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Background This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma. Methods Eligible patients had conventional chondrosarcoma of any grade with measurable tumors that were unresectable or metastatic. Patients with mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes and patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessments every 2 cycles. The primary endpoint was the disease control rate (DCR) at week 16 (4 cycles). Results Forty-seven patients were enrolled. The DCR at 16 weeks was 43% (95% confidence interval [CI], 28%-58%), which was superior to the null hypothesis rate of 30%, but the 2-sided P value (exact test) was .09 (1-sided P = .045). One patient had a partial response. The median overall survival was 17.6 months (95% CI, 11.3-35.0 months), and the median progression-free survival was 7.9 months (95% CI, 3.7-12.6 months). Grade 3 or higher adverse events were infrequent; hypertension (26%) and elevated alanine aminotransferase (9%) were most common. Conclusions This study provides evidence of positive drug activity for pazopanib in conventional chondrosarcoma.

Small-molecule chemotherapeutics are potent and effective against a variety of malignancies, but common and severe side effects restrict their clinical applications. Nanomedicine approaches represent a major focus for improving chemotherapy, but have met limited success. To overcome the limitations of chemotherapy drugs, we have developed a novel Single Protein Encapsulation (SPE)-based drug formulation and delivery platform and tested its utility in improving doxorubicin (DOX) treatment. Using this methodology, a series of SPEDOX complexes were generated by encapsulating various numbers of DOX molecules into a single human serum albumin (HSA) molecule. UV/fluorescence spectroscopy, membrane dialysis, and dynamic light scattering techniques showed that SPEDOXs are stable and uniform as monomeric HSA and display unique properties distinct from those of DOX and DOX-HSA mixture. Furthermore, detailed procedures to precisely monitor and control both DOX payload and binding strength to HSA were established. Breast cancer xenograft tumor studies revealed that SPEDOX-6 treatment displays improved pharmacokinetic profiles, higher antitumor efficacy, and lower DOX accumulation in the heart tissue compared with unformulated DOX. This SPE technology, which does not involve nanoparticle assembly and modifications to either small-molecule drugs or HSA, may open up a new avenue for developing new drug delivery systems to improve anticancer therapeutics.

Purpose: Most gastrointestinal stromal tumors (GIST) are driven by KIT/PDGFRa mutations. Tyrosine kinase inhibitor benefit is progressively less after imatinib failure. This phase II trial analyzed the efficacy of nivolumab (N) or nivolumab + ipilimumab (N + I) in patients with refractory GIST. Patients and Methods: Patients with advanced/metastatic GIST refractory to at least imatinib were randomized 1:1 in a noncomparative, parallel group, unblinded phase II trial of N (240 mg every 2 weeks) or N + I (240 mg every 2 weeks + 1 mg/kg every 6 weeks). The primary endpoint was the objective response rate of N alone or N+I by RECIST 1.1 in the intent-to-treat population. Results: A total of 36 patients with a median of 3 (1–6) prior lines of therapies were enrolled. Ten of 19 (52.6%) patients had stable disease (SD) for a clinical benefit rate (CBR) of 52.6% in the N arm and the median progression-free survival (PFS) was 11.7 weeks [95% confidence interval (CI), 7.0–17.4]. In the N+I arm, 1 of 16 (6.7%) patients had a complete response (CR) and 4/16 (25.0%) had SD for a CBR of 31.3% and a median PFS of 8.3 weeks (95% CI, 5.6–22.2). The 4- and 6-month PFS were 42.1% and 26.3%, respectively for N, and 31.3% and 18.8%, respectively for N+I. The most common adverse events (AE) attributed to N and N+I were fatigue: 13.9% and 22.2%, respectively. There were nine total attributable grade 3–4 AEs. Conclusions: The primary endpoint of response rate > 15% was not observed for N or N + I. In a heavily pretreated GIST population, responses and long-term disease control with both N and N+I were observed. No new safety signals have been observed.

Background NY-ESO-1–specific T cells (letetresgene autoleucel [lete-cel]; GSK3377794) are autologous CD4+ and CD8+ T cells transduced to express a high-affinity T-cell receptor that recognizes NY-ESO-1 antigen in complex with HLA-A*02. NY-ESO-1 is a cancer testis antigen that is expressed in many cancers, including synovial sarcoma (SS). Study 208466 (NCT01343043) is a Phase I clinical trial that assessed the safety and efficacy of lete-cel in patients with advanced SS (presented in complementary abstract). This abstract presents correlations of transduced cell kinetics and biomarkers with response. Methods Patients with unresectable, metastatic, or recurrent SS were enrolled to 4 cohorts based on NY-ESO-1 expression levels and received different lymphodepleting regimens (LDR) prior to lete-cel infusion (N=45) (table 1). Response was assessed per RECIST v1.1. Transduced cell kinetics (persistence) were measured by quantitative PCR of transgene vector copies in DNA extracted from peripheral blood mononuclear cells. Serum cytokines were measured by Meso Scale Discovery (MSD) immunoassay. Gene expression within tumor biopsies was evaluated by Nanostring. Post hoc analyses were evaluated in a hypothesis-driven manner using logistic and linear regression. Potential determinants of peak persistence and clinical response were tested using generalized linear models. Results Higher peak persistence (Pmax) was associated (p=0.012) with response across cohorts. Higher weight-normalized cell dose (p=0.00421) and LDR (p=0.000910) were associated with Pmax according to the generalized linear model: Pmax ~ cell dose + LDR. These relationships allowed for accurate retrospective prediction of probability of response. Low LDR resulted in higher endogenous lymphocyte counts on the day of dosing, which trended with lack of response within and across cohorts. While the impact of fludarabine on IL-15 levels has been previously reported, data presented here show a novel, positive correlation between IL-15 levels pre-infusion and response (p=0.0332). Post lete-cel infusion, the concentrations of IFNγ, IL-6, and IL-2RA within the first week were increased in responders vs non-responders. The peak expression of IL-2RA within the first week showed a linear correlation to Pmax. Analysis of tumor biopsies showed good correlation between NY-ESO-1 mRNA and protein expression. Conclusions Exposure–response analysis of study 208466 reveals that efficacy appears to be driven by weight-normalized cell dose and LDR via Pmax. Biomarker correlation analysis indicates that LDR impacts the level of IL-15 pre-infusion, which correlates with response directly. IFNγ, IL-6, and IL-2RA levels appear to be promising pharmacodynamic markers. Optimizing dose and LDR may offer opportunities to maximize antitumor efficacy. Acknowledgements This study (208466) was funded by GlaxoSmithKline (GSK). Trial Registration Clinicaltrials. gov NCT01343043 Ethics Approval This study was approved by the appropriate institutional review boards and independent ethics committees.

Trial Information Click here to access other published clinical trials. Lessons Learned The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist. Background Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients. Methods Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3 weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1. Results Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92–3.67) months for regorafenib versus 2.07 (95% CI, 1.64–3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16–23.48) months for regorafenib and 4.89 (95% CI, 3.02–9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31–1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib. Conclusion Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.

Purpose: NC-6300 is a novel nanoparticle formulation of epirubicin that has a pH-sensitive linker conjugated to epirubicin. It exhibits selective tumor accumulation owing to enhanced permeability and retention effect. We conducted a phase 1b trial to determine MTD and recommended phase II dose (RP2D) of NC-6300 monotherapy in advanced, metastatic, or unresectable solid tumors, including soft-tissue sarcomas. Patients and Methods: This phase 1b dose-escalation trial of NC-6300 monotherapy employed a Bayesian continuous reassessment method design. NC-6300 was administered on day 1 of every 21-day cycle, with epirubicin-equivalent dose increments from 125 to 215 mg/m2. Safety, efficacy, quality of life, and pharmacokinetic profile of NC-6300 monotherapy were evaluated. Results: Twenty-nine subjects (16 male) were enrolled: 17 with soft-tissue sarcoma, one with osteosarcoma, and 11 with other solid tumors. Observed dose-limiting toxicities included thrombocytopenia, stomatitis, lung infection, and febrile neutropenia. The most common grade 3/4 adverse events were neutropenia (59%), anemia (24%), thrombocytopenia (24%), and febrile neutropenia (21%). MTD and RP2D were determined to be 185 mg/m2 and 150 mg/m2, respectively. The objective response rate in the evaluable population was 11%. Partial response was observed in angiosarcoma and endometrial stromal sarcoma. A dose-dependent increase was observed in both total and released epirubicin concentrations. Conclusions: NC-6300 was well tolerated with a manageable side effect profile, despite the MTD and RP2D being higher than conventional epirubicin doses. A signal of preliminary activity was observed in angiosarcoma. NC-6300 warrants further investigation in patients with advanced solid tumors, including sarcoma.

