Abstract Background: ATR is a critical regulator of the cellular response to replication stress; it signals DNA damage repair, mediated through homologous recombination. Many cancers depend on ATR to survive DNA damage. M6620 is a potent, selective inhibitor of ATR that augments the anticancer activity of cisplatin in preclinical triple-negative breast cancer (TNBC) models. Given the high prevalence of TP53 mutations in TNBC and limited platinum responsiveness in patients lacking a BRCA1/2 mutation, this study was designed to evaluate the safety and efficacy of M6620 in combination with cisplatin in an expansion cohort of patients with BRCA1/2 wild-type advanced/metastatic TNBC. Methods: Eligible patients had advanced/metastatic ER-, PR-, and HER2- breast cancer with 0-2 prior non–platinum-based therapies and measurable disease per RECIST 1.1. First line patients were eligible if relapse occurred ≥3 months after prior (neo)adjuvant chemotherapy. Of a maximum 50 patients planned for enrollment, ≥30 were required to have BRCA1/2 germline wild-type status and basaloid molecular subtype tumors on central testing. Patients received intravenous cisplatin 75 mg/m2 on day 1 with intravenous M6620 140 mg/m2 on days 2 and 9 of each 21-day cycle. In patients intolerant of cisplatin or at investigator's discretion, cisplatin could be switched to carboplatin AUC 5 with M6620 90 mg/m2. Results: At the time of abstract submission, 35 female patients were enrolled in this study; 18 patients with confirmed BRCA1/2 wild-type and basaloid metastatic TNBC who received ≥1 cycle of study drug and had ≥1 baseline scan and ≥1 on-treatment scan at the time of the data cut were included in the primary efficacy analysis. Median progression-free survival (PFS) was 4.1 months (90% CI, 1.6-6.9 months). PFS was ≥ 6 months in 2 patients and ≥ 3 months in 8 patients. Preliminary unconfirmed objective response [complete response or partial response (PR)] was observed in 38.9% (90% CI, 19.9%-60.8%) of patients. All 7 patients with preliminary objective response had PR as best overall response; the longest duration of response was 183 days. Response was ongoing in 4 patients with PR at the time of data cutoff. Grade ≥3 related treatment-emergent adverse events occurred in 16 of 35 patients: neutropenia (n=8), anemia (n=5), vomiting (n=4), nausea (n=3), and, in 1 patient each, thrombocytopenia, neutrophil count decreased, platelet count decreased, hypokalemia, generalized weakness, rigors, and acute kidney injury. Conclusions: Combination of M6620 and cisplatin shows encouraging antitumor activity and tolerability in patients with advanced/metastatic TNBC. The study is ongoing; updated safety and efficacy results will be presented. Citation Format: Telli ML, Lord S, Dean E, Abramson V, Arkenau H-T, Murias C, Becerra C, Tang R, Penney MS, Pollard J, Conboy G, Fields SZ, Shapiro G, Tolaney SM. ATR inhibitor M6620 (formerly VX-970) with cisplatin in metastatic triple-negative breast cancer: Preliminary results from a phase 1 dose expansion cohort (NCT02157792) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-07.

