Carboplatin In Patients Research Articles

A pharmacokinetic and dose-escalating study of paclitaxel injection concentrate for nano-dispersion (PICN) alone and with carboplatin in patients with advanced solid tumors.

2557 Background: PICN is a novel Cremaphor-free composite of paclitaxel nano-particles stabilized with polymer and lipid using Nanotecton Technology. The MTD of PICN alone was previously determined to be 295 mg/m2 iv every 3 weeks in a South Asian population. This study aimed to determine the pharmacokinetic (PK) profile of PICN alone and with carboplatin (C), and the MTD of PICN plus C. Methods: Patients (pt) with advanced solid malignancies and ECOG PS 0-1 were eligible. Part A was a PK study designed to examine cohorts of 3 pts, receiving PICN over 30 min at dose levels of 175, 260, and 295 mg/m2 every 3 weeks; PK were performed at pre-determined time-points. Part B used a ‘3+3’ dose escalation scheme, designed to determine the MTD of PICN (220, 260, and 295 mg/m2) when combined with C at AUC 6. Only standard anti-emetic pre-medications were used. Adverse events (AEs) were graded using CTCAE 4.0 and tumor response by RECIST 1.1. Results: A total of 18 evaluable pts (9 in Part A, 9 in Part B) were enrolled from 2 US academic centers. No infusion reactions were observed with PICN. No dose limiting toxicity (DLT) was observed in Part A. In Part B, the DLTs were G3 febrile neutropenia and G4 thrombocytopenia requiring platelet transfusion at PICN 260/C AUC 6. A total of 6 pts were treated at PICN 220/C AUC 6 with no DLT. G3 or worse AEs for all cycles were as follow: Part A, bilateral lower extremity weakness, neuropathy, anorexia and neutropenia; Part B, anemia, thrombocytopenia, neutropenia and empyema. Partial responses were observed in biliary(Part A; PICN 260 mg/m2), breast (Part B 220/6) and anal cancers (Part B 260/6). PK analysis showed dose-proportional increase in total plasma paclitaxel level. Conclusions: PICN alone was tolerable in the dose range evaluated. When administered with C AUC 6, the MTD of PICN was 220 mg/m2 administered every 3 weeks. Anti-cancer activity was observed in biliary, breast, and anal cancers. Final PK, toxicity and efficacy data of PICN alone and with C will be presented at the conference. Clinical trial information: NCT01304303.

Two cycles of carboplatin as adjuvant therapy in stage I seminoma: 8-year experience by the Hellenic Co-operative Oncology Group (HECOG).

4558 Background: Adjuvant chemotherapy is used in stage I testicular seminoma. We have reported a risk-adapted strategy of 2 cycles of cisplatin/etoposide (EP) in 64 patients with age < 34 and/or tumor diameter > 4cm) (Bamias et al, Urology 2007), resulting in no relapses over a median follow up of 5 years. Following the establishment of adjuvant carboplatin as a standard, we adopted this treatment for all patients with stage I seminoma. We report our 8-year experience and compare these results with our previous EP strategy. Methods: Patients with stage I seminoma, treated with 2 cycles of carboplatin AUC 6 and a minimum follow up of 1 year after chemotherapy were selected. All patients consented for the use of their medical information and the analysis was approved by the centers involved. Survival functions were presented using Kaplan-Meier curves. The log-rank test was used to test for survival differences across different categories. Results: 137 patients (Median age: 34; Age<34: 49%, tumor diameter>4cm: 42%; rete testis invasion: 24%), treated between 11/2003-12/2011 were selected. During a median follow up of 4 years, there were 5 relapses (5-y relapse rate [RR]: 97% [SE: 2%]): retroperitoneal lymph nodes (n=4) and isolated brain (n=1). All patients with relapse had tumor diameter > 4cm and/or age < 34. No relapse was associated with rete testis invasion. Patients with at least 1 of the above risk factors (n=94) had a significantly higher relapse rate compared with a similar population (n=64) treated with 2 cycles of adjuvant EP: 5-y RR was 95% (SE: 2%) vs.100% (SE 0%), (p=0.033). All relapsed patients were treated with BEP chemotherapy and are currently alive with no evidence of relapse. Neutropenia and nausea/vomiting were less frequent with carboplatin than with EP (11% vs. 36% and 15% vs. 65%). Conclusions: Our analysis confirms the association of age and tumor diameter with relapse in stage I seminoma treated with adjuvant carboplatin. Although adjuvant carboplatin in patients with age<34 and/or tumor diameter> 4 cm is associated with higher RR than EP, the prognosis of these patients is excellent with salvage chemotherapy and, therefore, the use of less toxic treatment is justified.