Background Oral metronomic chemotherapy, which has low toxicity, has demonstrated promising anti-tumor and anti-angiogenic properties that may lead to prolonged progression-free survival and improved response rates in patients with recurrent epithelial ovarian cancer (EOC). These effects may be enhanced by the co-administration of anti-angiogenic agents. Methods We conducted a randomized phase II clinical trial to evaluate the therapeutic benefit of oral metronomic cyclophosphamide (CTX) alone and with the anti-angiogenic drug celecoxib in patients with gynecological malignancies. 52 patients were randomly assigned to two treatments arms: 50 mg oral CTX daily alone (Arm A) or with 400 mg celecoxib twice daily (Arm B). The primary endpoint was response rate. Secondary endpoints included toxicity, time to treatment failure, and overall survival. Results In Arm A (n = 26), 3 patients (12%) had stable disease >6 months and 1 (4%) had a partial response. In Arm B, 5 (19%) had stable disease >6 months and 1 patient (4%) had a partial response. There were no significant between-group differences in overall survival (9.69 months [95% CI 3.84–13.18] vs. 12.55 months [6.67–17.61]) or in median time to treatment failure (1.84 months [1.68–2.76] vs. 1.92 months [1.64–5.22]). The most common adverse events were nausea, vomiting, and abdominal pain. Conclusions Oral metronomic CTX has activity with no major toxicities in heavily pretreated recurrent gynecological cancers and may be considered in patients with indolent disease. We did not observe any additional benefit of celecoxib treatment, though this may be due to small sample sizes.

11562 Background: Sarcoma cells are most immunogenic earlier in the disease course and before treatment when the immune system can recognize and destroy them. Hypothesis: Immune checkpoint inhibitors would be most effective when given to previously untreated patients with metastatic soft tissue sarcoma. Methods: Eligible patients for this Phase 2 study are previously untreated patients ≥ 18 years of age with unresectable or metastatic soft tissue sarcoma, with measurable disease by RECIST v1.1. Immune checkpoint inhibitors Ipilimumab (I) and Nivolumab (N) were given with Trabectedin (T), a marine derived alkaloid with defined doses of I (1 mg/kg i.v. q 12 weeks), N (3 mg/kg i.v. q 2 weeks), and T (1.2 mg/m2 i.v. q 3 weeks). Primary endpoints: (1) Objective response rate by RECIST v1.1 via CT scan or MRI, (2) Progression-free survival (PFS): from first day of treatment to disease progression or death due to any cause; otherwise, it is censored at the time of last follow-up, and (3) Overall survival: from first day of treatment to death due to any cause; otherwise, it is censored at the time of last follow-up. Results: There were eighty-two evaluable subjects, having completed the first cycle of I, N, and T and have had a CT or MRI scan at the 6-week follow-up period. Best Overall Response by RECIST v1.1 = 7 CR (2 surgical CR), 9 PR, 54 SD, and 12 PD. Disease control rate was 85.4%. The median PFS was >6.4 (range: 0-32) months; 6-month PFS rate: 57.3%. The median OS was >12.0 (0-38) months; 6-month OS rate: 78.8%. Safety analysis: The most common Grade 3 TRAEs include increased ALT (26), anemia (11), increased AST (9), and fatigue (8). Common Grade 4 TRAEs include thrombocytopenia (2), increased AST (2), increased ALT (2), and increased CPK (2). There was one Grade 5 TRAE of rhabdomyolysis (1). Conclusions: Taken together, these results suggest that first-line combinatorial therapy with I, N, and T are (1) synergistic, and (2) may be equal or superior to, and safer than, standard first line therapy for advanced/metastatic soft tissue sarcoma. Clinical trial information: NCT03138161.

BACKGROUND Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined. RESULTS One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma. CONCLUSIONS Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2016. © 2016 American Cancer Society.

BACKGROUND Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma. METHODS Patients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of ≥6 months) with a target of ≥25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a

Importance Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. Objective To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. Design, Setting, and Participants This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog ( KIT ) and platelet-derived growth factor receptor α ( PDGFRA ) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. Interventions Dasatinib, 70 mg orally twice daily. Main Outcomes and Measures The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. Results In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. Conclusions and Relevance Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.

Background: The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted. Methods: Seventy-one adults with advanced STS who received ⩽2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS). Results: There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N=11) over single agent (N=10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P=0.01). Four-month PFS rate was 50% (95% confidence interval 0.19–0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each). Conclusions: While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.

11017 Background: Most GISTs are driven by mutations in KIT and PDGFRa and secondary mutations are felt to confer resistance to TKIs. In advanced/metastatic GIST, the benefit of second line TKIs and beyond is progressively less after imatinib failure. As such, novel non-TKI approaches are important to explore. Here we report interim analyses of safety and efficacy in advanced GIST patients treated with immunotherapy. Methods: Patients with advanced/metastatic GIST refractory to at least imatinib were enrolled on a randomized, parallel group, unblinded Phase 2 trial of either nivo (240 mg Q2wks) or nivo (240 mg Q2wks) with ipi (1mg/kg Q6wks) for up to 2 years. The primary endpoint was the objective response rate(ORR) of nivo alone or nivo + ipi by RECIST 1.1 criteria. Imaging was assessed by investigator and 3 independent radiologists. Patients were randomized 1:1 and were restaged every 8 weeks. With a sample size of 20 per group, an exact binomial test with a nominal 0.050 one-sided significance level will have 82% power to detect the difference between the null hypothesis response rate 1.5% and the alternative response rate of 15%. Secondary objectives are to ascertain the PFS, CBR, RR by Choi criteria and safety. Blood and biopsies are also being collected. Results: At cutoff, 29 patients (27 evaluable) with a median of 3 (1-7) lines of prior therapies have started on trial. In the nivo only arm, 7/15 pts had a best response of SD for a CBR of 46.7% with the median PFS being 8.57 wks. In the nivo + ipi arm, 1/12 patients had a PR and 2/12 have SD for a CBR of 25.0% (95% exact C.I. 5.5%-57.2%) with a median PFS of 9.1 wks. 8 patients have been on therapy for more than 6 months and two patients with a KIT Exon 17 mutation had radiographic disease shrinkage. Most AEs were grades 1-2 with fatigue (37%) being the most common. 4 Grade 3/4 AEs occurred in the nivo and ipi arm (hyperglycemia, weakness, diarrhea x 2) and 4 grade 3/4AEs occurred in the nivo arm (DKA, hyperglycemia, rash, fatigue). Pretreatment biopsies have been obtained in all patients and blood has been collected on all patients for correlative analysis. Conclusions: In a heavily pretreated GIST population, responses and disease control with both nivo and nivo + ipi were observed. To date, the drugs have been well tolerated and no new safety signals have been observed in this disease state. Clinical trial information: NCT02880020.

