Non-hematologic Treatment-related Adverse Events Research Articles

Abstract CT142: Phase 1 study of BPI-23314, a novel BET inhibitor and degrader, in advanced myeloid leukemia (AML)

Abstract Background: The novel small-molecule inhibitor and degrader, BPI-23314, targeting of the bromodomain and extra-terminal domain (BET) family proteins, BPI-23314, has been showndemonstrated promising preclinical efficacy in hematologic malignancies. This Phase 1 study aims to evaluate the safety, pharmacokinetics, and preliminary efficacy of BPI-23314 monotherapy in patients with relapsed or refractory acute myeloid leukemia (R/R AML). Methods: This ongoing phase 1 study of BPI-23314 enrolled adult patients with R/R AML. Dose escalation was conducted using a standard 3+3 design, followed by additional expansion cohorts to further assess safety and preliminary efficacy. BPI-23314 tablets were administered orally once daily (QD) or twice daily (BID) in consecutive 21-day cycles. The key endpoints included determining the recommended Phase 2 dose (RP2D), safety, pharmacokinetics, and preliminary efficacy. Results: As of July 31, 2022, a total of 22 patients diagnosed with R/R AML were treated with BPI-23314 at seven different dose levels, ranging from 5 to 60 mg QD or 40 to 50 mg BID. The median age of the patients was 48 years (range: 19-68 years), and the median treatment duration was 6 weeks (range: 2-9 weeks). The median number of prior therapy lines was 3 (range: 1-4), with 15 (68.2%) being refractory to last line of therapy. Due to the high incidence of grade≥3 anemia, thrombocytopenia, and neutropenia among the patients at baseline, most treatment-emergent adverse events (TEAE) of hematologic toxicities were mainly correlated with disease progression. Only one patient experienced grade 3 treatment-related adverse events (TRAE) comprising anemia (4.5%) and neutropenia (4.5%). Non-hematologic TRAEs were predominantly of grade 1-2. The most common TRAEs (≥10%) were gastrointestinal reactions (10/22, 45.5%), hypertriglyceridemia (6/22, 27.3%), hyperbilirubinemia (4/22, 18.2%), elevated alanine aminotransferase levels (3/22, 13.6%), and increased gamma-glutamyl transferase levels (3/22, 13.6%). Gastrointestinal reactions characterized by nausea and/or diarrhea were the most commonly reported toxicities. The most common TEAEs associated with disease progression were infection and bleeding. No dose-limiting toxicity or treatment-related deaths were reported during the study period, and the maximum tolerated dose was not reached. Among the evaluable responses in all dose levels for R/R AML patients (n=21), one patient achieved complete response (CR) at a dosage of 40 mg BID while three patients maintained stable disease (SD) across various dosages, including QD at 60 mg and BID at both 40 mg and 50 mg. Furthermore, BPI-23314 demonstrated moderate elimination kinetics, with a plasma half-life ranging from 8.6 to 23.3 hours, while exhibiting dose-proportional exposure. Conclusion: BPI-23314 monotherapy exhibited preliminary clinical efficacy with manageable adverse events in patients with R/R AML. The study is ongoing. The satisfactory pharmacokinetic attribute and outstanding safety profile of BPI-23314 provide compelling rationales for further exploration of its therapeutic potential. Citation Format: Mingyuan Sun, Xiangyu Jin, Jing Guo, Xiaoyun Liu, Yan Xu, Hong Lan, Jiabing Wang, Jiangnan Zhen, Jing Yang, Lieming Ding, Junyuan Qi. Phase 1 study of BPI-23314, a novel BET inhibitor and degrader, in advanced myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT142.

Efficacy and Safety of Recombinant Erwinia Asparaginase (JZP458) in Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL): Complete Follow-up of the Children's Oncology Group (COG) AALL1931 Study