Efficacy of the combination of ABT-888 (veliparib) and carboplatin in patients with BRCA-associated breast cancer.

1024 Background: The combination of platinum agents and PARP inhibitors may benefit patients (pts) with BRCA-associated metastatic breast cancer (MBC). We report on the response and clinical benefit rates when combining the PARP inhibitor veliparib (V) and carboplatin (carb) in a phase I trial. Methods: BRCA carriers with MBC were eligible. Carb starting at an AUC of 6 was given IV in 21-day cycles (C) and V was given orally twice daily (BID) at dose levels (L) L1 through L5. Results: Twenty-eight pts (26 eligible) carrying BRCA1 (12) or BRCA2 (15), or both (1) mutations were accrued between June 2010 and June 2012. The median age (32-66) was 45 years. The number (#) of prior chemotherapy regimens given for MBC was 1 (0-5); 70% of BCs were ER+, and 7% were HER2+. The schema, dose limiting toxicities (DLT) during C 1, median # of Cs on trial, and maximum tolerated dose (MTD) are shown. There were 3 (12%) complete and 9 (35%) partial responses (PR). Unconfirmed PR or stable MBC (median duration: 8 months [6-10+]) were seen in 7 pts (27%); the clinical benefit rate was74%. The median progression-free survival (PFS) is 7.8 months (95% CI 7.3-9.5). The pt with Fallopian tube cancer had a CR. DLTs with C 1 were seen in 2/6 evaluable pts at L1 (1 pt w/grade 3 hyponatremia and dehydration, and 1pt w/grade 4 thrombocytopenia [PLT]), leading to de-escalation of carb. At L2, 1 pt had grade 4 PLT. At L5, 1 pt had grade 4 PLT, and 2 pts grade 3 PLT (1 pt also experienced grade 4 granulocytopenia [ANC]), defining the MTD at carb AUC 5 and V 150 mg BID (L4). Dose delays and/or dose adjustments due to grade ≥ 2 toxicities for ANC or PLT were seen during the first 3 Cs at L1 (100%), L2 (50 %), L3 (67%), L4 (83 %), and at L5 (67%). Conclusions: The combination of carb and V is active, and is associated with substantial clinical benefit rate and managable hematologic toxicities in BRCA carriers with MBC. Further definition of the role of V is warranted. [Table: see text]

Chemoradiation With Paclitaxel and Carboplatin in High-Risk Cervical Cancer Patients After Radical Hysterectomy: A Korean Gynecologic Oncology Group Study

To evaluate the efficacy and toxicity of concurrent chemoradiation with paclitaxel and carboplatin in patients with high-risk cervical cancer. Patients after radical hysterectomy for cervical cancer, with at least 1 high-risk characteristic, were administered paclitaxel 135 mg/m(2), carboplatin area under the curve = 5 every 3 weeks for 3 cycles concomitant with radiation therapy as adjuvant treatment. This prospective study enrolled 71 consecutive patients. Sixty-six patients (93%) completed the planned treatment. The majority of grade 3/4 neutropenia or nonhematologic toxicities were usually self-limited. Diarrhea grades 3/4 were observed in 4 patients (5.6%). One patient developed anaphylactic shock after infusion of paclitaxel. With a median follow-up of 57 months, recurrences occurred in 16 patients. Multivariable analysis indicated that common iliac lymph node involvement is an independent risk factor for disease recurrence (odds ratio 13.48; 95% confidence interval 2.93-62.03). In the intent-to-treat population (n=71), the estimated 5-year disease-free survival and overall survival rates were 77.3% and 80.3% respectively. In the per-protocol population (n=62), disease-free survival was 78.9% and overall survival was 83.9%. Concurrent chemoradiation with paclitaxel/carboplatin is well tolerated and seems to be effective for patients who undergo radical hysterectomy. Therefore, a prospective, randomized controlled study should be designed to evaluate efficacy of this approach for patients with high-risk cervical cancer.