Background: NY-ESO-1c259T-cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 (SPEAR T-cells) are being studied in an ongoing multi-cohort clinical trial in synovial sarcoma (NCT01343043). We compared safety, efficacy and cell persistence between two cohorts using different doses of lymphodepleting chemotherapy. Methods: There are four cohorts separated by differing antigen expression levels and lymphodepletion regimens, and this assessment compares cohorts 1 (closed) and 4 (ongoing). In both, ≥50% patient tumor cells expressed NY-ESO-1 at 2+/3+ levels by immunohistochemistry. Following apheresis, T-cells are isolated, activated, transduced to express NY-ESO-1c259T and expanded. Lymphodepletion in cohort 1 consists of fludarabine 30 mg/m2/d × 4 d and cyclophosphamide 1800 mg/m2/d × 2d, and in cohort 4 consists of fludarabine 30 mg/m2/d × 3d and cyclophosphamide 600 mg/m2/d × 3d. Target dose is 1–6 × 109 transduced cells. Disease is assessed at weeks 4, 8 and 12 and every 3 months until disease progression. Results: 12 patients were treated in cohort 1 and 14 patients in cohort 4 (as of 23Nov17). Median transduced cell dose was 3.6 × 109 cells in cohort 1 and 2.6 × 109 cells in cohort 4. Treatment-related adverse events (AEs) were observed in 100% of patients in cohort 1 and 86% in cohort 4; related serious adverse events (SAEs) were reported in 50% of cohort 1 and 14% of cohort 4. There were no fatal AEs. Overall response rate (ORR) in cohort 4 is 29% vs 50% in cohort 1, and duration of response is in cohort 4 is 16 weeks vs 31 weeks in cohort 1. The best overall response of stable is 50% in cohort 1 and 64% in cohort 4. Median peak expansion of transduced T-cells in peripheral blood in responders is lower in cohort 4 (40,137 copies/μg DNA) vs cohort 1 (106,174 copies/μg DNA). Median absolute lymphocyte counts following lymphodepletion were 1×107/L (range 0-3) in cohort 1 and 9×107/L (0-40) in cohort 4. Conclusions: The greater ORR and higher peak expansion in cohort 1 may be attributable to the dose intensity of the lymphodepleting regimen. Although related SAEs were reported in a higher proportion in cohort 1 than 4, the safety and tolerability are acceptable in both, and cell doses were similar. The data and overall benefit:risk considerations support utilizing higher doses of preconditioning chemotherapy in future trials. Citation Format: Sandra P. D'Angelo, Dejka Araujo, Brian Van Tine, George Demetri, Mihaela Dutra, John Glod, Warren Chow, Stephen Grupp, Alibiruni Abdul Razak, William Tap, Breelyn Wilky, Erin Van Winkle, Elliott Norry, Samik Basu, Karen Chagin, Malini Iyengar, Trupti Trivedi, Rafael Amado, Crystal Mackall. Comparison of pretreatment conditioning on efficacy in two cohorts of a pilot study of genetically engineered NY-ESO-1c259T-cells in patients with synovial sarcoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A007.

Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m(2) and later bi-weekly at 12, 15, and 18 mg/m(2). The maximum tolerated dose (MTD) was determined at 15 mg/m(2) bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n = 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.

HIV protease inhibitors are associated with HIV protease inhibitor-related lipodystrophy syndrome. We hypothesized that liposarcomas would be similarly susceptible to the apoptotic effects of an HIV protease inhibitor, nelfinavir.We conducted a phase I trial of nelfinavir for liposarcomas. There was no limit to prior chemotherapy. The starting dose was 1,250 mg twice daily (Level 1). Doses were escalated in cohorts of three to a maximally evaluated dose of 4,250 mg (Level 5). One cycle was 28 days. Steady-state pharmacokinetics (PKs) for nelfinavir and its primary active metabolite, M8, were determined at Levels 4 (3,000 mg) and 5.Twenty subjects (13 males) were enrolled. Median (range) age was 64 years (37-81). One subject at Level 1 experienced reversible, grade 3 pancreatitis after 1 week and was replaced. No other dose-limiting toxicities were observed. Median (range) number of cycles was 3 (0.6-13.5). Overall best responses observed were 1 partial response, 1 minor response, 4 stable disease, and 13 progressive disease. Mean peak plasma levels and AUCs for nelfinavir were higher at Level 4 (7.3 mg/L; 60.9 mg/L × h) than 5 (6.3 mg/L; 37.7 mg/L × h). The mean ratio of M8:nelfinavir AUCs for both levels was ~1:3.PKs demonstrate auto-induction of nelfinavir clearance at the doses studied, although the mechanism remains unclear. Peak plasma concentrations were within range where anticancer activity was demonstrated in vitro. M8 metabolite is present at ~1/3 the level of nelfinavir and may also contribute to the anticancer activity observed.

Nelfinavir induces apoptosis in liposarcoma by inhibiting site-2 protease (S2P) activity, which leads to suppression of regulated intramembrane proteolysis. We postulate similar effects in castration-resistant prostate cancer because it exhibits a lipogenic phenotype. Nelfinavir inhibited androgen receptor activation in androgen-sensitive prostate cancer and the nuclear translocation of the fusion proteins sterol regulatory element binding protein-1 (SREBP-1)-enhanced green fluorescence protein (EGFP) and activating transcription factor 6 (ATF6)-EGFP in castration-resistant prostate cancer cells, viewed under confocal microscopy. Nelfinavir and site-1 protease (S1P) and S2P small interfering RNAs (siRNAs) reduced the proliferation of castration-resistant prostate cancer and induced apoptosis, which was opposed by autophagy. Inhibition of autophagy with hydroxychloroquine was additive to the apoptotic effect of nelfinavir. Western blotting of S1P and S2P siRNA knockdown and/or nelfinavir-treated cells confirmed the accumulation of precursor SREBP-1 and ATF6. 3,4-Dichloroisocoumarin, an S1P inhibitor, did not affect SREBP-1 processing. In contrast, 1,10-phenanthroline, an S2P inhibitor, reproduced the nelfinavir-treated molecular and biological phenotype. Nelfinavir-mediated inhibition of regulated intramembrane proteolysis led to the accumulation of unprocessed SREBP-1 and ATF6. This resulted in sequential endoplasmic reticulum stress, inhibition of the unfolded protein response, reduced fatty acid synthase expression and apoptosis, which was countered by autophagy. Inhibition of autophagy was at least additive to this pro-apoptotic effect. These findings provide new insights into nelfinavir-induced endoplasmic reticulum stress and cancer cell death, and lead us to propose investigating its clinical activity in castration-resistant prostate cancer. This report validates S2P as a therapeutic target in castration-resistant prostate cancer.

The primary objective was to determine the maximum tolerated doses (MTDs) of the combination of bortezomib and temozolomide in patients with solid tumors. The secondary objective was to evaluate the pharmacokinetics (PK) of bortezomib with and without concurrent hepatic enzyme-inducing anticonvulsants (HEIAs).Bortezomib was administered on days 2, 5, 9, and 12; temozolomide on days 1-5 of a 28-day cycle. Dose escalation proceeded using a standard 3+3 design. Patients with primary or metastatic brain tumors were eligible and were stratified based on whether they were taking HEIAs or not.Of the 25 patients enrolled, 22 were not taking HEIAs. MTDs were only given to patients not receiving HEIAs. Dose-limiting toxicities (DLTs) consisted of grade-3 constipation, hyponatremia, fatigue, elevated hepatic enzymes, and grade-4 neutropenia, thrombocytopenia, constipation, and abdominal pain. Stable disease (8 weeks) was observed in 5 patients. Bortezomib systemic clearance (CL(sys)) on day 9 was 51% of the CL(sys) on day 2 (P 0.01) Similarly, the normalized area under the concentration-time curve (norm AUC) on day 9 was 1.9 times the norm AUC on day 2 (P 0.01). The median bortezomib CL(sys) on days 2 and 9 was significantly higher (P 0.04) in patients taking HEIAs, and the median norm AUC was correspondingly lower (P 0.04).The MTDs for the combination of bortezomib and temozolomide in patients not taking HEIAs are 1.3 and 200 mg/m(2), respectively. The rate of bortezomib elimination in patients taking HEIAs was increased twofold. Additional trials are needed to better define the optimal dosing in such patients.

Background The California Cancer Consortium has performed a Phase II trial of infusional bryostatin, a protein kinase C inhibitor isolated from the marine invertebrate bryozoan, Bugula Neritina, a member of the phylum Ectoprocta, in combination with cisplatin, in patients (pts) with recurrent platinum-sensitive or resistant ovarian cancer (OC). Methods Pts received bryostatin 45 mcg/m2 as a 72 h continuous infusion followed by cisplatin 50 mg/m2. Cycles were repeated every 3 weeks. Dosages were chosen based on phase I data obtained by the CCC in a population of pts with mixed tumor types. Results Eight pts with recurrent or persistent epithelial OC received 23 cycles of treatment. All pts had received previous platinum-based chemotherapy; two pts had received one prior course, five had received two prior courses, and one had received three prior courses of chemotherapy. The median age was 64 (range 32–72), and Karnofsky performance status 90 (range 80–100). A median of 3 cycles of chemotherapy were delivered (range: 1–5). The median progression-free and overall survivals were 3 and 8.2 months respectively. Best responses included two partial responses (one in a platinum-resistant pt), three pts with stable disease, and three progressions. All pts experienced Grade 3 or 4 toxicities including severe myalgias/pain/fatigue/asthenia in six pts, and severe nausea/vomiting/constipation in two other pts. One pt experienced a seizure and liver function tests were elevated in one other. Conclusions A modest response rate is observed in pts with recurrent or persistent ovarian cancer treated with the combination of bryostatin and cisplatin. The toxicity profile, however, observed in this pt population (primarily severe myalgias), precludes tolerability and prevents this combination from further investigation at this dose and schedule. It is possible that platinum pre-exposure in OC patients exacerbates observed toxicity. Phase II dosages of investigational agents in OC pts that are determined by phase I trials in pts with other tumor types should be chosen cautiously.