Background: L-asparaginase is an important component of multi-agent treatment regimens for pediatric and adult patients with ALL/LBL. However, hypersensitivity reactions to E. coli-derived asparaginases often lead to treatment delay or discontinuation. JZP458, a recombinant Erwinia asparaginase (ASP) derived from a Pseudomonas fluorescens expression platform, was evaluated in study AALL1931, a 2-part, open-label, phase 2/3 trial conducted with the Children's Oncology Group investigating efficacy, safety, and pharmacokinetics (PK) of JZP458 in patients with ALL/LBL (ClinicalTrials.gov ID: NCT04145531). Based on interim results from part A of AALL1931, intramuscular (IM) JZP458 (Rylaze®) was approved by the US Food and Drug Administration for treatment of ALL/LBL in June 2021. Here, we report the efficacy and safety of JZP458 at the completion of AALL1931. Methods: Eligible patients with ALL/LBL who daeveloped hypersensitivity (grade ≥3 allergic reaction or silent inactivation) to E. coli-derived pegaspargase received JZP458 as part of their multi-agent treatment plan. Each dose of pegaspargase was substituted with 6 doses of JZP458 administered either IM (part A) or intravenously (IV, part B) on Monday/Wednesday/Friday (MWF) over 2 weeks, defined as 1 course. The study enrolled 3 IM cohorts [1a (25 mg/m 2 MWF), 1b (37.5 mg/m 2 MWF), and 1c (25/25/50 mg/m 2 MWF)], and 1 IV cohort (25/25/50 mg/m 2 MWF). Efficacy was assessed by proportion of patients maintaining therapeutic nadir serum ASP activity (NSAA) ≥0.1 IU/mL at the last 72-hour (primary endpoint) or 48-hour (key secondary endpoint) timepoint during course 1. A population PK (PPK) model was developed based on serum ASP activity (SAA) data from AALL1931 to characterize the PK of JZP458 and simulations using the PPK model were performed to provide additional information on alternative dosing regimens. Results: At the final cutoff date of November 22, 2022, a total of 167 patients received IM JZP458 (1a, n=33; 1b, n=83; 1c, n=51) and 61 patients received IV JZP458. The median (range) of JZP458 courses received was 5 (0, 14), 4 (0, 15), 5 (1, 10), and 3 (0, 15) for IM cohorts 1a, 1b, 1c, and IV cohort, respectively. Table 1 shows the proportion of patients who achieved therapeutic NSAA levels and the mean SAA levels per cohort in course 1. With IM cohort 1c (25/25/50 mg/m 2 MWF), the proportion (95% CI) of patients achieving NSAA levels ≥0.1 IU/mL at 72 and 48 hours were 90% (81, 98) and 96% (90, 100), respectively. Treatment-related adverse events (TRAEs) ≥ grade 3 occurred in 126/228 (55%) patients; but no TRAE led to death. Table 2 shows the most commonly reported (≥10% of patients) nonhematologic TRAEs. A total of 22 patients (13%) across all IM cohorts (2 patients in 1a, 14 in 1b, and 6 in 1c) and 20 patients (33%) in the IV cohort experienced a TRAE leading to treatment discontinuation.The most common TRAEs leading to treatment discontinuation were pancreatitis (6%) in the IM cohort, and drug hypersensitivity (15%) in the IV cohort. PPK model-based simulations predicted that therapeutic NSAA levels are achieved in the vast majority of patients when JZP458 is administered IM at 25 mg/m 2 every 48 hours (7 doses) or 25/25/50 mg/m 2 MWF (6 doses), when JZP458 is administered IV at 25 mg/m 2 every 48 hours (7 doses), or when JZP458 is administered IV at 25 mg/m 2 M/W and IM at 50 mg/m 2 F (6 doses). Conclusions: Results at the completion of AALL1931 in patients with ALL/LBL and allergic reactions or silent inactivation to E. coli-derived asparaginase show the safety profile of JZP458 is consistent with other asparaginases, with no new adverse safety signals. Treatment-related discontinuation rates with IV JZP458 were greater than with IM, primarily due to increased incidence of hypersensitivity/infusion-related reactions along with nausea and vomiting; however, the study was not statistically powered to compare different dosing cohorts. Observed and PPK modeling data demonstrate JZP458 achieves therapeutic NSAA levels via multiple IM and IV dosing schedules, with IM dosing having more sustained SAA, and therefore providing flexibility to patients and physicians.