Phase I dose-escalating study of TAS-106 in combination with carboplatin in patients with solid tumors

Summary Background TAS-106 was designed to inhibit RNA synthesis by blocking RNA polymerases I, II, and III. Methods This was a single-center, open-label, phase I study to identify the maximum tolerated dose (MTD), pharmacokinetics, and biologic effects of the combination of TAS-106 and carboplatin, following a standard 3 + 3 design. This phase I trial was comprised of a regimen of a 60-min IV infusion of carboplatin on day 1 of each 21-day cycle followed by a 24-h infusion of TAS-106, also on day 1 of each cycle. Results 39 patients were treated (21 male, 18 female, median age 62 years, range 21–80 years). Median number of prior therapies was 4. Maximum Tolerated Dose (MTD) was 3 mg/m2 TAS-106 with AU 4 carboplatin. Dose-limiting toxicities were neutropenia and thrombocytopenia, with and without growth factor support. While no patients achieved a complete or partial response, four patients had stable disease lasting ≥4 months, including one patient each with ovarian, non-small cell lung, basal cell and colorectal cancer. Conclusions In summary, the combination of TAS-106 and carboplatin was well-tolerated, and further studies in non-small cell lung and ovarian cancer are warranted to assess the efficacy of this drug combination.

Randomized Phase II Study of Ixabepilone or Paclitaxel Plus Carboplatin in Patients With Non–Small-Cell Lung Cancer Prospectively Stratified by Beta-3 Tubulin Status

Retrospective studies have reported that tumor expression of the beta-3 tubulin (β3T) isoform is an unfavorable prognostic factor in non-small-cell lung cancer (NSCLC) treated with tubulin-inhibiting chemotherapy. Ixabepilone is a tubulin-inhibiting agent with low susceptibility to multiple resistance mechanisms including β3T isoform expression in several tumor models. This randomized phase II study evaluated ixabepilone-based chemotherapy in stage IIIb/IV NSCLC, compared with paclitaxel-based chemotherapy. Tumor specimens were prospectively evaluated for β3T expression. Patients were stratified by β3T status (positive v negative) and randomly assigned at a ratio of 1:1 to receive ixabepilone (32 mg/m(2)) and carboplatin (area under concentration-time curve [AUC], 6) or paclitaxel (200 mg/m(2)) and carboplatin (AUC, 6) for up to six cycles. The primary end point was progression-free survival (PFS) in the β3T-positive subgroup. Ninety-five patients (β3T positive, 52; β3T negative, 43) received ixabepilone plus carboplatin; 96 patients (β3T positive, 49; β3T negative, 47) received paclitaxel plus carboplatin. No significant differences in median PFS were observed between arms for either subgroup (β3T positive, 4.3 months in both arms; β3T negative, 5.8 v 5.3 months). Ixabepilone did not significantly improve overall survival (OS) for the β3T-positive subset or the overall population. Adverse events were similar between the two arms and comparable with those in previous studies. There was no predictive value of β3T in differentiating clinical activity of ixabepilone- or paclitaxel-containing regimens. Ixabepilone did not improve PFS or OS in patients with β3T-positive tumors. β3T-positive patients had worse PFS relative to β3T-negative patients, regardless of treatment; hence, β3T expression seems to be a negative prognostic factor, but not a predictive factor, in advanced NSCLC treated with either ixabepilone or paclitaxel platinum-based doublets.

Abstract 4623: The novel, small molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer.

Abstract Background: Ovarian cancer (OC) progression is associated with accumulation of epigenetic changes leading to transcriptional silencing of tumor suppressor and chemo-responsiveness associated genes. We recently demonstrated for the first time in a clinical trial that therapeutic interventions targeting the OC methylome reverse drug resistance and induce meaningful clinical responses. While the FDA-approved demethylating agent decitabine is prone to deamination by cytidine deaminase, SGI-110 (Astex Pharmaceuticals, Inc.), a dinucleotide analogue of decitabine, is more stable, less toxic, and a promising alternative to restoring silenced TSG expression in cancer cells by reversal of DNA methylation. Our previous preclinical evaluation demonstrated that SGI-110 resensitized platinum-resistant OC cell lines to cisplatin (CDDP) (3-fold reduction in IC50) and reduced the CDDP IC50 by >2-fold in the A2780 platinum sensitive OC cell line. SGI-110 treatment induced significant demethylation and subsequent transcriptional derepression of tumor suppressors and differentiation-associated genes in A2780 ovarian cancer cells. In addition, non-tumor bearing mice tolerated SGI-110 alone or in combination with CDDP. Methods: In the current study, we assessed the activity of SGI-110 in combination with CDDP to retard the growth of platinum sensitive or drug resistant human ovarian cancer xenografts. Mice were injected with SGI-110 (2 mg/kg or 5 mg/kg, SQ.) or CDDP (2 mg/kg or 4 mg/kg, IP.) treatment or in combination in a biweekly or QD5 regimen. Results: Significant antitumor activity was observed in the single SGI-110 and SGI-110 + CDDP treatment in both the biweekly and QD5 regimen mice bearing a subcutaneous A2780 OC xenograft. The effect of SGI-110 treatment alone was greater than CDDP treatment alone. Pyrosequencing analysis was use to reaffirm global demethylation by SGI-110 treatment, based on significant demethylation of LINE1 in peripheral blood mononuclear cells. As expected, SGI-110 treatment resulted in derepression of TSGs (MLH1 and RASSF1A), HOXA10 and HOXA11 (differentiation-associated genes), CSNK1D (DNA repair), IL2RG (receptor subunit in Jak/STAT pathway), and STAT5B (transcription factor) in tumors (as observed in the in vitro study). To test the hypothesis that SGI-110 treatment influenced DNA adduct formation and repair of cisplatin-DNA damage, we are currently analyzing the amount of platinum-DNA damage induced by CDDP treatment using mass spectrometry. Conclusions: The results of our preclinical study support our recently activated clinical trial using SGI-110 in combination with carboplatin in patients with recurrent, platinum-resistant OC. Citation Format: Jessica Tang, Fang Fang, Yinu Wang, Pietro Taverna, David F.B. Miller, Gavin Choy, Mohammad Azab, Daniela Matei, Katherine S. Pawelczak, Pamela VanderVere-Carozza, Michael Wagner, John J. Turchi, Kenneth P. Nephew. The novel, small molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4623. doi:10.1158/1538-7445.AM2013-4623