11505Background: Pazopanib, a multi-targeted tyrosine kinase inhibitor, has shown activity in various soft tissue sarcomas. Activity in liposarcoma, however, is limited. Regorafenib is a multi-kina...

8517Background: Treatment options for ED-SCLC are limited, with standard first-line platinum and etoposide and second-line topotecan having limited clinical activity. Beyond these agents, no approv...

Nelfinavir and its analogs inhibit proliferation and induce apoptosis of castration-resistant prostate cancer through inhibition of site-2 protease (S2P) activity, which leads to suppression of regulated intramembrane proteolysis. Western blotting in nelfinavir and its analog treated cells confirms accumulation of precursor SREBP-1 and ATF6. Nelfinavir and its analogs inhibit human homolog M. jannaschii S2P cleavage of an artificial protein substrate CED-9 in an in vitro proteolysis assay in a dose-dependent manner. Nelfinavir and its analogs are more potent inhibitors of S2P cleavage activity than 1,10-phenanthroline, a metalloprotease-specific inhibitor. Further, cluster analysis of gene expression from treated DU145 and PC3 cell lines demonstrate a close similarity of nelfinavir, its analogs and 1,10-phenanthroline. These results show nelfinavir and its analogs inhibit castration-resistant prostate cancer proliferation by blocking regulated intramembrane proteolysis through suppression of S2P cleavage activity. This leads to accumulation of precursor SREBP-1 and ATF6 and development of insufficient reserves of their transcriptionally-active forms. The present results validate S2P and regulated intramembrane proteolysis as novel therapeutic targets for castration-resistant prostate cancer therapeutics. A clinical trial of nelfinavir or its analogs should be developed for castration-resistant prostate cancer.

Chondrosarcomas are the second most common primary malignant tumor of bone. Chemotherapy for conventional chondrosarcomas is generally ineffective. Methylthioadenosine phosphorylase (MTAP) is a ubiquitous enzyme, essential in the salvage pathway of adenine and in methionine synthesis. MTAP-deficient cells are more susceptible than wild-type cells to pharmacologic inhibitors of de novo purine synthesis. Homozygous deletions of MTAP have been reported in hematologic and solid tumor malignancies. Based on these observations, we investigated the frequency of MTAP deletions in conventional, grade II chondrosarcomas by fluorescence in situ hybridization (FISH) analysis: 23 conventional, grade II chondrosarcoma patient samples from the Cleveland Clinic Foundation were analyzed for MTAP deletions. Nuclei were successfully extracted from 14 of 23 samples (61% evaluable) for FISH analysis: 7 of 14 samples (50%) showed either homozygous or hemizygous deletion of the MTAP gene, 6 of 14 (43%) failed to show deletion, and 1 of 14 (7%) was inconclusive. These findings suggest that approximately one-half of conventional, grade II chondrosarcomas may be preferentially sensitive to pharmacologic inhibitors of de novo purine synthesis. The present study led to development by the Intergroup Coalition Against Sarcomas of a phase II trial of pemetrexed, a multitargeted anti-folate, for advanced chondrosarcomas.

To determine the response rate to 26-h continuous infusion cyclosporine A (CSA) combined with a fixed dose level of carboplatin (CBDCA) in patients with recurrent ovarian cancer, and to determine the effect of CSA on the pharmacokinetics of CBDCA.To examine the effect of duration of CSA exposure on reversal of CBDCA resistance, clonogenic assays were performed in vitro in platinum-resistant A2780 cells. CBDCA (AUC 4) with CSA repeated every 3 weeks was then administered to patients on this phase II study. Pharmacokinetics of CSA and CBDCA were determined in a subset of patients.Preincubation of platinum-resistant A2780 cells with CSA reversed CBDCA resistance in a concentration-dependent and time-dependent manner. A group of 23 patients received 58 courses of CBDCA/CSA therapy. One partial response was observed. Eight patients achieved disease stabilization. Toxicity was similar to that observed in our previous phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean +/- SD end-of-infusion CSA level (HPLC assay) was 1253 +/- 400 microg/ml. The pharmacokinetic studies suggest that CSA does not increase CBDCA AUC.Steady-state levels of1 microg/ml CSA (HPLC assay) are achievable in vivo. Modest partial reversal of platinum resistance (in one patient with an objective response and in eight patients with stable disease noted) is achievable in vivo in patients pretreated with CSA. This phenomenon is not explained by alterations in CBDCA pharmacokinetics.

Dexrazoxane administration prior to short infusion doxorubicin prevents anthracycline-related heart damage. Since delivery of doxorubicin by 96-h continuous intravenous infusion also reduces cardiac injury, we studied delivering dexrazoxane and doxorubicin concomitantly by prolonged intravenous infusion.Patients with advanced malignancies received tandem cycles of concurrent 96-h infusions of dexrazoxane 500 mg/m2 and doxorubicin 165 mg/m2, and 24 h after completion of chemotherapy, granulocyte-colony stimulating factor (5 microg/kg) and oral levofloxacin (500 mg) were administered daily until the white blood cell count reached 10,000 microl(-1). Plasma samples were analyzed for dexrazoxane and doxorubicin concentrations.Ten patients were enrolled; eight patients had measurable disease. Two partial responses were observed in patients with soft-tissue sarcoma. The median number of days of granulocytopenia (500 microl(-1)) was nine and of platelet count20,000 microl(-1) was seven. Six patients received a single cycle because of progression (one), stable disease (four), or reversible, asymptomatic 10% decrease in cardiac ejection fraction (two). Principal grade 3/4 toxicities included hypotension (two), anorexia (four), stomatitis (four), typhlitis (two), and febrile neutropenia (seven), with documented infection (three). One death from neutropenic sepsis occurred. Dexrazoxane levels ranged from 1270 to 2800 nM, and doxorubicin levels ranged from 59.1 to 106.9 nM.These results suggest that tandem cycles of concurrent 96-h infusions of dexrazoxane and high-dose doxorubicin can be administered with minimal cardiac toxicity, and have activity in patients with recurrent sarcomas. However, significant non-cardiac toxicities indicate that the cardiac sparing potential of this approach would be maximized at lower dose levels of doxorubicin.

We report on a predictive model of long-term outcome in 114 high-risk breast cancer patients treated with high-dose chemotherapy between 1989 and 1994. Paraffin-blocks from 90 of the 114 primaries were assessed for the presence of five risk factors: grade, mitotic index, protein expression of p53, HER2/neu, and oestrogen/progesterone receptor status; we could analyse the effect of risk factors in 84 of these 90 tumours. Seven-year relapse-free and overall survival was 58% (95% confidence interval 44–74%) and 82% (95% confidence interval 71–94%) vs 33% (95% confidence interval 21–52%) and 41% (95% confidence interval 28–60%) for patients whose primary tumours displayed ⩾3 risk factors vs patients with ⩽2 risk factors. For the entire group of 168 high-risk breast cancer patients, inflammatory stage IIIB disease and involved post-mastectomy margins were associated with decreased relapse-free survival and overall survival; patients treated with non-doxorubicin containing standard adjuvant therapy experienced worse overall survival (RR, 2.08; 95% confidence interval 1.04 to 4.16; P=0.04), while adjuvant tamoxifen improved overall survival (RR, 0.65; 95% confidence interval 0.41–1.01; P=0.054). Future trial designs and patient selection for studies specific for high-risk breast cancer patients should include appropriate prognostic models. Validation of such models could come from recently completed randomised, prospective trials. British Journal of Cancer (2002) 87, 281–288. doi:10.1038/sj.bjc.6600450 www.bjcancer.com © 2002 Cancer Research UK