Olverembatinib(HQP1351)-Based Therapy in Adults with Relapsed or Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Advanced Chronic Myeloid Leukemia: Results of the Real-Life Study

Background Relapsed or refractory (R/R) Philadelphia chromosome positive acute lymphoid leukemia (ALL) and advanced chronic myeloid leukemia (CML) including accelerated phase (AP) and blast phase (BP) usually result in treatment failure due to therapeutic resistance, intolerance, T315I mutations, or compound mutations, with a poor prognosis. Olverembatinib (HQP1351) is a novel third generation BCR-ABL tyrosine kinase inhibitor (3G-TKI), exhibiting a high potency of inhibition on wild and almost all mutated BCR-ABL1 kinases, including the T315I mutation and exhibiting preliminary favorable efficacy and safety profile in clinical trials. Methods In this open label, single-arm, single-center study, patients with advanced Ph+ leukemia (including CML-BP, CML-AP and R/R Ph+ ALL) were enrolled. Patients with severe cardiovascular diseases, arterial occlusion, hypertension, and pulmonary arterial hypertension were excluded . Eligible patient received olverembatinib monotherapy, combined chemotherapy, or combined immunotherapy. The primary endpoints was overall response rate (ORR) at 28 days, including complete remission (CR) and complete remission with incomplete hematological recovery (CRi), in patients with advanced Ph+ leukemia. Results Between Dec 8, 2021, to Jun 1, 2023, a total of 56 patients (Ph+ALL (n=40), CML-BP (n=13) and CML-AP(n=3)) assessed were included and received olverembatinib-based therapy. 34(60.7%) patients were men and 22 (39.3%) were women. The median age was 38 years old (IQR 29-48) and the median duration of follow-up was 8.3 months (IQR 4.6-11.9). BCR::ABL1 transcript was of p210 type in 29 (51.8%), p190 in 27 (48.2%). 13 (23.2%) and 11 (19.6%) patients had received 2 and ≥ 3 prior TKIs, respectively. 17 (30.4%) patients were pretreated with third-generation TKI (ponatinib). Genetic testing revealed mutations in 48 (85.7%) patients including compound mutation in 11 (19.6%%) patients, of whom 8 (72.3%) patients had the T315I mutation. 11 (19.6%) patients had central nervous system leukemia (CNSL) and 1 (1.8%) had extramedullary disease. Of 56 evaluable patients, 48 (85.7%) patients reached CR/CRi. After achieving CR/CRi, 13/48 (27.1%) patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT), 3/48 (6.3%) patients received donor lymphocyte infusion (DLI), and 3/48 (6.3%) patients received chimeric antigen receptor T-cell immunotherapy (CAR-T therapy). During further follow-up, 24 (42.9%) patients achieved BCR::ABL1< 0.1% and 29 (49.2%) achieved BCR::ABL1 < 1%. In additional, probabilities of DFS, EFS and OS at 12 months were 80.3% (95%CI 61.0%-90.7%), 80.2% (95%CI 61.0%-90.7%), 93.3% (95%CI 75.8%-98.3%) in R/R Ph+ALL and 55.4% (95%CI 18.4%-81.4%), 38.6% (95%CI 9.8%-67.6%), 80.0% (95%CI 37.4%-95.1%) in advanced CML, respectively (Fig. 1). Common treatment-related adverse events (TRAEs) included skin hyperpigmentation, proteinuria, Elevated liver enzyme and hypertriglyceridemia (Table 1). Most nonhematologic TRAEs were grade 1/2. Only one patient died from pulmonary embolism. As of the data cutoff date, 37 (66.1%) patients continued on treatment and 19(33.9%) discontinued because of disease progression, intolerance, loss to follow-up or death. Conclusion Olverembatinib-based therapy showed strong efficacy and tolerable toxicity in advanced Ph+ leukemia.

Low-dose gemcitabine plus nab-paclitaxel versus standard-dose gemcitabine plus nab-paclitaxel in elderly patients with metastatic pancreatic cancer: A randomized Phase II trial.

A multicenter, open-label randomized Phase II trial was conducted to determine whether low-dose gemcitabine plus nab-paclitaxel (GnP) could improve tolerability and show equivalent efficacy to the standard-dose GnP for elderly patients with metastatic pancreatic cancer. Consecutive patients aged ≥65 years with metastatic pancreatic cancer who presented at one of four Japanese referral centers between November 2016 and January 2021 were enrolled. The 60 patients were randomly assigned to low- or standard-dose groups with a 1:1 ratio. Patients in the low-dose GnP group received gemcitabine at a dose of 250 mg/m2 and nab-paclitaxel at 125 mg/m2. Low-dose GnP significantly decreased the rate of cases requiring dose reduction (16.7% vs 63.3%). The response rate (36.7% vs 33.3%) and progression-free survival (7.3 vs 8 months) were comparable between the low- and standard-dose groups as determined by independent review. The difference in the median overall survival between the two groups was not significant (7.9 vs 12 months). The proportion of patients with hematologic and non-hematologic treatment-related adverse events was comparable between the two groups. Low-dose GnP had an equivalent efficacy to conventional therapy; however, it did not reduce adverse events.