Efficacy and safety of weekly nab-paclitaxel plus carboplatin in patients with advanced non-small cell lung cancer

PurposeIn a large multicenter international phase III study (CA031) of nab-paclitaxel (nab-P, 130nm albumin-bound paclitaxel particles)+carboplatin (C) vs solvent-based paclitaxel (sb-P)+C, conducted in 6 countries including Japan, nab-PC produced significantly higher overall response rate (ORR), primary end point compared with sb-PC, and acceptable safety profile. The aim of this analysis was to evaluate the efficacy and tolerability of nab-PC vs sb-PC in Japanese patients with advanced non-small-cell lung cancer (NSCLC) who were enrolled in the CA031 study. Patients and methodsIn the CA031 study, a total of 1052 patients were randomized to receive either nab-P 100mg/m2 weekly or sb-P 200mg/m2 every 3 weeks both in combination with C at area under the concentration-time curve (AUC)=6 on day 1 of each 3-week cycle. This analysis included 149 Japanese patients with previously untreated stage IIIB or IV NSCLC. ResultsThe baseline and histologic characteristics of patients were well balanced between the two arms. ORR was higher with nab-PC vs sb-PC (35% vs 27%; response rate ratio=1.318). Progression-free survival (median 6.9 vs 5.6 months; hazard ratio [HR]=0.845) and overall survival (median 16.7 vs 15.9 months; HR=0.930) were better with nab-PC vs sb-PC. Of the grade ≥3 treatment-related adverse events, anemia and thrombocytopenia were more common in nab-PC arm, but sensory neuropathy was less common. ConclusionThe nab-PC treatment yielded promising results regarding the efficacy endpoint, and it was generally well tolerated as first-line therapy for Japanese patients with advanced NSCLC.

Erratum to: Phase I trial of verubulin (MPC-6827) plus carboplatin in patients with relapsed glioblastoma multiforme

Erratum to: Phase I trial of verubulin (MPC-6827) plus carboplatin in patients with relapsed glioblastoma multiforme

Chemotherapy management of malignant pleural mesothelioma: a phase II study comparing two popular chemotherapy regimens

The aim of this prospective, phase II clinical study is to evaluate the activity of gemcitabine and cisplatin in comparison to pemetrexed and carboplatin in patients with malignant pleural mesothelioma. The patients were recruited from May 2008 to May 2011. One group included 21 cases who received cisplatin and gemcitabine. The other group included 19 cases who received pemetrexed and carboplatin. Response is superior in the pemetrexed group (p = 0.041). The median follow-up was 18 months (range 6-30 months). Cumulative survival at 1.5 years was 57.8 % for the pemetrexed carboplatin group. For the gemcitabine cisplatin group, the cumulative survival proportion at 1.5 years was 41 % (p = 0.0599). Pemetrexed plus carboplatin are a step forward in the treatment of mesothelioma, the prognosis for these patients remains poor. Cheaper combinations as gemcitabine and cisplatin may be considered sufficient to treat cases with advanced mesothelioma.