We evaluated the feasibility of tandem-cycle high-dose chemotherapy (HDCT) with cisplatin, melphalan, and peripheral blood progenitor cells (PBPCs). Fifty patients with high-risk primary (n = 17) or stage IV breast cancer (n = 29) or other malignancies (n = 4) received 2 cycles of intravenous melphalan, 20 to 151.8 mg/m2, and cisplatin, 200 mg/m2, followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF. Starting at 40 mg/m2 of melphalan, patients also received PBPCs. Delayed platelet recovery defined the maximum tolerated dose (MTD) for melphalan at 101.2 mg/m2 per cycle. There were no treatment-related deaths. Cycle 2 was delivered at a median of 1.7 months after cycle 1; 72% of patients treated at the MTD received both cycles. Cycle 2 was omitted when patients refused it or had disease progression or toxicities, primarily prolonged thrombocytopenia. Complete response rates in stage IV breast cancer patients increased from 28% pre-HDCT to 55% after cycle 2. At a median follow-up of 4.6 years (range, 1.5-8.1 years), 11 of 29 patients with stage IV breast carcinoma were alive with 5-year projected progression-free and overall survival rates of 19% (95% confidence interval [CI], 7%-41%) and 39% (95% CI, 20%-62%), respectively. Five-year projected progression-free and overall survival rates for patients with stage IV breast cancer in complete response following HDCT versus all others were 35% (95% CI, 15%-70%) versus 0% (P = .01) and 61% (95% CI, 35%-91%) versus 10% (95% CI, 2%-60%) (P = .003; log-rank test), respectively. Estrogen-receptor positivity was predictive of reduced risk of progression (relative risk [RR], 0.25; 95% CI, 0.10-0.65; P = .003) and death (RR, 0.27; 95% CI, 0.10-0.72; P = .009) after adjusting for response status. Five-year projected relapse-free and overall survival rates were 71% (95% CI, 43%-96%) and 82% (95% CI, 56%-100%), respectively, for the 17 patients with high-risk primary breast cancer. Tandem-cycle high-dose melphalan and cisplatin with PBPCs is feasible. Preliminary data suggest significant activity in selected patients with stage IV responding breast carcinoma.Biol Blood Marrow Transplant 2001;7(5):284-93.

We assessed the feasibility and pharmacokinetics of high-dose infusional paclitaxel in combination with doxorubicin, cyclophosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patients with high-risk primary [stage II with ≥ 10 axillary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53)] or with stage IV responsive breast cancer (n = 10) received paclitaxel 150–775 mg/m2infused over 24 hours, doxorubicin 165 mg/m2as a continuous infusion over 96 hours, and cyclophosphamide 100 mg kg–1. There were no treatment-related deaths. Dose-limiting toxicity was reversible, predominantly sensory neuropathy following administration of paclitaxel at the 775 mg/m2dose level. Paclitaxel pharmacokinetics were non-linear at higher dose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation between stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacokinetics was found. Kaplan–Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51–83%) and 77% (95% CI; 64–93%). Paclitaxel up to 725 mg/m2infused over 24 hours in combination with with doxorubicin 165 mg/m2and cyclophosphamide 100 mg kg–1is tolerable. A randomized study testing this regimen against high-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing. © 2001 Cancer Research Campaign http://www.bjcancer.com

Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 μg/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 μg/kg on days −3, −1, and 1, or 0.6 μg/kg on days −1 and 1. G-CSF, 5 μg/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34+ cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 × 106/kg (range, 1.3 to 17.6) versus 0.8 × 106/ kg (range, 0.3 to 4.2), P = .0003. The targeted minimum yield of 3 × 106CD34+ cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF–mobilized group versus 10% of G-CSF–mobilized patients (P = .001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P= .0001) and platelet recovery (day 9 v 10, P= .07) were accelerated, and fewer erythrocyte (3 v 4,P = .02) and platelet (4 v 5, P = .02) transfusions were needed compared with G-CSF–mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P < .0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 μg/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF–mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.

Based on the in vitro and in vivo synergy between cytosine arabinoside (Ara-C) and cis-diamminedichloroplatinum (cisplatin), we designed a phase II trial of Ara-C with cisplatin for patients with colorectal adenocarcinoma. Forty-eight eligible patients received continuous infusion Ara-C, 30 mg/m2/day over 72 hr, plus cisplatin, 30 mg/m2 for three doses at hours 12, 36, and 60 of the Ara-C infusion. The objective partial response rate for patients with colon carcinoma was 3% (1/32 patients; 95% CI, 0-16%) with a median response duration of 2.8 months. None of the 16 patients treated for rectal carcinoma responded. Myelosuppression was the most severe toxicity. Significant gastrointestinal and hepatic toxicities occurred in a small number of patients. Nephrotoxicity and neurotoxicity were mild. We conclude that the prolonged infusion of Ara-C in combination with divided doses of cisplatin offers no significant therapeutic advantage.

We have conducted a pilot study to investigate the role of high-dose therapy and autologous bone marrow/stem cell transplantation (ASCT) during first complete or partial remission in 52 patients with poor-risk aggressive lymphoma. There were 42 patients with intermediate-grade or immunoblastic lymphoma who were considered to be high (60%) and high-intermediate risk (40%) groups at diagnosis based on the age-adjusted International Prognostic Index (IPI) and 10 patients with high-grade, SNCCL (small non-cleaved cell, Burkitt's, and non-Burkitt's), who at presentation had poor-risk features defined as elevated serum lactate dehydrogenase level, stage IV, and bulky mass ≥10 cm. The median age was 34 years (range, 16 to 56 years). Thirty-nine were transplanted in first complete remission and 13 in first partial remission after conventional therapy. Conditioning regimens consisted of total body irradiation (TBI) administered as a single fraction 750 cGy in 3 patients and in fractionated doses for a total of 1,200 cGy in 44 patients, in combination with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide. Five patients with prior radiotherapy received 450 mg/m2 carmustine instead of TBI. Stem cell sources were either bone marrow and/or peripheral blood. No in vitro purging was used. All patients engrafted. Two SNCCL patients died of venoocclusive disease at 25 days and acute leukemia at 27 months posttransplantation. There were six relapses at 1.5 to 12.8 months posttransplantation. At a median follow-up of 44 months (range, 1 to 113 months), the estimated 3-year overall survival (OS) and disease-free survival (DFS) for all patients was 84% (95% confidence interval [CI], 70% to 92%) and 82% (95% CI, 68% to 91%), respectively. In the subset of patients with intermediate-grade and immunoblastic lymphoma, the 3-year DFS was 89% (95% CI, 74% to 96%) for all patients, 87% (95% CI, 67% to 96%) for high-risk patients, and 92% (95 CI, 61% to 99%) for high-intermediate risk patients. The 3-year OS and DFS for SNCCL patients were identical at 60% (95% CI, 30% to 84%). These results suggest that high-dose therapy and ASCT during first remission may improve the survival and prognosis of patients with poor-risk intermediate- and high-grade lymphoma. A prospective randomized study comparing high-dose therapy and ASCT with conventional chemotherapy in IPI high-risk patients with aggressive non-Hodgkin's lymphoma should be undertaken.

We evaluated the effects of various schedules of peripheral blood stem cell (PBSC) reinfusion, granulocyte colony-stimulating factor (G-CSF ) priming, and CD34+ enrichment on hematopoietic recovery in 88 patients with advanced breast cancer treated with high-dose chemotherapy, consisting of cisplatin 250 mg/m2, etoposide 60 mg/kg, and cyclophosphamide 100 mg/kg. PBSC (≥7.5 × 108 nucleated cells/kg) were collected following priming with G-CSF and were either immediately cryopreserved (48 patients; cohorts A and B) or were first processed for CD34+ enrichment (40 patients; cohorts C and D). Patients in cohorts A and C received PBSC on day 0; patients in cohorts B and D received 25% of their nucleated cells on day −2 and 75% on day 0 (split reinfusion). Patients in cohorts A, B, and C were primed with G-CSF 10 μg/kg, subcutaneously (SC), once a day; patients in cohort D were primed with 5 μg/kg G-CSF, SC, twice daily (bid). Bid administration of G-CSF yielded 2.3 to 4.7 × higher numbers of CD34+ cells in the PBSC product than the same total dose given once a day (P = .002). Reinfusion of 25% of unselected PBSC on day −2 (median, 2.26 × 108/kg nucleated cells [range, 1.7 to 3.3 × 108/kg]) with the remaining cells reinfused on day 0 resulted in earlier granulocyte recovery to ≥500/μL when compared with reinfusion of all stem cells on day 0 (group B, median of 8 days [range, 7 to 11] v group A, 10 days [range, 8 to 11], P = .0003); no schedule-dependent difference was noted in reaching platelet independence (group B, 11.5 days [range, 5 to 21]; group A, 12 days [range, 8 to 24], P = not significant). Split schedule reinfusion of CD34+-selected PBSC did not accelerate granulocyte recovery. In groups D and C, the median number of days to granulocyte recovery was 12 (range, 8 to 22) and 11.5 (range, 9 to 13); patients became platelet independent by day 15 (range, 6 to 22) and 14 (range, 12 to 23), respectively. CD34+-selected PBSC rescue decreased the incidence of postreinfusion nausea, emesis, and oxygen desaturation in comparison to unselected PBSC reinfusion (P ≤ .005 for each). Hematopoietic recovery may be accelerated by earlier reinfusion of ≈ 2.26 × 108/kg unselected nucleated cells. Earlier recovery may be triggered by components other than the progenitors included in the CD34+ cell population. Sustained hematopoietic recovery can also be achieved with CD34+-selected PBSC alone. Dosing of G-CSF on a bid schedule generates higher CD34+ cell yield in the leukapheresis product. Whether even earlier “sacrificial” reinfusion of approximately 2 × 108/kg unselected nucleated cells concomitant with the administration of high-dose chemotherapy would reduce the duration of absolute granulocytopenia further while initiating sustained long-term hematopoietic recovery will require further investigation.