Background: ATR is a regulator of the cellular response to replication stress and signals DNA damage repair through homologous recombination. Many cancers depend on ATR to survive DNA damage. VX-970 is a potent, selective inhibitor of ATR with preclinical anticancer activity in combination with DNA-damaging chemotherapy in TNBC models. Given the prevalence of DNA damage repair defects in TNBC, this study evaluated the safety and efficacy of VX-970 in combination with Cis in an expansion cohort of pts with BRCA1/2 wild-type mTNBC. Methods: Eligible pts had advanced ER-, PR-, and HER2- BC with 0-2 prior non–platinum-based therapies. First line pts were eligible if relapse occurred ≥ 3 months after prior (neo)adjuvant chemotherapy. Measurable disease per RECIST 1.1 was required. Of a maximum 50 pts planned for enrollment, ≥30 were required to be BRCA1/2 germline wild-type and to have basaloid molecular subtype tumors on central testing. Pts received intravenous Cis 75 mg/m2 on day 1 with VX-970 140 mg/m2 on days 2 and 9 of each 21-day cycle. In pts intolerant to Cis or at investigator's discretion, treatment could be switched to carboplatin AUC 5 with VX-970 90 mg/m2. Results: At the time of this analysis, 35 female pts with mTNBC who received ≥1 cycle of study drug were included in the safety set (median age, 48 y [range 35-74 y]). Grade ≥3 related TEAEs occurred in 16/35 pts: neutropenia (n = 8), anemia (n = 5), vomiting (n = 4), nausea (n = 3), and 1 pt each with thrombocytopenia, neutrophil count decreased, platelet count decreased, hypokalemia, generalized weakness, rigors, and acute kidney injury. Of these 35 pts, 18 were BRCA1/2 wild-type and had basaloid TNBC with at least 1 baseline scan and 1 on-treatment scan at the time of the data cut. Preliminary objective response rate was 38.9% (n = 7 [all partial response]), and disease control rate (CR+PR+SD) was 72.2% (n = 13). Conclusions: Combination VX-970 and Cis shows encouraging antitumor activity and tolerability in mTNBC. The study is ongoing; updated safety and efficacy results will be presented. Clinical trial identification: NCT02157792 Legal entity responsible for the study: Vertex Pharmaceuticals Incorporated Funding: Vertex Pharmaceuticals Incorporated Disclosure: M.L. Telli: Advisory role for AstraZeneca, PharmaMar, Tesaro, and Vertex, and contracted research with Calithera, Genentech, Medivation, Novartis, OncoSec, Pfizer, PharmaMar, Tesaro, and Vertex. E. Dean: Employee of AstraZeneca. Research funding from Vertex. S.M. Tolaney: Research funding from Genentech, Merck, Pfizer, Novartis, Lilly, Exelixis, Nektar, and AstraZeneca. R. Tang, M.S. Penney, G. Conboy, S.Z. Fields: Employee of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. J. Pollard: Employee of Vertex Pharmaceuticals Limited and may own stock or stock options in that company. G. Shapiro: Research funding from Vertex and Pfizer. Advisory role for Vertex, G1 Therapeutics, Lilly, Millenium/Takeda, Tesaro, Chugai, and EMD Serono. All other authors have declared no conflicts of interest.

Abstract Background: The efficacy of chemotherapeutic agents such as doxorubicin, which cause lethal DNA double-strand breaks (DSBs), is diminished by efficient repair of the damaged DNA in cancer cells. DNA-PK is a key regulator of the non-homologous end joining (NHEJ) pathway, which is responsible for repairing DSBs. Studies of nonselective inhibitors of DNA-PK have shown that cancer cells depend on DNA-PK for survival following treatment with DSB-inducing agents. However, a comprehensive characterization of DNA-PK inhibition has been hampered by a lack of selective inhibitors. Here we describe VX-984, a potent and selective inhibitor of DNA-PK, and its preclinical profile in combination with doxorubicin both in vitro and in vivo. Methods: VX-984 was examined as a single agent and in combination with doxorubicin or pegylated liposomal doxorubicin (PLD) in a panel of breast cancer cell lines and in mouse xenograft models, respectively. Results: In vitro, inhibition of DNA-PK by VX-984 enhanced the cytotoxic activity of doxorubicin in established breast cancer cell lines and in primary ovarian tumor explants. Notably, mean Bliss DE >10% (strong synergy) were observed for doxorubicin in the presence of VX-984 in 22 of 35 breast cancer cell lines and 21 of 44 ovarian cancer cell lines in a broad cancer cell line screen. Further, the efficacy observed with VX-984 was associated with increased DNA damage as measured by phosphorylated histone H2AX (gamma-H2AX) and phosphorylated Kruppel-associated protein (pKAP1) in DU4475, MDA-MB-436 and MDA-MB-468 breast cancer cell lines, which is consistent with diminished DSB repair. In vivo, VX-984 significantly enhanced the efficacy of PLD in ovarian cancer patient-derived xenograft models and in cell line xenograft models. Conclusions: These data provide evidence that inhibition of DNA-PK by VX-984 enhances the efficacy of doxorubicin in preclinical models and support the use of VX-984 in combination with DSB agents such as anthracyclines including PLD for the treatment of breast and ovarian cancers. VX-984 is currently in a Phase 1 clinical trial in combination with PLD. Sponsored by Vertex Pharmaceuticals Incorporated. Citation Format: Boucher D, Newsome D, Takemoto D, Hillier S, Wang Y, Arimoto R, Maxwell J, Charifson P, Fields SZ, Tanner K, Penney MS. Preclinical characterization of VX-984, a selective DNA-dependent protein kinase (DNA-PK) inhibitor in combination with doxorubicin in breast and ovarian cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-06-05.