Population Pharmacokinetics of UCN-01

UCN-01 (7-Hydroxystaurosporine) is an investigational anticancer agent that is currently being evaluated as targeted therapy in phase II clinical studies. The aims of this work were to describe the population pharmacokinetics of UCN-01 in patients with advanced solid tumors, and to identify covariates in patients with advanced solid tumors that affected the pharmacokinetic parameters of UCN-01. The utility of performing this research is to provide optimization of treatment and individualized dose therapy for minimization of toxicity. So, in addition to elucidating the population pharmacokinetic parameter estimates from a Phase I trial where UCN-01 was given in combination with carboplatin in patients with advanced solid tumors, and a trial where the drug was given alone as a 72-hour infusion in the same type of population, a covariate analysis was performed in order to identify pharmacokinetic determinants of UCN-01. Using NONMEM to perform nonlinear mixed-effects modeling, a linear two-compartment model was found to provide the best fit for UCN-01 data. A meta-analysis was performed, which included pooled 3-hour and 72-hour infusion data, and provided population pharmacokinetic estimates for CL (0.0157 L/hr [6.1%RSE]), V1 (2.51 L [10.0% RSE]), Q (4.05 L/hr [14.3% RSE]), and V2 (8.39 L [6.6% RSE]). Inter-individual variability was found for each of the main pharmacokinetic parameters to be ETACL (44.9% [20.8% RSE]), ETAV1 (43.9% [39.8% RSE]), ETAQ (6.09% [62.5% RSE]), and ETAV2 (4.17% [30.0% RSE]). Body surface area was found to be a statistically-significant variable from one of the individual study analyses (3-hour infusion). Population PK modeling has contributed to a better understanding of the clinical pharmacology of UCN-01. Dose individualization may improve treatment with UCN-01. Further clinical development may be supported by optimization of combination chemotherapy.

Abstract P5-20-05: A Phase 2 trial of RAD 001 and Carboplatin in patients with triple negative metastatic breast cancer

Abstract BACKGROUND: RAD001 is an oral mTOR inhibitor that has exhibited activity in breast cancer. Triple negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents that cause interstrand cross-links. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in at least two different breast cancer cell lines (including ER/PR negative cell lines). We propose that combination RAD001 and carboplatin may have activity in triple-negative breast cancer. MATERIALS AND METHODS: The primary objective of the study is to determine clinical benefit (complete remission (CR) + partial remission (PR) + stable disease (SD more than 6 months)) and the toxicity of this combination in triple negative metastatic breast cancer who have had 0–3 prior chemotherapy regimens for metastatic disease. Twenty-five subjects were to be entered in this Phase II study. This design has greater than 80% power to test the null hypothesis that the clinical benefit rate is less than or equal to 10% versus the alternative hypothesis that clinical benefit rate is greater than or equal to 30%. Prior carboplatin is allowed. Women with treated brain metastasis are eligible. Secondary objectives are to determine progression free survival and relationship between pretreatment sensitivity (biopsy at baseline) and clinical response (biopsy post 2 cycles) using IHC staining for abundance of key proteins in the Akt-mTOR pathway and their activity using surrogate phosphorylation site-specific antibodies. According to the original study plan, carboplatin AUC 6, was to be given intravenously every three weeks. Five mg of RAD001 was to be given daily with a 3 patient run-in and then 10 mg daily if there were no dose-limiting toxicities. Due to a surprising amount of thrombocytopenia with this combination the dose of carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001 (and no plan to escalate to 10 mg). RESULTS: 23 patients of a planned 25 have been recruited thus far. Median age is 59. Of the 20 patients assessable for response at this time, there have been 1 CR, 5 PRs, 8 SDs and 6 PDs. One SD was achieved in a patient progressing on single agent Carboplatin at study entry. Median duration of CR+ SD +PR thus far is 13 weeks (range: 6–74 weeks). 5 of 22 patients assessable for toxicity had grade 3/4 thrombocytopenia and 4 patients had grade 3 neutropenia (no febrile neutropenia). 13 out of eighteen patients have had treatment held and/or dose reductions secondary to hematological toxicity, however, since amendment for starting dose of Carboplatin to AUC 4 the regimen has been very well tolerated with only 1 out of eleven patients with grade 3 neutropenia and grade 3 thrombocytopenia. 1 patient suffered from grade 3 dehydration. The estimated clinical benefit rate is 45% (95% confidence interval: 23%, 67%). Median time to progression or death is 85 days from start of treatment. CONCLUSIONS: Our study has met the primary end point of demonstrating clinical benefit in triple negative metastatic breast cancer. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. We continue to accrue study subjects at the amended dosing. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-05.