Purpose We investigated the efficacy and toxicity of sorafenib, a multikinase inhibitor of vascular endothelial growth factor receptor tyrosine kinase, in combination with vinorelbine therapy in a phase I/II trial in patients with metastatic breast cancer. Patients and Methods We enrolled 11 patients in the phase I portion to determine the maximum tolerated dose (MTD) of the combination, followed by 35 extra patients treated at the MTD in phase II. The median age of patients was 54 years old (range, 31-72 years old). Tumors were estrogen receptor and progesterone receptor (ER/PR) positive in 54% (22/54) of patients, and triple negative (ER − , PR − , HER2 − ) in 41% (17/54) of patients. Of all patients, 22% received sorafenib and vinorelbine as first-line therapy, 37% as second-line therapy, and 41% as third-line therapy. Results In total, 41 patients were treated at the MTD (6 during phase I; 35 in phase II). The observed 44% 4-month progression-free survival rate was similar to the estimated historical rate of 43% with vinorelbine treatment. The combination was tolerated with expected toxicities. Patients treated at the MTD who had received prior bevacizumab treatment received a median of 1.5 cycles (range, 1-10 cycles) compared with a median of 5 cycles (range, 2-12 cycles) for patients without prior bevacizumab treatment. Conclusion Further evaluation of vinorelbine and sorafenib in bevacizumab-naive patients may be of interest if specific biomarkers guiding patient selection can be identified.

Systemic therapy options for sarcomas historically have been limited once these tumors become resistant to traditional cytotoxic chemotherapy. Ongoing preclinical research into their biology and clinical trials based on rational biologic targeting have identified novel therapies. For example, the success of imatinib in gastrointestinal stromal tumor has led to the use of other tyrosine kinase inhibitors in other sarcoma subtypes. Other novel therapies include targeting of the mTOR pathway, and IGF-1 receptor. The heterogeneity of these tumors demands intelligently designed protocols in recognizing efficacy that may be restricted to certain histologic subtypes. This article will cover recent trials of new biologic agents in sarcomas that have exhibited promising activity.

This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid.Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m(2)/d IV, administered as a 72 h continuous infusion on days 1-3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks.Seventeen patients received 39 cycles of treatment: median 2, (range 1-5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60-90%) and age: 52 (range 24-75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m(2)/d, the median CSF/plasma ratio was 19.4% (range 15.1-59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02-3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2-5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs.The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m(2)/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.

GTI-2040 is a 20-mer antisense oligonucleotide targeting the mRNA of ribonucleotide reductase M2. It was combined with oxaliplatin and capecitabine in a phase I trial in patients with advance solid tumors based on previous studies demonstrating potentiation of chemotherapy with ribonucleotide reductase inhibitors.Patients at least 18 years of age with advanced incurable solid tumors and normal organ function as well as a Karnofsky performance status ofor =60% were eligible. One prior chemotherapy regimen for advanced disease or relapse within 12 months of adjuvant chemotherapy was required. Patients could have received prior fluoropyrimidines, including capecitabine, but not oxaliplatin. Treatment cycles were 21 days. In each cycle, GTI-2040 was given as a continuous intravenous infusion over 14 days, oxaliplatin as a 2-h intravenous infusion on day 1, and capecitabine orally twice a day for 14 days. In cycle 1 only, oxaliplatin and capecitabine were started on day 2 to allow ribonucleotide reductase mRNA levels to be measured with and without oxaliplatin and capecitabine. Doses were escalated in cohorts of three patients using a standard 3 + 3 design until the maximum tolerated dose was established, defined as no more than one first-cycle dose-limiting toxicity among six patients treated at a given dose level.The maximum tolerated dose was estimated to be the combination of GTI-2040 3 mg/kg per day for 14 days, capecitabine 600 mg/m(2) twice daily for 14 days, and oxaliplatin 100 mg/m(2) every 21 days. Dose-limiting toxicities were hematologic. GTI-2040 pharmacokinetics, obtained at steady-state on days 7 and 14, showed the high inter-patient variability previously reported. Two of six patients had stable disease at the maximum tolerated dose and one patient, with heavily pre-treated non-small cell lung cancer, had a partial response at a higher dose level. In samples from a limited number of patients, there was no clear decrease in ribonucleotide reductase expression in peripheral blood mononuclear cells during treatment.A combination of GTI-2040, capecitabine and oxaliplatin is feasible in patients with advanced solid tumors.

Background: Imatinib was approved in 2002 for unresectable and metastatic gastrointestinal stromal tumors. Our objective was to determine if the introduction of imatinib coincided with improved survival from metastatic gastrointestinal stromal tumor in the U.S. population and in specific socioeconomic groups. Methods: Query of the Surveillance, Epidemiology, and End Results registry identified 552 patients with metastatic gastrointestinal stromal tumor between 1995 and 2004. Year of diagnosis was categorized into two periods, 1995 to 2000 and 2001 to 2004, to account for the effect of imatinib. Kaplan-Meier and multivariate Cox regression analyses were used to examine differences in survival between periods and among socioeconomic groups. Results: Median survival increased from 12 to 33 months from 1995 to 2000 to 2001 to 2004 (P < 0.001); survival at 47 months increased from 21% to 41%, respectively (P < 0.001). Median survival times for White, Black, Hispanic, and Asian or Pacific Islander, and for low-, middle-, and high-income groups increased significantly in the era of imatinib (all P < 0.05). On multivariate analysis, Black race [hazard ratio, 1.96; 95% confidence interval (95% CI), 1.15-3.32; P = 0.013], Hispanic race (hazard ratio, 2.11; 95% CI, 1.14-3.88; P = 0.017), and low income (hazard ratio, 1.81; 95% CI, 1.13-2.89; P = 0.014) were associated with the poorest survival during the 1995 to 2000 period. During 2001 to 2004, these disparities in survival were no longer statistically apparent. Conclusions: Survival from metastatic gastrointestinal stromal tumor has improved significantly in the era of imatinib. This improvement has been uniform across all socioeconomic groups, with concomitant elimination of socioeconomic survival disparities potentially due to an assistance program intended to provide universal access to imatinib therapy. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2194–201)

Purpose: To determine the maximally tolerated dose, toxicity, and pharmacokinetics of i.p. gemcitabine. Experimental Design: Patients had peritoneal carcinomatosis. Gemcitabine (40, 80, 120, or 160 mg/m2) was administered into the peritoneal cavity in 2 L of warmed saline on days 1, 4, 8, and 12 of a 28-day cycle. Results: Thirty patients received 63 (median, 2; range, 0-6) courses. Tumors included ovary (14), uterus (2), colon (6), pancreas (3), and others (5). Dose-limiting toxicity included nausea, vomiting, diarrhea, dyspnea, fatal respiratory failure, and grade 3 elevation of alanine aminotransferase in three patients. Hematologic toxicity and pain were ≤grade 2. Three patients had decreased or resolved ascites. Of 19 patients evaluable for response, 10 had stable disease (median, 3.5 courses) and 9 had progressive disease. The median peak peritoneal concentration was 1,116-fold (range, 456-1,886) higher than the peak plasma level. Plasma and peritoneal levels were undetectable within 8 to 12 h. At 120 mg/m2, the median peritoneal area under the concentration versus time curve (AUC) was 82,612 ng/mL × h (range, 53,296-199,830) and the plasma AUC was 231 ng/mL × h (range, 47.6-259.5). The mean peritoneal advantage (AUCperitoneal/AUCplasma) was 847 (range, 356-1,385). Conclusions: I.p. administration of gemcitabine is tolerated within the tested dosage range. Technical problems with the Porta-Cath device and i.p. therapy per se may have been exacerbated by the enrollment of many patients with a variety of advanced i.p. diseases. Given the significant increase in local dose intensity and the documented activity of this drug, this agent may be an excellent candidate for i.p. therapy in optimally debulked ovarian cancer, either alone or in combination.