The efficacy of chemotherapeutic agents such as doxorubicin and etoposide, which cause lethal DNA double-strand breaks (DSBs), is compromised by efficient repair of the damaged DNA in cancer cells. The DNA-PK is a critical regulator of the non-homologous end joining (NHEJ) repair pathway, which is responsible for repairing DSBs. Studies of nonselective inhibitors of DNA-PK have shown that cancer cells depend on DNA-PK for survival following treatment with DSB-inducing agents. However, a comprehensive characterization of DNA-PK inhibition has been hampered by a lack of selective inhibitors. Here we describe VX-984, a potent and selective inhibitor of DNA-PK, and its preclinical profile in combination with DSB-inducing chemotherapeutic agents. VX-984 was examined as a single agent and in combination with either doxorubicin or etoposide in a panel of cancer cell lines and primary tumor explants and in mouse xenograft models. In vitro, inhibition of DNA-PK by VX-984 had potent cytotoxic activity in combination with doxorubicin and etoposide in established cancer cell lines and in primary tumor explants from ovarian and endometrial cancers (doxorubicin) and small cell lung cancer (etoposide). Bliss synergy scores of ≤23% (strong synergy) were observed for doxorubicin and etoposide in the presence of VX-984. Further, the activity observed with VX-984 was associated with enhanced DNA damage as measured by phosphorylated Kruppel-associated protein (pKAP1) and phosphorylated histone H2AX (gamma-H2AX), consistent with failed DSB repair. In vivo, VX-984 significantly enhanced the efficacy of pegylated liposomal doxorubicin (PLD) in an ovarian cancer patient-derived xenograft model as well as in cancer cell line xenograft models. These data provide evidence that inhibition of DNA-PK by VX-984 enhances the efficacy of DSB-inducing agents in preclinical models and support the use of VX-984 in combination with agents such as PLD for the treatment of ovarian and endometrial cancers. VX-984 is currently in a Phase 1 clinical trial in combination with PLD.

Abstract Background: Inherited alterations in BRCA1/2 genes increase genomic instability and cancer susceptibility. DNA sequencing detects BRCA1/2 mutations, but has the following limitations; 1) mutations may have unknown functional significance, 2) epigenetic alterations and mutations in other Homologous Recombination (HR) pathway components are not detected, and 3) the combined effects of pathway mutations are not understood. Thus a functional assessment of HR competence at the single cell level remains an unmet need as BRCA1/2 sequencing does not holistically inform on functionality of the HR pathway. Single Cell Network Profiling (SCNP) is a multiparametric flow cytometry-based assay that simultaneously measures, at the single cell level, extracellular surface markers and functional changes in intracellular signaling in response to extracellular modulators (Kornblau et al. Clin Cancer Res 2010). In this study, we tested the ability of SCNP to detect and quantify functional changes in HR signaling using peripheral blood mononuclear cell (PBMC) samples from BRCA1 mutation carriers (MUT) and wild type (WT) subjects. Methods: HR pathway activity was examined in PBMCs from BRCA1 MUT (n = 21) or WT (n = 20) subjects. Cell lines carrying BRCA1 MUTor WT genes were used as controls. PBMCs were stimulated with anti-CD3 and anti-CD28 for 24 hours to induce T cell proliferation then treated with PARP inhibitor (PARPi) AZD2281 +/− Temozolomide (TMZ) for 48h or 72h to induce DNA damage. DNA damage response (DDR) readouts were measured in both CyclinA2- and CyclinA2+ T cell subsets. Measurements included induced levels of p21, p53 and phosphorylation (p−) of p-H2AX, p-DNA-PKcs, p-RPA2/32, and p-BRCA1. Results: As expected based on the mechanism of action of PARPi, higher levels of induced p-H2AX and p53 were observed in CyclinA2+ cells of BRCA1 