Abstract P5-20-10: Panitumumab, Gemcitabine and Carboplatin in Triple-Negative Metastatic Breast Cancer: Preliminary Results of a Phase II Trial of the Sarah Cannon Research Institute

Abstract Background: Triple-negative breast cancer (TNBC) is a poor prognosis subtype with treatment limited to chemotherapy. Over expression of epidermal growth factor receptor (EGFR) occurs in up to 70% of TNBC providing a potential targetable receptor for treatment. Panitumumab is an approved fully human, IgG2 monoclonal anti-EGFR antibody that inhibits intracellular growth signals dependent on receptor activation. The gemcitabine/platinum combination has demonstrated activity in metastatic as well as TNBC at various schedules and doses. We therefore investigated the efficacy and safety of panitumumab in combination with gemcitabine and carboplatin in patients (pts) with TNBC. Methods: Eligibility criteria included: females with metastatic TNBC, 0–1 prior chemotherapy regimen for metastatic disease, ECOG PS 0–1, no brain metastases, no previous EGFR inhibitors and adequate organ function. All pts received gemcitabine 1500 mg/m2 IV, carboplatin AUC = 2.5 IV, and panitumumab 6 mg/kg IV every 2 weeks. A prophylactic skin regimen consisting of moisturizer, sunscreen and topical steroid was to be used 24 hours prior to study treatment and continued until panitumumab was discontinued. Pts were restaged after 3 treatment cycles and continued treatment until unacceptable toxicity or disease progression. If treatment benefit was demonstrated, and pts were experiencing toxicity or intolerance to gemcitabine, carboplatin or both, pts were allowed to discontinue either one or both agents and continue study treatment with panitumumab as a single agent or in combination. The primary endpoint of this study is progression free survival (PFS) with accrual of 70 pts necessary to detect an improvement in median PFS from 3.6 to 5.4 months (80% power, 10% level of significance). Results: Between May 2010 and May 2012, 61 patients were enrolled with an accrual goal of 70 pts. This analysis is based on 47 pts. Pt characteristics include: median age 56, prior hormonal therapy 4%, no prior chemotherapy for metastatic disease in 87% (28% de novo stage IV), 1 prior chemotherapy for metastatic disease in 13%. Sites of metastatic disease included local regional/lymph nodes 70%, lung 57%, liver 32%, bone 26%, and others 23%. Best response to treatment was as follows: CR − 1 (2%), PR − 14 (30%), SD − 20 (43%), PD − 11 (23%), UE − 1 (2%). As 1st line TNBC therapy, the ORR was 34%. The most common grade 3/4 heme toxicities were neutropenia − 12 (25%), leucopenia − 7 (15%), anemia − 3 (6%) and thrombocytopenia − 2 (4%). Grade 3/4 non-hematologic toxicities were rash − 4 (9% with 1 grade 4), fatigue − 3 (6%) and DVT − 3 (6%). Grade 1 and 2 rash was present in 19 and 9 pts respectively. Archival tumor tissue was collected for correlative biomarker analysis to include PI3KCA, p53, PTEN, EGFR, and K-ras status. Conclusions: The addition of panitumumab to gemcitabine and carboplatin in metastatic TNBC was active with an ORR of 32%. No new safety signals were identified and treatment was generally well tolerated with easily manageable toxicity. Full study results and correlative biomarker assessments will be reported. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-10.

Abstract OT2-3-10: Phase II study of panitumumab, nab-paclitaxel, and carboplatin for patients with primary inflammatory breast cancer (IBC) without HER2 overexpression