Oxaliplatin has in vitro activity similar to or higher than other platinum agents. Preclinically, gemcitabine has demonstrated synergy when combined with platinum compounds. These facts formed the rationale for determining the maximum tolerated dose (MTD) of gemcitabine in combination with oxaliplatin. Eligible patients with advanced incurable solid tumors were given oxaliplatin 130 mg/m2 as a 2-h infusion on day 1 followed by escalating doses of gemcitabine given over 30 min on day 1 and 8 of a 21-day cycle. A total of 43 patients were enrolled, including 30 patients at the MTD in an expanded cohort. At a gemcitabine dose of 800 mg/m2, 1/6 patients had a dose limiting toxicity (DLT) (grade 3 blurred vision and memory loss). At 1,000 mg/m2, 1/6 patients had a DLT (grade 3 increase in AST). At 1,200 mg/m2, 2/3 patients had a DLT (grade 4 thrombocytopenia and grade 3 confusion). The MTD of gemcitabine with 130 mg/m2 of oxaliplatin was therefore 1,000 mg/m2. The clearances of gemcitabine and ultrafilterable platinum are within the ranges previously reported for single agents. A patient with colon cancer had a partial response, and 21 patients had a best response of stable disease. In patients with tumor biopsies treated at the MTD, decreased ribonucleotide reductase M2 expression correlated with response. Treatment with gemcitabine and oxaliplatin was well tolerated with primarily hematologic toxicity at the MTD. Study of biochemical correlates of response remain of interest althought current results remain exploratory.

We evaluated the antitumor activity of tandem cycles of high-dose chemotherapy with autologous peripheral stem cell transplantation (aPSCT) in relapsed germ cell tumors by using high-dose paclitaxel, carboplatin, etoposide, and ifosfamide. Thirty-three patients were entered, and 31 underwent protocol therapy. Paclitaxel 350 mg/m2 (5 patients) or 425 mg/m2 (26 patients) by 24-hour continuous intravenous infusion was followed by 3 daily doses of carboplatin and either etoposide (cycle 1) or ifosfamide/mesna (cycle 2). The carboplatin dose had a calculated area under the curve of 7 mg-min/mL, and the daily dose of etoposide was 20 mg/kg (cycle 1). Ifosfamide 3 g/m2/d for 3 days (with mesna uroprotection) was substituted for etoposide in cycle 2. Each cycle was supported by granulocyte colony-stimulating factor–mobilized peripheral blood stem cells. Thirty-one patients were evaluable for response, toxicity, and long-term disease control. Two patients did not undergo aPSCT because of rapid disease progression. Nineteen patients received both cycles of aPSCT, 8 progressed after cycle 1, 3 refused the second cycle, and 1 died of fungal infection during cycle 1. Twelve patients remain relapse free at a median of 67 months from the initiation of therapy. Whereas the International Germ Cell Cancer Collaborative Group category at the time of initial diagnosis did not seem to predict outcome, the patient's probability of achieving durable remission was significantly associated with the Beyer prognostic score at the time of protocol entry. Regimens containing the most active agents in relapsed nonseminomatous germ cell tumors, including high-dose paclitaxel, are well tolerated and have promising activity even in patients with poor-risk features who do not achieve durable remissions with standard therapy. The Beyer prognostic system is a valuable predictor for patients undergoing aPSCT.

Preclinical studies in our laboratory have demonstrated that prior exposure to hydroxyurea increases the percentage of cells in S phase, enhancing the cytotoxicity of subsequent gemcitabine treatment in human oropharyngeal KB cells. To evaluate the clinical implications of this time- and sequence-dependent potentiation, we performed a phase I trial of hydroxyurea given over 24 h followed by a 30-min infusion of gemcitabine in weeks 1 and 2 of a 3-week cycle. The dose of hydroxyurea was fixed at 500 mg orally every 6 h for four doses starting 24 h before each dose of gemcitabine. The initial dose level of gemcitabine was 250 mg/m(2) on days 2 and 9, and this was escalated stepwise to 1000 mg/m(2) on days 2 and 9. Gemcitabine pharmacokinetics were determined on days 2 and 9 of the first cycle. Of 27 patients enrolled (12 female, 15 male), 24 were evaluable for response and 23 were evaluable for toxicity. Their median age was 56 years (range 27-76 years). Tumor types included lung, head and neck, pancreas, breast, colon, prostate, stomach, ovary, esophagus, germ cell, thyroid, gallbladder, and unknown primary. A total of 80 cycles of treatment were completed. One patient (unknown primary) had an objective partial response lasting 21 months, and 12 patients had stable disease. All observed dose-limiting toxicities were related to myelosuppression. The gemcitabine maximum tolerated dose was established at 750 mg/m(2) on days 2 and 9. Hydroxyurea had no effect on the plasma pharmacokinetics of gemcitabine. These results suggest that hydroxyurea followed by gemcitabine can be safely administered and has activity on this schedule. We are presently developing a phase II trial of this regimen for patients with platinum-resistant head and neck cancer.

10526 Background: Outcomes for advanced soft-tissue sarcomas (STS) are poor given their relative insensitivity to chemotherapy. AZD6244 (AZD) is a MEK1/2 inhibitor that suppresses STS proliferation...

Purpose: The purpose of these sequential phase I studies was to evaluate the antiemetic efficacy and pharmacokinetics of high-dose continuous infusion prochlorperazine. Methods: A total of 52 patients with advanced cancer were treated in two sequential phase I studies utilizing high-dose prochlorperazine. In study 1, designed to investigate the antiemetic effects of dose-intensive prochlorperazine, various cisplatin-based multiagent chemotherapeutic regimens were administered in combination with escalating doses of prochlorperazine. In study 2, a fixed dose of cisplatin (60 mg/m2) was administered over 24 h as a continuous intravenous infusion in combination with infusional high-dose prochlorperazine. Antiemetic efficacy in the first trial was assessed in terms of the number of episodes of nausea, retching, and/or emesis during the 24 h following cisplatin administration. The pharmacokinetics of high-dose prochlorperazine were evaluated in eight patients treated in study 2 at the two dose levels below those at which dose-limiting toxicity was noted. Results: The maximally tolerated dose of prochlorperazine in combination with cisplatin (60 mg/m2 administered as a continuous infusion over 24 h) was 24 mg/h. The dose-limiting toxicity was grade 4 agitation and confusion noted in one patient treated at 26 mg/h. This patient died 3 days following cessation of chemotherapy due to the toxicity of the regimen in combination with the debilitating pulmonary effects of the disease. The mean end of infusion prochlorperazine level at the 24 mg/h dose level was 1.1 µM, a concentration previously reported to be consistent with the reversal of the multidrug resistance phenotype. Two partial responses were observed in study 2. Conclusions: We conclude that the antiemetic efficacy of high-dose infusional prochlorperazine does not appear to be improved over more convenient bolus administration. However, prochlorperazine levels consistent with those required in vitro for drug resistance reversal are attainable within the dose range having a tolerable toxicity profile.