MUT versus WT cell line controls. In PBMCs, T cell proliferation (%CyclinA2+) was positively associated with PARPi induced DDR readouts. After controlling for proliferation, statistically significant differences in PARPi induced DDR signaling were observed between BRCA1 MUT and WT samples in many simultaneously assessed readouts including p-H2AX, p53 and p21 (increased in MUT), particularly in CyclinA2+ cells. Additionally, BRCA1 MUT samples displayed lower basal p-BRCA1 but higher induced p-BRCA1 levels compared to BRCA1 WT samples. Conclusions: SCNP was able to detect and quantify functional differences between PBMC samples from BRCA1 MUT (haploinsufficient) and WT donors by quantitatively assessing DDR signaling in CyclinA2+ T cells. Once verified on a larger data set, the assay could form the basis for the development of screening tests to identify subjects at higher risk of developing cancer or stratification tests to inform on cancer patient selection for treatment with PARP inhibitors. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-31.

2546 Background: Camptothecin analogs possess a labile lactone ring, which readily undergoes a pH dependent, albeit reversible, hydrolysis in plasma to yield a carboxylate moiety. The latter is considered inactive due to its electronegative charge that impedes transport into cells. Furthermore, the carboxylate is cleared rapidly and causes toxicity in eliminating organs due to lactonation. AR-67 is a highly lipophilic 3 rd generation analog with superior stability of its lactone form in preclinical models. This report describes the PK of AR-67 in patients with refractory solid tumors enrolled in a phase I study. Methods: AR-67 was infused over 1 hr for 5 days every 21-days. PK was performed on the 1 st and 4 th day of cycle 1. Blood, plasma, and urine were collected (0–24 hrs) from 26 patients (see 09-AB-30336-ASCOAM) treated at 9 dose levels: 1.2–12.4 (mg/m 2 /day). AR-67 carboxylate and lactone were assayed with a validated chromatography method. Results: AR-67 was detectable at all dose levels. Blood concentrations mirrored those in plasma and were superimposable when adjusted by the hematocrit. AR-67 concentration peaked at the end of the 1-hr infusion and declined biexponentially with a terminal t 1/2 of 1.4 hr (plasma lactone). A linear relationship was observed between dose and AUC. The lactone clearance on Day 1 was 16.6 (±5.5) vs. 19.6 (±6.3) L/hr/m 2 on Day 5. The carboxylate clearance was ∼ 6-fold higher. Lactone was the major form in all samples and its area under the time vs. concentration curve (AUC) was 85.5% (range 74.0%-94.1%) of the total AUC. Urine (0–24 hr) contained 2.5% (0.3%-6.7%) of the dose on Day 1 vs. 2.7% (0.9–11.1%) on Day 4. Extensive metabolite peaks were not observed in plasma, blood, or urine samples. Plasma protein binding of the carboxylate was 90% (range 80%-96%) vs. 95% (range 90%-98%) for the lactone. Conclusions: AR-67 is a lipophilic camptothecin with a unique PK profile. Unlike other clinically approved analogs with lower lactone stability (35%-65%), over 85% of the AR-67 AUC is in the active lactone form. This high lactone-low carboxylate exposure coupled with the apparently limited metabolism of AR-67 may result in increased activity and decreased toxicity. [Table: see text]

2534 Background: AR-67 is a 3rd generation camptothecin analog selected for development based on the high in vitro stability of its pharmacologically active lactone form and high potency in preclinical models. This report describes the initial phase I study of intravenous AR-67 in adults with refractory solid tumors. Methods: AR-67 was infused over 1 hour for 5 days of a 21-day cycle using an accelerated titration phase I trial design. PK was performed on the 1st and 4th day of cycle 1. AR-67 was assayed with a validated chromatography method. Toxicity and response were assessed using NCI CTC (v3) grading scale and RECIST. Results: In total, 26 patients were treated at 9 dose levels (mg/m2/day): 1.2 (n=2), 1.67 (n=3), 2.34 (n=3), 3.2 (n=3); 4.5 (n=1), 6.3 (n=1), 7.5 (n=7), 8.9 (n=4) and 12.4 (n=2). Median age 62 (range 31–79), 15M/11F, median prior therapies 3 (range 1 to 6). Tumor types included: colorectal (8), non-small cell lung (NSCLC) (4), small cell lung (3), soft tissue sarcoma, (3), head and neck (2), prostate (2), and other (4). 