Abstract Background: Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer. The outcome for patients with IBC is bleak despite multimodality treatment approaches. 10-year disease-free survival rates after combined anthracycline and taxane-containing chemotherapy, surgery, and radiation are only 20%–25%. Our recent study found EGFR overexpression, a predictive factor of poor outcome, in 12 of 40 (30%) patients with IBC. Panitumumab has shown activity against EGFR overexpressing breast cancer xenograft model. Trial design: This is a single center, open-label, phase II study to evaluate the safety and efficacy of panitumumab in combination with preoperative chemotherapy. The treatment regimen consists panitumumab 2.5 mg/Kg given intravenously alone for the first week, followed by weekly panitumumab, nab-paclitaxel (100mg/m2) and carboplatin (2 AUC) (PNC) for 12 weeks. Patients then will receive 5-FU, epirubicin, and cyclophosphamide (FEC) every 3 weeks for 4 cycles prior to surgery. Eligibility criteria: 1) Histological confirmation of breast carcinoma with pathologic evidence of dermal lymphatic invasion and clinical diagnosis of IBC, including diffuse erythema, heat, ridging, and peau d'orange; 2) Normal HER2 expression; 3) No prior therapies for IBC; 4) Adequate hematologic, cardiac, renal and hepatic functions. Specific aims: 1) Primary objective is to determine the pathologic complete response (pCR) rate in patients with primary IBC without HER2 overexpression; 2) Secondary objectives are to determine the disease-free survival (DFS), overall survival (OS), the safety and tolerability of PNC regimens and the correlates of pathologic response rate and EGFR expression level. Statistical methods: 1) Previous studies have shown that this IBC patient population achieved a 13% pCR rate on the standard of care. We assume a beta (0.26, 1.74) prior distribution for the pCR rate. This prior distribution has a mean of 13% and a standard deviation of 19%. 2) We will stop the trial early if P (pCR rate >/= 13%) is < 0.01. If we determine that there is less than a 1% chance that the pCR rate is 13% or more we will consider stopping the trial. 3) Once we have completed the study we will estimate the pCR rate with a 90% credible interval. If we have pCR in 4 of the 40 patients (10%), then our 90% credible interval for the pCR rate will be 4.0–19.6%. If we have pCR in 8 of the 40 patients (20%), then our 90% credible interval for the pCR rate will be 10.6–30.4%. We will also report the posterior probability that the pCR rate is 13% or more. For example, if we have pCR in 8 of the 40 patients (20%), then the probability that the pCR rate is 13% or more is 0.869. Present accrual and target accrual: To date, 13 patients have been enrolled. Target accrual is 40 patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-10.

598 A Phase 1b Study of Demcizumab Plus Pemetrexed and Carboplatin in Patients with 1st Line Non-Small Cell Lung Cancer (NSCLC)

598 A Phase 1b Study of Demcizumab Plus Pemetrexed and Carboplatin in Patients with 1st Line Non-Small Cell Lung Cancer (NSCLC)

Radiation with cisplatin or carboplatin for locally advanced cervix cancer: The experience of a tertiary cancer centre

Definitive treatment with concurrent cisplatin and radiation is the standard of care for locally advanced cervix cancer. The optimal management of patients with a contraindication to cisplatin has not been established. We conducted a retrospective audit of concurrent chemotherapy in a cohort of patients with locally advanced cervix cancer. All patients with locally advanced cervix cancer treated with definitive radiation were entered into a prospective database. Information regarding their demographics, stage, histology, recurrence and survival were recorded. Pharmacy records were reviewed to determine concurrent chemotherapy use. A total of 442 patients were included in the audit. Two hundred sixty-nine patients received cisplatin, 59 received carboplatin and 114 received no concurrent chemotherapy. Overall survival was significantly improved with the use of concurrent cisplatin compared with radiation alone (adjusted hazard ratio 0.53, P = 0.001), as was disease-free survival and rate of distant failure. The use of carboplatin was not associated with any significant benefit in terms of overall survival or disease-free survival. The results of this audit are consistent with the known significant survival benefit with concurrent cisplatin chemotherapy. However, there did not appear to be any significant benefit with carboplatin although there were potential confounding factors. The available evidence in the literature would favour the use of non-platinum chemotherapy rather than carboplatin in patients with contraindications to cisplatin.

O1-032 - A Prospective, Feasibility Study of S-1 and Carboplatin for Patients with Pulmonary Fibrosis (PF) and Advanced Non-Small-Cell Lung Cancer (NSCLC)