Purpose: In recognition of the variety of available chemotherapeutic modulating agents and their potential to enhance the efficacy of platinum-based therapy, we embarked upon a phase I study to investigate the feasibility of combining fixed doses of carboplatinum (CBDCA) and etoposide (VP-16) with 24-h concurrent infusions of dipyridamole (DP), prochlorperazine (PCZ) and cyclosporine A (CSA) administered in escalating doses. Methods: Patients received intravenous VP-16 (200 mg/m2) and CBDCA (300 mg/m2), each over 30 min, starting at hour 6 of the modulator infusions. Resistance modulators were escalated sequentially to determine their respective maximally tolerated doses (MTDs). The pharmacokinetics (PK) of VP-16, CBDCA, and the three drug resistance (DR) modifiers were studied in eight patients. Results: A total of 59 patients were entered on study. The MTD was established at DP 5 mg/kg per day, PCZ 24 mg/h, and CSA 9.5 mg/kg per day. Dose-limiting toxicities included hypotension and severe sedation, presumably related to PCZ. No objective responses were seen. PK studies were performed when PCZ and DP doses were 24 mg/h and 3.3 mg/kg, and the CSA dose was either 8.5 mg/kg (five patients) or 9.5 mg/kg (three patients). The median clearance of VP-16 was 0.96 l/h per m2 (range 0.8–1.5 l/h per m2), which is lower than for VP-16 alone and similar to previously reported effects of CSA on VP-16 elimination. The median measured CBDCA AUC was 3.0 mg/ml · min (range 2.4–4.8 mg/ml · min). CBDCA AUC predicted by the Calvert formula using measured creatinine clearance underestimated the actual AUC in seven of the eight patients, in one case by as much as twofold. The median end of infusion PCZ and total DP plasma concentrations were 1.2 μM (range 0.5–2.2 μM) and 4.4 μM (range 1.3–5.9 μM), respectively, consistent with in vitro resistance modulatory levels. However, free DP was only 0.02 μM (range 0.004–0.04 μM). The median CSA level at 24 h of 1450 μg/l (range 1075–1640 μg/l) is in agreement with concentrations required for partial DR reversal in vitro, although it is much lower than levels achieved in our previous phase I study of CBDCA + CSA alone using similar doses of CSA. The CSA dose on the current trial was escalated beyond the MTD for the previous phase I study, suggesting that there may be an interaction between CSA and one of the other modulators. Conclusion: These results demonstrate that in vitro DR- reversing levels of two of the three agents used in this study can be achieved in vivo, and that this combination of DR modulators has significant effects on the pharmacokinetics of VP-16.

PURPOSE To examine the predictive value of tumor- and treatment-specific prognostic indicators of relapse-free survival (RFS) and overall survival (OS) in patients with high-risk breast cancer (HRBC) treated with high-dose chemotherapy (HDCT) and stem-cell rescue. PATIENTS AND METHODS Between June 1989 and September 1994, 114 patients with HRBC (stage II with > or = 10 axillary lymph nodes involved, stage IIIA, and stage IIIB inflammatory carcinoma) received adjuvant chemotherapy followed by HDCT with etoposide, cyclophosphamide, and either doxorubicin (CAVP) or cisplatin (CCVP). Variables analyzed included stage, tumor size, number of axillary nodes involved, grade and receptor status, and types of adjuvant chemotherapy and radiation therapy and HDCT. RESULTS With a median follow-up time of 46 months (range, 23 to 93), Kaplan-Meier estimates of 3.5-year OS for stage II, IIIA, and IIIB HRBC are 82% (95% confidence interval [CI], 67% to 97%), 79% (95% CI, 67% to 91%), and 72% (95% CI, 53% to 91%); RFS estimates are 71% (95% CI, 56% to 85%), 57% (95% CI, 43% to 72%), and 50% (95% CI, 29% to 71%) irrespective of the HDCT regimen. In univariate analysis, the risk of relapse was lower for patients with progesterone receptor (PR)-positive tumors (risk ratio [RR], 0.43; 95% CI, 0.22 to 0.81; P = .01) and higher for patients with inflammatory carcinoma (RR, 2.20; 95% CI, 1.02 to 4.76; P = .05). OS was better for patients with PR (RR, 0.16; 95% CI, 0.05 to 0.55; P = .003) and estrogen receptor (ER)-positive tumors (RR, 0.42; 95% CI, 0.17 to 1.02; P = .05); OS was worse for patients with high-grade primary tumors (RR, 4.08; 95% CI, 1.21-13.7; P = .02). In multivariate analysis, PR positivity was associated with improved RFS (P = .01) and OS (P = .001). CONCLUSION HDCT in selected patients with HRBC is safe and warrants further evaluation. Patients with receptor-negative, high-grade, or inflammatory tumors require improvement in their therapeutic options. Better assessment of the role of HDCT awaits completion of ongoing randomized trials.

A group of 18 patients with advanced cancer were entered on a phase I study of a 120-h continuous intravenous infusion of hydroxyurea. The dose of hydroxyurea was escalated in cohorts of patients from 1 to 2 to 3.2 g/ m2 per day. The primary dose-limiting toxicity was neutropenia, often accompanied by leukopenia, thrombocytopenia and generalized skin rash. Prophylactic treatment of patients with dexamethasone and diphenhydramine hydrochloride prevented the skin rash, but not the hematopoietic toxicities. The pharmacokinetics of hydroxyurea were studied in all patients. The steady-state concentrations of hydroxyurea were linearly correlated with the dose (R2 = 0.71, n = 18, P0.0001). The mean +/- SE concentrations were 93 +/- 16, 230 +/- 6 and 302 +/- 27 microM at 1, 2 and 3.2 g/m2 per day, respectively. The mean +/- SE renal and nonrenal clearances of hydroxyurea were 2.14 +/- 0.18 and 3.39 +/- 0.28 l/h per m2 (n = 16), neither of which correlated with the dose. The concentration of hydroxyurea in plasma decayed monoexponentially with a mean +/- SE half-life of 3.25 +/- 0.18 h (n = 17). The steady-state concentration of hydroxyurea was200 microM in all nine patients treated at 2 g/m2 per day, a dose which was well tolerated for 5 days. We recommend this dose for phase II trials in combination with other antineoplastic agents.

3108 Background: Preclinical data has demonstrated that B when combined with camptothecins enhances apoptotic effects which may be independent of NF-κB status and dependent on the sequence of exposure to the proteasome inhibitor. Other data suggests PK interactions of B with some chemotherapeutic agents. It is hypothesized that B will act synergistically with T and enhance the apoptotic effects of T. Conflicting data exists regarding schedule dependent synergistic cytotoxicity of the combination. This study examined both sequences of administration and determined the PK of each sequence. Methods: A standard 3 + 3 schedule was used in both sequences (S). The dose of B was fixed with escalating doses of T. S1: B 1.3 mg/m2 on days 1, 4, 8, and 11. T 2 to 3.5 mg/m2 on days 1 and 8 was given 6 h before B. S2: B 1.3 mg/m2 on days 1, 4, 8, 11 followed by T 2 to 3 mg/m2 given 6 h after B. Cycle length was q28 days. PK sampling for both sequences was performed. Results: 54 pts (S1: 27, S2: 27) received a median of 2 cycles (range 1-7) of therapy. Pts were heavily pre-treated. For S1, the maximum tolerated dose (MTD) of B and T were 1.3 and 3 mg/m2 respectively. For S2, the MTD of B and T were 1.3 and 2.5 mg/m2 respectively. Dose-limiting toxicities (2 pt in each sequence) were gr 3 thrombocytopenia in S1, and gr 4 thrombocytopenia in S2. Stable disease was seen in 6/27 pts in S1, and 6/27 in S2. PK results for S2 show no significant difference between the day 1 and day 8 PKs. However, the mean AUC (454±150 mg/Lxhr) and Cmax (123±51 mg/L) at the MTD of 2.5 mg/m2 reached on this trial is similar to those reported with single agent doses of 4 mg/m2 given over 30 minutes weekly x 3. As a result, the estimated topotecan clearance (11.3±5 L/hr) when given following bortezomib is approximately one half of the reported clearance for the single agent. (Curtis et al, J Clin Pharmacol, 50:268, 2010). Conclusions: The tolerability and toxicity of both sequences was similar. MTD differs with S2 having a lower tolerated dose of T. PK results suggest a possible drug-drug interaction with decreased clearance of T with S2. PK results for S1 are pending. Supported by CCSG CA62505.

10009 Background: Treatment (tx) options are limited after GIST pts develop resistance to IM and SU. SOR inhibits KIT, VEGFR, PDGFR-β, and BRAF kinases. In preclinical GIST models, SOR inhibits many secondary resistance mutations, including IM-RES ATP-binding pocket and IM/SU-RES activation loop mutations (Heinrich, Proc ASCO 2009). Methods: We performed a multi-center, phase II trial of SOR in KIT-expressing GIST pts who had disease progression (PD) on IM by RECIST. After FDA approval of SU for GIST, the amended study required PD after both IM and SU. Pts received SOR 400 mg orally twice daily. Primary endpoint: objective response rate. A Simon minimax 2-stage design required 1 response in 18 pts for a 2nd stage, and 4 responses in 32 IM/SU RES pts for further study. Results: 38 pts (6 IM-RES, 32 IM/SU-RES) enrolled 1/06-9/09 at 6 centers. Pt characteristics: male 55%; median age 57 (range 42-85); PS 0/1/2: 47%/47%/5%; liver metastases 74%; primary drug resistance (PD ≤ 6 mo): IM 3%, SU 59%. Baseline mut...