21 subjects completed 2 or more cycles of therapy, 5 subjects received 1 cycle of therapy and had rapid disease progression (1 received 2d of drug prior to PD), 1 subject is still under treatment after 9 cycles. DLTs were observed in 5 patients: 2 of 2 at 12.4 mg/m2/day (Gr 4 febrile neutropenia, Gr 3 fatigue); 2 of 4 at 8.9 mg/m2/day (Gr 4 thrombocytopenia), 1 of 7 at 7.5 mg/m2/day (Gr 4 thrombocytopenia). Common C1 worst-grade drug related toxicities (CTC I/II % vs III/IV %): Hg (27/8), WBC (11/19), ANC (19/8), platelets (19/12), fatigue (15/8) insomnia (8/0), flushing (15//0), constipation (8/0), nausea (23/0), ALT elevation (12/0), hiccups (8/0). Antitumor activity, assessed by development of PR and SD, was observed in NSCLC, SCLC, colon and bladder cancer. The lactone form was predominant in plasma (>85% of AUC) at all time points. Clearance was constant with increasing dose and exposure (AUC) correlated with toxicity. Conclusions: AR-67 has superior lactone stability compared to approved analogs, has a predictable toxicity profile that did not include diarrhea and has activity in NSCLC. The RP2D is 7.5 mg/m2/day for 5 days of a 21-day cycle. This work was supported by R21-CA-123867 and Arno Therapeutics. [Table: see text]

7546 Background: Eribulin is a structurally-simplified, fully synthetic analog of the marine sponge natural product halichondrin B. Eribulin inhibits microtubule dynamics via a mechanistically novel mode of action. Methods: An open-label, single-arm, Phase II study of eribulin was conducted in patients with advanced NSCLC (ECOG of 0 or 1) who were treated with platinum-based doublet chemotherapy and stratified by prior taxane exposure. A total of 103 patients (83 with prior taxanes and 20 taxane naïve) were treated with eribulin (1.4 mg/m2), administered as a bolus infusion over 2 –5 minutes on Days 1, 8, and 15 of a 28-day cycle (N=77). Due to delays or skipped doses secondary to myelosuppression at Day 15 with recovery by Day 21, the protocol was amended to a schedule of Days 1 and 8 of a 21-day cycle (N=26). The primary efficacy endpoint was objective response rate. Independent radiologic review was used to confirm responses. Results: Of 106 enrolled patients, 103 received eribulin. Median age was 65 years and median number of prior therapies was 2, including taxanes (81%), gemcitabine (40%), pemetrexed (23%), and EGFR inhibitors (34%). Median number of cycles administered was 3 (range 1–15). Drug related toxicities included neutropenia grade 3 (23%) and 4 (26%), febrile neutropenia (4%), grade 3 fatigue (11%), grade 3 nausea (2%), and peripheral neuropathy grade 1/2 (37%) and 3 (2%). Based on RECIST criteria, the overall response rate (all partial responses) was 9.7% (95% CI: 4.0–15.4 %), with 10.8% PR in taxane pre-treated, and 5% PR in taxane naïve patients. Overall disease control rate (PR + SD) was 55.3%. 12-week progression free survival (PFS) rate was 53.0% (95% CI: 42.6–63.3%) and median PFS was 102 days (range 1–408+). Median duration of response was 176 days (range 50–291+), and median overall survival was 287 days (range 16–423+). The one year survival rate was 46.4% (95% CI: 34.9–58.0%). Conclusions: In this group of NSCLC patients who were treated with a median of two prior therapies, consisting in the majority of cases of two cytotoxic regimens, eribulin demonstrated an overall PR rate of 9.7% (10.8% in the taxane pre-treated) and 9.6 months median survival. No significant financial relationships to disclose.