ABSTRACT Background PF is commonly concomitant disorder with lung cancer. Because PF sometimes deteriorates and results unfavorable clinical course, patients with PF are excluded from most cancer clinical trials. S-1 is a novel active oral fluoropyrimidine anticancer agent consisting of tegafur, gimeracil, and oteracil potassium. Although most of the anti-cancer agents have pulmonary toxicity, post marketing surveillance reported that S-1 has lower pulmonary toxicity incidence. We have conducted a feasibility study of S-1 and carboplatin combination for patients with advanced or ineligible for other treatment modality of NSCLC patients. Methods Patients with histologically or cytologically confirmed NSCLC, clinically diagnosed pulmonary fibrosis, aged 80 years old or younger, performance status 0–2 and chemo-naive were eligible for the study. Carboplatin (AUC 5) was administered on day 1 and S-1 (80 mg/m2/day) on day 1 to 14 for four to six cycles. End points were response rate, common safety profiles and effect to PF. Results From March 2009 to December 2011, 21 patients (19 males/2 females, median age 67 years old, ranged 55 to 77, 10 adenocarcinoma, 10 squamous, 1 adenosquamous, stage IIA: 1, IIIA: 3, IIIB: 9, IV: 4, recurrence: 4) were enrolled. All patients had moderate or severe PF. Treatment delivery; 1 cycle: 3 patients, 2: 3 patients, 3: 3 patients, 4: 10 patients, 5; 1 patient, 6: 1 patients. Partial responses were observed in 7 patients (RR; 33%). The median progression-free survival duration was 4.0 months, and the median overall survival duration in 10.4 months. During the treatment, two patients experienced moderate deterioration of pulmonary fibrosis, one experienced infectious pneumonia—all three patients recovered from the event. There was no treatment related death. Besides pulmonary toxicity, most common adverse events were myelotoxicities. Conclusions This is the first trial of S-1 and carboplatin combination for patients with PF and NSCLC. The study revealed S-1 and carboplatin combination was feasible and active even in patients with PF and NSCLC who are usually excluded from cancer clinical trials.

A Phase I Trial of Dasatinib, an Src-Family Kinase Inhibitor, in Combination with Paclitaxel and Carboplatin in Patients with Advanced or Recurrent Ovarian Cancer

We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics. Using a "3+3" design, cohorts of three to six patients received paclitaxel (175 mg/m(2)) and carboplatin (AUC 6) every 3 weeks with escalating doses of dasatinib (100, 120, and 150 mg daily), followed by an eight-patient expansion cohort. Twenty patients were enrolled between June 2007 and December 2009. The median age was 61 years (range: 42-82) with a median of 2 prior regimens (range: 0-6), and 71% had platinum-sensitive disease. There were three to six patients in each cohort, and eight in the expansion cohort. Pharmacokinetics were observed over the first two cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3-4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 40% [three complete responses, (15%); five partial responses, (25%)],10 patients (50%) had stable disease, and two were not evaluable. The PFS(6-month) actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. Due to the high incidence of myelosuppression with subsequent cycles, the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity.

1334 - A Prospective, Feasibility Study of S-1 and Carboplatin for Patients with Advanced Non Small Cell Lung Cancer (NSCLC) Concomitant with Pulmonary Fibrosis (PF)

ABSTRACT Background PF is commonly concomitant disorder with lung cancer. Because PF sometimes deteriorates and results unfavorable clinical course, patients with PF are excluded from most cancer clinical trials. S-1 is a novel active oral fluoropyrimidine anticancer agent consisting of tegafur, gimeracil and oteracil potassium. Although most anti-cancer agent has pulmonary toxicity, post marketing surveillance reported S-1 has lower pulmonary toxicity incidence. We have conducted feasibility study of S-1 and carboplatin combination for patients with advanced or ineligible for other treatment modality of NSCLC patients. Methods Patients with histologically or cytologically confirmed NSCLC, clinically diagnosed pulmonary fibrosis, aged 80 years old or younger, performance status 0-2 and chemo-naive patients were eligible for the study. Carboplatin (AUC 5) was administered on day 1 and S-1 (80mg/m2/day) on day 1 to 14 for four to six cycles. Endpoints were response rate, common safety profiles and effect to PF. Results From March 2009 to December 2011, 21 pts (19 males/ 2 females, median age 67 years old, ranged 55 to 77, 10 adenocarcinoma, 10 squamous, 1 adenosquamous, stage IIA: 1, IIIA: 3, IIIB: 9, IV: 4, recurrence: 4) were enrolled. All patients had moderate or severe PF. Treatment delivery; 1 cycle: 3pts, 2: 3pts, 3: 3pts, 4: 10pts, 5; 1pts, 6: 1pts. Partial responses were observed in 7 patients (RR; 33%). The median progression free survival duration was 4.0 months and the median overall survival duration in 10.4 months. During the treatment, 2 patient experienced moderate deterioration of pulmonary fibrosis, 1 experienced infectious pneumonia, all three patients recovered from the event. There was no treatment related death. Besides pulmonary toxicity, most common adverse events were myelotoxicities. Conclusions This is the first trial of S-1 and carboplatin combination for patients with PF and NSCLC. The study revealed S-1 and carboplatin combination was feasible and active even in patients with PF and NSCLC who are usually excluded from cancer clinical trials. Disclosure All authors have declared no conflicts of interest.

How to approach patients in relapse

How to approach patients in relapse