INNV-10. SAFETY OF APIXABAN FOR VENOUS THROMBOEMBOLISM PREVENTION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract Venous thromboembolism (VTE) impacts an estimated one in every three patients with malignant glioma (MG), resulting in increased morbidity and mortality. Despite the high prevalence and serious consequences of VTE, there is no outpatient standard of care prevention strategy. There have been three prospective clinical trials of VTE prophylaxis in patients with newly diagnosed MG, all of which used an injectable low molecular weight heparin (LMWH) product. We performed an open-label safety study of apixaban, a direct oral anticoagulant (DOAC), for VTE prevention in patients with newly diagnosed MG. All patients had surgery or biopsy two to twenty-one days prior to enrollment in the study. Patients were treated with apixaban 2.5 mg twice daily for up to 6 months. Peak and trough apixaban concentrations were measured at the beginning and end of treatment. Thirteen patients consented to the study and ten enrolled (2 screen-fail, 1 withdrawal). The patients have completed a mean of 4.5 cycles of apixaban (range 2 to 6, with 2 patients still undergoing treatment). There were no bleeding events while receiving apixaban. There were no hematologic or non-hematologic treatment-related adverse events. There were no VTE events observed in patients receiving apixaban. Two patients who came off treatment early due to disease progression developed VTEs after stopping prophylactic apixaban. Quality of life analysis is ongoing. In this pilot study we found that prophylactic dosing of 2.5 mg twice daily of apixaban was safe in the post-operative period for patients with newly diagnosed MG. Our preliminary results suggest that this may be a safe and effective prevention strategy for VTE prophylaxis in this high risk group of patients.

Weekly nab-Rapamycin in Patients with Advanced Nonhematologic Malignancies: Final Results of a Phase I Trial

This dose-finding phase I study investigated the maximum-tolerated dose (MTD) and safety of weekly nanoparticle albumin-bound rapamycin (nab-rapamycin) in patients with untreatable advanced nonhematologic malignancies. nab-Rapamycin was administered weekly for 3 weeks followed by 1 week of rest, with a starting dose of 45 mg/m(2). Additional doses were 56.25, 100, 150, and 125 mg/m(2). Of 27 enrolled patients, 26 were treated. Two dose-limiting toxicities (DLT) occurred at 150 mg/m(2) [grade 3 aspartate aminotransferase (AST) elevation and grade 4 thrombocytopenia], and two DLTs occurred at 125 mg/m(2) (grade 3 suicidal ideation and grade 3 hypophosphatemia). Thus, the MTD was declared at 100 mg/m(2). Most treatment-related adverse events (TRAE) were grade 1/2, including thrombocytopenia (58%), hypokalemia (23%), mucositis (38%), fatigue (27%), rash (23%), diarrhea (23%), nausea (19%), anemia (19%), hypophosphatemia (19%), neutropenia (15%), and hypertriglyceridemia (15%). Only one grade 3 nonhematologic TRAE (dyspnea) and one grade 3 hematologic event (anemia) occurred at the MTD. One patient with kidney cancer had a partial response and 2 patients remained on study for 365 days (patient with mesothelioma) and 238 days (patient with neuroendocrine tumor). The peak concentration (Cmax) and area under the concentration-time curve (AUC) of rapamycin increased with dose between 45 and 150 mg/m(2), except for a relatively low AUC at 125 mg/m(2). nab-Rapamycin significantly inhibited mTOR targets S6K and 4EBP1. The clinical dose of single-agent nab-rapamycin was established at 100 mg/m(2) weekly (3 of 4 weeks) given intravenously, which was well tolerated with preliminary evidence of response and stable disease, and produced a fairly dose-proportional pharmacokinetic profile in patients with unresectable advanced nonhematologic malignancies.