1034 Background: Eribulin is a structurally simplified analog of halichondrin B, which inhibits microtubule dynamics via a novel mechanism characterized by suppression of microtubule growth, lack of effect on microtubule depolymerization, and sequestration of tubulin into nonfunctional aggregates. This study was designed to assess the activity and tolerance of eribulin in chemotherapy refractory patients with advanced breast cancer. Methods: Eribulin was evaluated in a single-arm Phase II trial in female patients with refractory breast cancer, ECOG performance status of 0–1, measurable disease, and neuropathy ≤ Grade 2. Patients received ≥ 1 prior chemotherapy regimen, including an anthracycline and a taxane. Eribulin was administered as a 2–5 min IV bolus of 1.4 mg/m2 on Days 1, 8, and 15 of a 28-Day cycle (Group 1). The schedule was modified to Days 1 and 8 of a 21-Day cycle (Group 2), because of dose delays. The primary efficacy endpoint was ORR according to RECIST criteria based upon independent review (IR) of tumor assessment. Results: Of 104 patients enrolled, 103 received eribulin treatment: 70 in Group 1, 33 in Group 2. Median age was 55 yrs (range 32–84). Patients had received a median of 4 prior chemotherapy regimens (range 1–11). Sixty-one percent of tumors were ER+, 14% Her2/neu 3+, and 29% were triple (ER, PR, Her-2) negative. The incidence of dose interruption, delay, or omission during Cycle 1 was 63% (Group 1) and 18% (Group 2). The most common drug related toxicities were neutropenia (75%, Grades 3: 31%, Grade 4: 30%, febrile neutropenia: 3.9%), fatigue (52%, Grade 3: 2.9%, no Grade 4), alopecia (Grade 1/2: 41%), nausea (37%, Grade 3: 1%, no Grade 4), and anemia (36%, Grade 3: 1%, no Grade 4). Peripheral neuropathy occurred in 34% of patients (Grade 3: 3.9%, no Grade 4). Best overall response rate (all PR) by IR was 14.5% and 15.2% in Groups 1 and 2, respectively; the combined ORR was 14.7% (95 % CI: 9–23%). Median PFS was 85 days, and the 6 mo PFS rate was 31%. Conclusions: Eribulin given as a 2–5 min IV infusion on Days 1, 8 of a 21-Day cycle or Days 1, 8, 15 of a 28-Day cycle exhibited a 15% PR rate by IR and a low incidence of Grade 3 neuropathy in this heavily chemotherapy pretreated population. The most common toxicity was neutropenia. The 21-Day schedule had an acceptable toxicity profile. No significant financial relationships to disclose.

