract 372). Clinical data in healthy volunteers have shown that treatment with sotatercept results in increased red blood cell (RBC) parameters, including hemoglobin level (Ruckle J, et al. J Bone Miner Res. 2009;24:744-52). RAP-011, a murine ortholog of sotatercept, was efficacious in a mouse model of β-thalassemia intermedia, reducing ineffective erythropoiesis as well as significantly improving anemia and decreasing bilirubin levels, supporting the clinical development of sotatercept (Dussiot M et al. Blood 2012;120:abstract 247). MethodsThis is an ongoing phase 2a, multicenter, open-label, dose-finding study to determine a safe and active dose level of sotatercept in adult patients with RBC-transfusion dependent (TD) β-thalassemia major or patients with β-thalassemia intermedia who are either TD or non-transfusion dependent (NTD). The dose levels of sotatercept studied to date are 0.1, 0.3, and 0.5 mg/kg, given subcutaneously once every 3 weeks. Safety is assessed according to NCI-CTC grading. Efficacy is assessed by hemoglobin increase from baseline and/or reduction in transfusion burden. Secondary endpoints include assessment of biomarkers for erythropoiesis, hemolysis, iron metabolism, and bone metabolism, as well as in vitro dyserythropoiesis. Dose escalation to higher dose levels is planned contingent on data review and favorable safety profile as determined by the Steering Committee. ResultsPatient demographics. A total of 25 patients have been enrolled as of July 26, 2013; 8 in the 0.1 mg/kg cohort, 9 in the 0.3 mg/kg cohort, and 8 in the 0.5 mg/kg cohort. Treatment and analysis for the 0.5 mg/kg cohort is underway and will be updated and presented. In the 0.1 and 0.3 mg/kg cohorts, 3 (18%) patients had β-thalassemia major and 14 (82%) had β-thalassemia intermedia (12 of whom were NTD and 2 of whom were TD). Of the 12 NTD β-thalassemia intermedia patients, 6 were treated at the 0.1 mg/kg dose level and 6 at the 0.3 mg/kg dose level. Median baseline hemoglobin for these NTD patients was 8.6 g/dL (range 5.8 to 10.7 g/dL). Median number of sotatercept doses administered was 4 (range 2 to 7) in the 0.1 mg/kg cohort and 8 (range 3 to 9) in the 0.3 mg/kg cohort; 13/17 (76%) patients remained on treatment.Safety.Sotatercept was generally well tolerated. There were no dose-limiting toxicities reported. Two serious adverse events were reported in the 0.1 mg/kg cohort: a grade 2 phlebitis in an NTD patient with a history of high D-dimer at baseline, and a worsening grade 3 bone pain in a TD β-thalassemia major patient with a history of osteoporosis; both were considered possibly study drug-related.Hemoglobin levels/transfusion requirements. Among NTD patients, preliminary data showed that 1 (17%) patient in the 0.1 mg/kg cohort and all 6 (100%) patients in the 0.3 mg/kg cohort had at least a 1 g/dL increase in hemoglobin level from baseline; among these, 1 patient treated with sotatercept 0.3 mg/kg showed a 2 g/dL hemoglobin level increase from baseline as well as a decrease in total bilirubin level from 2.7 × upper limit of normal (ULN) at baseline to 1.8 × ULN. No other relevant decrease in total bilirubin level was reported at the lower dose levels (0.1 mg/kg or 0.3 mg/kg).Three TD patients were still receiving treatment (2 β-thalassemia intermedia and 1 β-thalassemia major). There had been no appreciable reduction in transfusion burden in the 0.1 and 0.3 mg/kg cohorts to date; however further follow up is warranted and an update will be presented. ConclusionBased on these preliminary data, sotatercept administered subcutaneously every 3 weeks may improve anemia via a novel mechanism of action with a favorable safety profile, thereby addressing a significant unmet medical need for patients with NTD β-thalassemia intermedia. The current data suggest a dose-dependent response that supports further evaluation of the exposure–effect relationship of sotatercept in patients with NTD β-thalassemia intermedia.The first, second, and last authors contributed equally to this abstract. Disclosures:Cappellini:Genzyme: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Off Label Use: Sotatercept is an investigational agent that is being assessed for efficacy and safety in beta-thalassemia. Porter:Novartis: Consultancy, Research Funding; Shire: Consultancy; Celgene: Honoraria. Forni:Celgene: Research Funding; Shire: Research Funding; Novartis Pharma: Research Funding. Laadem:Celgene Corp.: Employment, Equity Ownership. Galacteros:Celgene: Consultancy. Miteva:Celgene Corp.: Employment. Sung:Celgene Corp.: Employment, Equity Ownership. Chopra:Celgene Corp.: Employment, Equity Ownership. Klesczewski:Celgene Corp.: Employment. Attie:Acceleron Pharma: Employment. Hermine:Celgene Corporation: Consultancy, Research Funding.