Cabazitaxel plus cisplatin coadministration and drug-interaction study in patients with advanced solid tumors.

e15116 Background: Cabazitaxel (Cbz) is a novel taxane with in vivo efficacy in taxane-sensitive and -resistant tumors. Therapeutic synergism of Cbz/cisplatin (Cis) has been shown in tumor-bearing mice. Since Cbz is primarily metabolized by CYP3A, drug interactions may occur with modulators of CYP3A. Methods: The primary objective of part 1 of this phase I study (NCT00925743) was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz/Cis. Secondary objectives included safety, pharmacokinetics (PK) and efficacy. The objective of part 2 was to assess efficacy at the MTD. The effect of the antiemetic aprepitant (a moderate CYP3A inhibitor) on the PK of Cbz was also examined. Eligible patients (pts) had ECOG PS ≤ 1 and confirmed metastatic or unresectable solid tumors for which Cis therapy was considered appropriate. A 3 + 3 dose escalation at a starting dose (level 0) of 20/75 mg/m2 (Cbz/Cis), administered IV Q3W, was used. The MTD was the highest dose at which 0/3 or ≤ 1/6 pts experienced a DLT in Cycle 1. Results: Pts (n = 25; 10 in part 1; 15 in part 2) with a median age of 56 yrs were enrolled. The most frequent primary tumors were lung (n = 4), prostate, ovary and pancreas (each n = 2). Of 6 evaluable pts, 2 had a DLT at dose level 0 (Grade 3 acute renal failure; febrile neutropenia). The MTD was 15/75 mg/m2 as no DLTs were observed; 18 pts were treated at the MTD and 60 cycles were administered (median = 3; range 1–8). The most frequent non-hematologic treatment-related adverse events (all grades/grade 3–4) were nausea (78%/22%), vomiting (72%/11%), fatigue (61%/17%), anorexia (67%/11%) and diarrhea (44%/0%). Incidence of grade 3–4 neutropenia was 78%; 1 pt had febrile neutropenia. The combined PK profile of Cbz/Cis did not appear to differ vs those of the single agents. The ratio of Cbz clearance with vs without aprepitant co-administration was 0.81 (90% CI 0.36–1.85). Stable disease was seen in 11 pts; 1 pt (prostate carcinoma) had an unconfirmed partial response. Conclusions: The MTD of Cbz/Cis was 15/75 mg/m2. The combination had a manageable safety profile consistent with a platinum/taxane combination. No PK interactions between Cis and Cbz were seen; aprepitant did not appear to alter the PK of Cbz.

Phase I trial of cabazitaxel plus cisplatin in patients with advanced solid tumors.

162 Background: Cabazitaxel (Cbz) is a novel taxane with broad in vivo efficacy in taxane-sensitive and -resistant tumors. Clinical activity of Cbz was confirmed in the Phase III TROPIC trial ( NCT00417079 ); Cbz significantly improved overall survival compared with mitoxantrone in patients (pts) with metastatic castration-resistant prostate cancer whose disease had progressed during or after a prior docetaxel-containing regimen. Therapeutic synergism of Cbz/cisplatin (Cis) has been demonstrated in tumor-bearing mice. Methods: The primary objective in part 1 of this Phase I study ( NCT00925743 ) was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz/Cis. Secondary objectives were safety, pharmacokinetics (PK) and efficacy. The primary objective of part 2 was to determine the antitumor activity at the MTD. Eligible pts were ≥ 18 yrs, ECOG PS ≤ 1, with confirmed metastatic or unresectable solid tumors for which Cis therapy was considered appropriate. A 3 + 3 dose escalation with a starting dose (level 0) of 20/75 mg/m2 (Cbz/Cis), administered IV Q3W, was used. The MTD was the highest dose at which 0/3 or ≤ 1/6 pts experienced a DLT in Cycle 1. Results: Pts (N = 25; 10 in part 1; 15 in part 2) with a median age of 56 yrs were enrolled. The most frequent primary tumors were lung (n = 4), prostate, ovary and pancreas (each n = 2). 2 of 6 evaluable pts experienced a DLT at dose level 0 (Grade 3 acute renal failure; febrile neutropenia). The MTD was 15/75 mg/m2 as no DLTs were observed. Eighteen pts were treated at the MTD and 60 cycles were administered (median = 3; range 1–8). The most frequent non-hematologic treatment-related adverse events (all Grade/Grade 3–4) were nausea (78%/22%), vomiting (72%/11%), fatigue (61%/17%), anorexia (67%/11%) and diarrhea (44%/0%). Incidence of Grade 3–4 neutropenia was 78% and 1 pt had febrile neutropenia. No PK interactions between Cbz and Cis were observed. Stable disease was seen in 11 pts. No objective responses were reported. Conclusions: The MTD of Cbz/Cis was 15/75 mg/m2. The combination had a manageable safety profile consistent with that of a platinum/taxane combination. No PK interactions were seen. Further investigations into the combined treatment combination are planned.