653 Background: E7389 is a synthetic analog of halichondrin B, with a broad anti- proliferative activity against tumor cells. Methods: E7389 was evaluated in an open-label, single-arm Phase II trial as monotherapy for patients with refractory breast cancer (≥2 prior chemotherapy regimens, which must have included an anthracycline and a taxane). E7389 was administered as an IV bolus of 1.4 mg/m 2 on Days 1, 8, and 15 of a 28-day cycle (group 1), or on Days 1 and 8 of a 21-day cycle (group 2). The primary efficacy endpoint was ORR. Results: As of 9 December 2005, 88 patients had received treatment, 68 in group 1 and 20 in group 2. Median age was 55 yrs (range 36–84) and ECOG performance status 0–1. Sixty-six percent of the tumors were ductal carcinomas, 6% lobular, and 27% were unclassified. Sixty percent of the tumors were ER+, 47% PR+, and 17% Her2/neu 3+. The patients had received at least two previous regimens, with a median number of 5 (range 2–14). Forty-eight percent of the patients had also used hormonal therapy. Forty-nine patients in group 1 and 12 patients in group 2 had completed their 2 nd cycle of treatment, and twenty-one in group1 and 1 in group 2 their 4 th cycle. Safety: The major toxicity related to study drug was neutropenia. Among 73 patients with preliminary safety data available, two patients had Grade 3 febrile neutropenia, and 31 had Grade 3 or 4 neutropenia or leukopenia. The other Grade 3 toxicities encountered in more than two patients were dehydration (4 patients) and dyspnea (4 patients). Grade 3 peripheral neuropathy was reported in 2 patients. Efficacy: At the end of cycle four there were 10 (15.2%) confirmed partial responses (PRs) out of 66 evaluable patients in group 1, and 1 confirmed PR (5.6%) out of 18 evaluable patients in group 2. The median duration of confirmed responses was 113 days. Conclusions: Based on the safety and efficacy in this refractory breast cancer population, E7389 appears to be a therapy worthy of continued investigation in patients with heavily pretreated breast cancer. In order to comply with the current demand for individualized cancer care, bio-markers which would predict the sensitivity to E7389 are being searched in the tumor samples of the patients in the current and forthcoming studies. [Table: see text]

Purpose: We conducted a single-center, dose-escalation study evaluating the safety, pharmacokinetics, and efficacy of epratuzumab, an anti-CD22 humanized monoclonal antibody, in patients with aggressive non-Hodgkin's lymphoma.Experimental Design: Epratuzumab was administered once weekly for 4 weeks at 120-1000-mg/m(2) doses to 56 patients [most (it = 35) with diffuse large B-cell lymphoma].Results: Patients were heavily pretreated (median, 4 prior therapies), 25% received prior high-dose chemotherapy with stem cell transplant, and 84% had bulky disease (greater than or equal to5 cm). Epratuzumab was well tolerated, with no dose-limiting toxicity. Most (95%) infusions were completed within 1 h. The mean serum half-life was 23.9 days. Across all dose levels and histologies, objective responses (ORs) were observed in five patients (10%; 95% confidence interval, 3-21 %), including three complete responses. In patients with diffuse large B-cell lymphoma, 15% had ORs. Overall, 11 (20%) patients experienced some tumor mass reduction. Median duration of OR was 26.3 weeks, and median time to progression for responders was 35 weeks. Two responses are ongoing at greater than or equal to34 months, including one rituximab-refractory patient.Conclusions: These data demonstrate that epratuzumab has a good safety profile and exerts antitumor activity in aggressive non-Hodgkin"s lymphoma at doses of greater than or equal to240 mg/m(2), thus warranting further evaluation in this clinical setting.

A multicentre, randomised study was carried out in Europe, South Africa and North America to compare the activity and tolerability of oral versus intravenous (i.v.) topotecan in patients with relapsed epithelial ovarian cancer. Patients who had failed first-line therapy after one platinum-based regimen, which could have included a taxane, were randomised to treatment with either oral (p.o.) topotecan, 2.3 mg/m(2)/day or i.v. topotecan 1.5 mg/m(2)/day for 5 days every 21 days. Patients were stratified by prior paclitaxel exposure, interval from previous platinum therapy and tumour diameter. 266 patients were randomised. Response rates were 13% orally (p.o.) and 20% (i.v.) with a complete response in 2 and 4 patients, respectively. The difference in the response rates was not statistically significant. Median survival was 51 weeks (p.o.) and 58 weeks (i.v.) with a risk ratio of death (p.o. to i.v. treatment) of 1.361 (95% confidence interval (CI): 1.001, 1.850). Median time to progression was 13 weeks (p.o.) and 17 weeks (i.v.). The principal toxicity was myelosuppression although grade 3/4 neutropenia occurred less frequently in those receiving oral topotecan. Toxicity was non-cumulative and infectious complications were relatively infrequent. Non-haematological toxicity was generally mild or moderate. The incidence of grade 3/4 gastrointestinal events was slightly higher for oral than i.v. topotecan. Oral topotecan shows activity in second-line ovarian cancer and neutropenia may be less frequent than with the i.v. formulation. A small, but statistically significant, difference in survival favoured the i.v. formulation, but the clinical significance of this needs to be interpreted in the context of second-line palliative treatment. Oral topotecan is convenient and well tolerated and further studies to clarify its role are ongoing.

Topotecan is a topoisomerase I inhibitor and an analogue of camptothecin with demonstrated activity in small-cell lung cancer. However, less is known about the potential role of topotecan in advanced non-small-cell lung cancer (NSCLC). Platinum-based combination therapy is currently recommended in NSCLC patients presenting with good performance status. Because topotecan demonstrates a novel mechanism of action, its investigation in platinum combinations is warranted. In phase I/II trials of topotecan given as part of a cisplatin-based regimen, significant antitumor activity has been observed, providing the rationale for conducting further studies aimed at assessing survival benefit. However, this combination exhibits sequence dependence, with increasing hematologic toxicity observed when cisplatin is administered on day 1 of a 5-day topotecan course. Cisplatin has been associated with dose-limiting nonhematologic toxicities. Carboplatin exhibits a different toxicity profile compared with cisplatin, which makes it an attractive agent to study in combination. A hypothesis can be made that carboplatin in combination with newer agents such as topotecan might compare favorably with classic cisplatin-based regimens, particularly with respect to efficacy:toxicity ratio. Therefore, a phase II study was initiated to determine the efficacy, toxicity, and safety of carboplatin-topotecan combination in advanced NSCLC. Preliminary results reported here show that topotecan with carboplatin is generally well tolerated with manageable hematologic toxicity. Indirect comparison with cisplatin-topotecan combination suggests a lower incidence of dose-limiting nonhematologic toxicity. Whether or not the carboplatin-topotecan regimen is able to offer tumor response and survival benefit comparable to those observed with cisplatin-based combinations remains to be established.

PURPOSE: A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non–cross-resistance between these two compounds. PATIENTS AND METHODS: Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m2/d) × 5 every 21 days (n = 112) or paclitaxel (175 mg/m2 over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy. RESULTS: Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P = .638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression; grade 4 neutropenia was more frequent with topotecan (81.4% of patients) than with paclitaxel (22.9% of patients). CONCLUSION: Topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non–cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.

PURPOSE:To evaluate oral topotecan as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen. PATIENTS AND METHODS:Patients (N = 116) received oral topotecan 2.3 mg/m2 daily for 5 days every 21 days. Eligibility criteria included histologic diagnosis of International Federation of Gynecology and Obstetrics stage III or IV epithelial ovarian cancer, bidimensionally measurable disease, prior platinum-containing chemotherapy, age > or = 18 years, performance status < or = 2, and life expectancy > or = 12 weeks. RESULTS:Overall response rate was 21.6% (25 of 116 patients). Median duration of response was 25.0 weeks; median time to response was 8.4 weeks. Median time to progression was 14.1 weeks; median survival was 62.2 weeks. Grade 4 neutropenia was experienced by 50.4% of patients in 13.4% of courses administered. Grade 4 thrombocytopenia was experienced by 22.1% of patients in 5.1% of courses. Grade 3 or 4 anemia was experienced by 29.2% of patients in 8.5% of courses. Most frequent nonhematologic toxicities were predominantly (> 90%) grade 1 or 2 and included nausea, alopecia, diarrhea, and vomiting. CONCLUSION:Second-line oral topotecan administered at 2.3 mg/m2 for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan. Oral topotecan is an active, tolerable, and convenient formulation of an established agent for the second-line treatment of advanced epithelial ovarian cancer and may also facilitate exploring prolonged treatment schedules.