Sunitinib Malate for Gastrointestinal Stromal Tumour in Imatinib Mesylate–Resistant Patients: Recommendations and Evidence

Is sunitinib malate-marketed as Sutent (Pfizer Canada, Kirkland, QC)-superior to placebo or other interventions for primary outcomes of interest in adult patients with gastrointestinal stromal tumour (GIST) who have developed resistance or who exhibit intolerance to imatinib mesylate (IM)? In patients with resectable disease, surgery is the mainstay of treatment for GIST; in patients with unresectable or metastatic disease, the tyrosine kinase inhibitor IM is the therapy of choice. However, some patients have primary resistance or intolerance to IM, or they progress after optimal exposure (including an escalated dose). Here, we review the evidence for treating IM-resistant GIST with sunitinib malate. Studies of sunitinib malate were identified through MEDLINE, EMBASE, the Cochrane Library databases, and Web sites of guideline organizations. Outcomes of interest included time to progression, progression-free survival, overall survival, and toxicity. One phase III randomized controlled trial, and one abstract and presentation describing that trial, served as the evidentiary base for this clinical practice guideline. Trial data confidently show that both time to progression and progression-free survival are highly statistically significant (p < 0.0001) in favour of sunitinib malate over placebo. Overall survival was improved with sunitinib malate (hazard ratio: 0.49; 95% confidence interval: 0.29 to 0.83; p = 0.007; absolute difference in weeks not reported). The most frequent of all adverse effects (experienced in greater proportion by patients on sunitinib malate) were grades 1 and 2 leucopenia (52% vs. 5% with placebo), neutropenia (43% vs. 4%), and thrombocytopenia (36% vs. 4%). Grade 3 hematologic adverse events were also reported more frequently in the sunitinib malate group, including leucopenia (4% vs. 0%), neutropenia (8% vs. 4%), lymphopenia (9% vs. 2%), and thrombocytopenia (4% vs. 0%). Toxicity comparisons did not include p values. The incidence of grades 1-3 fatigue was greater for the sunitinib malate group (34% vs. 22% with placebo). Other grade 3 nonhematologic treatment-related adverse events that occurred more frequently on sunitinib malate included hand-foot syndrome (4% vs. 0%), diarrhea (3% vs. 0%), and hypertension (3% vs. 0%). No grade 4 adverse events were observed. In the target population, sunitinib malate is the recommended option for second-line therapy of metastatic GIST.

Safety and efficacy of bosutinib in patients with AP and BP CML and ph+ ALL following resistance/intolerance to imatinib and other TKIs: Update from study SKI-200.

6509 Background: Bosutinib (SKI-606) is an oral Src/Abl kinase inhibitor currently evaluated in a phase I/II study in Ph+ leukemia patients (pts) with resistance/intolerance to imatinib. Methods: Advanced leukemia pts received 500 mg daily of bosutinib. Results: 134 pts were enrolled (63 accelerated phase [AP], 48 blast phase [BP], 23 ALL), median age was 50 yrs, 40% female and median follow-up 8.3 months. Prior therapy besides imatinib included interferon (43 pts), dasatinib (45 pts), nilotinib (16 pts) and stem cell transplant (12 pts). Nonhematologic treatment-related adverse events (AEs) occurring in ≥10% of pts were diarrhea (67%), vomiting (40%), nausea (37%), rash (20%), fatigue (10%). Grade 3/4 AEs of any causality occurring in ≥5% of pts were: diarrhea (6%), pneumonia (6%), elevated ALT (6%), vomiting (5%), dyspnoea (5%). Grade 3/4 hematologic abnormalities of any causality were anemia (37%), neutropenia (46%), thrombocytopenia (65%). 27 pts required dose-reductions and median daily dose was 477 mg. Overall efficacy analysis is presented in Table. Among 66 pts with baseline sequencing analysis, 16 distinct Bcr-Abl mutations were found in 40 pts. CHR and MCyR were achieved in 50% and 47% of evaluable pts with mutations, and in 47% and 54% of evaluable pts without mutations, respectively. 9/10 pts with T315I were resistant to bosutinib. Conclusions: Bosutinib is effective and well tolerated in advanced leukemia pts, with primarily transient low-grade gastrointestinal AEs. Clinical responses are achieved across a wide range of mutations, except with T315I. Diagnosis at time of bosutinib start AP N (%) BP N (%) ALL N (%) Hematologic response Evaluable* 33 22 4 Overall 21 (64) 7 (32) 1 (25) Complete 20 (61) 7 (32) 1 (25) Cytogenetic response Evaluable* 27 21 2 Major 13 (48) 11 (52) 2 (100) Complete 9 (33) 6 (29) 2 (100) Molecular response Evaluable* 26 25 13 Major 4 (15) 7 (28) 6 (46) Complete 1 (4) 3 (12) 3 (23) Progression-free survival (ITT) n=56 n=45 n=23 Median, Kaplan-Meier estimate, 95% C.I. 11.6 7.8 2.7 Range (months) (8.4, 20.1) (4.0, 8.8) (1.3, 4.2) * Pts without CHR, CCyR or CMR at baseline, and with ≥1 post-baseline assessment for respective response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, Wyeth Pfizer Pfizer

C-1311, a novel inhibitor of FLT3 and topoisomerase II: A phase 1 trial of a once every three week schedule in patients with advanced solid tumors

2576 Background: C-1311 (Symadex) is a lead compound in the novel class of imidazoacridinones, inhibitors of both topoisomerase II and certain receptor tyrosine kinases (RTK) including FLT3, being tested for the treatment of cancer and autoimmune diseases. This phase 1 trial assessed safety, determined the maximum tolerated dose (MTD) and recommended dose (RD) of C-1311 in patients (pts) with advanced solid tumors. Methods: Pts with tumors refractory to conventional therapy were enrolled. The dosing schedule was a 1-hr infusion daily for 5 consecutive days every 3 weeks (dx5), subsequently amended to once every 3 weeks (q3w). The maximum tolerated dose (MTD) is where 2 or more of at least 3 pts experience dose-limiting toxicity (DLT). The recommended dose (RD) is the dose level below the MTD. An expanded RD cohort of 9 pts was also evaluated. Systemic pharmacokinetics were assessed. Results: 36 pts were treated. No DLTs were observed in the first 5 single patient cohorts on a dx5 schedule at 6, 12, 24, 48 and 96 mg/m2/day. Subsequent pts were treated in 3+3 patient cohorts at 640, 850 and 1,100 mg/m2, and 950 mg/m², which was the MTD. All DLT were hematologic, reversible neutropenia and occasional thrombocytopenia. Grade 3 and 4 neutropenia was observed in 19% and 17% of pts in the first treatment cycle (no associated sepsis). No cumulative toxicity was observed. Nonhematologic treatment-related adverse events (AEs) were lethargy (75%), nausea (50%), vomiting (44%), neutropenia (36%), dizziness (31%) and fatigue and infusion site pain (22% each), with grade 3/4 AEs being lethargy, atypical pneumonia, and dyspnea in one patient (3%) each. No nonhematologic DLT or abnormal LVEF were observed. Partial response and stable disease (SD) were observed in 1 (3%) and 17 (47%) pts. Conclusions: C1311 is a novel imidazoacridinone targeting both topoisomerase II and FLT 3 family of RTK. The RD on a q3w schedule of 850 mg/m2 has acceptable safety. DLT is only reversible dose-related neutropenia. SD in heavily pretreated pts with sarcomas and epithelial malignancies suggests preliminary evidence of antitumor activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Xanthus Pharmaceuticals Xanthus Pharmaceuticals

A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade™), in combination with paclitaxel and carboplatin in patients with advanced malignancies

Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity. Patients with advanced malignancies were alternately assigned to receive (schedule A) paclitaxel and carboplatin (IV d1) followed by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin (IV d2) on a 21-day cycle. Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10) for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B 50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild (primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m2, paclitaxel 135 mg/m2 and carboplatin AUC = 6 for schedule A and bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2 and carboplatin AUC = 6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A. Similar proteasome inhibition was achieved at MTD for both schedules. Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted.