Carboplatin Dose Research Articles

Biweekly Carboplatin Plus Gemcitabine as First-Line Treatment of Elderly Patients With Advanced Squamous Non–Small-cell Lung Cancer: A Multicenter Phase I-II Trial by the Hellenic Oncology Research Group

BackgroundThe present study was a phase I/II study to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities of the biweekly carboplatin/gemcitabine combination and evaluate its safety and efficacy in patients aged ≥ 70 years with advanced squamous non–small-cell lung cancer (NSCLC). Patients and MethodsPatients aged ≥ 70 years with advanced or metastatic squamous NSCLC received escalated doses of carboplatin (area under the curve [AUC] 2-2.5 intravenously) and gemcitabine (800-1100 mg/m2 intravenously) every 2 weeks (phase I). In the phase II, the drugs were administered at their previously defined MTDs (carboplatin, AUC 2.5; gemcitabine, 1100 mg/m2). The primary endpoint was the overall response rate. ResultsA total of 69 patients were enrolled (phase I, n = 15). The median age was 76 years (range, 70-84 years); 52 patients had stage IV disease, and 61 and 8 patients had Eastern Cooperative Oncology Group performance status of 0 to 1 and 2, respectively. The MTDs could not be reached at the predefined last dose levels. The dose-limiting toxicities were grade 5 renal toxicity and grade 3 thrombocytopenia. In the phase II study, the overall response rate was 35.8% (95% confidence interval [CI], 23.0%-48.8%). In the intention-to-treat analysis, the median progression-free survival was 6.7 months (95% CI, 4.2-8.8 months), and the median overall survival was 13.3 months (95% CI, 7.1-19.6 months). Grade 3 or 4 neutropenia was observed in 7 patients (12.3%), grade 3 or 4 thrombocytopenia in 4 patients (7.1%), and grade 2 or 3 fatigue in 10 patients (17.5%). One toxic death occurred in the phase I of the study. ConclusionThe biweekly regimen of gemcitabine and carboplatin showed satisfactory efficacy and a favorable toxicity profile in elderly patients with advanced or metastatic squamous cell NSCLC.

Impact of Isotope Dilution Mass Spectrometry (IDMS) Standardization on Carboplatin Dose and Adverse Events

When using area under the concentration-time curve-based strategies for dosing carboplatin, accurate estimation of glomerular filtration rate is required for determining dose. Commonly, the Cockcroft-Gault equationis used, which is dependent on measurement of serum creatinine (SCr). Because analysis of SCr changed to an isotope dilution mass spectrometry (IDMS) standard, we sought to determine the impact of this assay change on carboplatin dosing and related toxicity. This was a single-center, retrospective chart review of adults treated with carboplatin between April 2008 and April 2010 divided into cohorts that initiated carboplatin before or after IDMS standardization. End points included grade 3 thrombocytopenia, decrease in platelet count, and hospitalization and were evaluated in cohorts based on concomitant chemotherapy. The chart review identified 158 patients, with 63 patients in the pre-IDMS group and 95 patients in the post-IDMS group. Average SCr (pre 1.01mg/dl vs post 0.86mg/dl, p<0.001) and average carboplatin dose (pre 580mg vs post 703mg, p<0.001) were significantly different between the groups. The frequency of grade 3 thrombocytopenia was not statistically significant across three partner chemotherapy cohorts before and after IDMS implementation. IDMS standardization led to an overall decrease in SCr with subsequent increase in carboplatin doses. However, no increase in recorded adverse events was observed, suggesting that the clinical relevance in toxicity from higher doses was minimal.

Impaired Brain Dopamine and Serotonin Release and Uptake in Wistar Rats Following Treatment with Carboplatin.

Chemotherapy-induced cognitive impairment, known also as “chemobrain”, is a medical complication of cancer treatment that is characterized by a general decline in cognition affecting visual and verbal memory, attention, complex problem solving skills, and motor function. It is estimated that one-third of patients who undergo chemotherapy treatment will experience cognitive impairment. Alterations in the release and uptake of dopamine and serotonin, central nervous system neurotransmitters that play important roles in cognition, could potentially contribute to impaired intellectual performance in those impacted by chemobrain. To investigate how chemotherapy treatment affects these systems, fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes was used to measure dopamine and serotonin release and uptake in coronal brain slices containing the striatum and dorsal raphe nucleus, respectively. Measurements were taken from rats treated weekly with selected doses of carboplatin and from control rats treated with saline. Modeling the stimulated dopamine release plots revealed an impairment of dopamine release per stimulus pulse (80% of saline control at 5 mg/kg and 58% at 20 mg/kg) after 4 weeks of carboplatin treatment. Moreover, Vmax, the maximum uptake rate of dopamine, was also decreased (55% of saline control at 5 mg/kg and 57% at 20 mg/kg). Nevertheless, overall dopamine content, measured in striatal brain lysates by high performance liquid chromatography, and reserve pool dopamine, measured by FSCV after pharmacological manipulation, did not significantly change, suggesting that chemotherapy treatment selectively impairs the dopamine release and uptake processes. Similarly, serotonin release upon electrical stimulation was impaired (45% of saline control at 20 mg/kg). Measurements of spatial learning discrimination were taken throughout the treatment period and carboplatin was found to alter cognition. These studies support the need for additional neurochemical and behavioral analyses to identify the underlying mechanisms of chemotherapy-induced cognitive disorders.

The accuracy of carboplatin area under the curve (AUC) estimated by Calvert formula using Cockcroft-Gault formula and Thai eGFR in Thai cancer patients.

e14017Background: In current practice, carboplatin dose is calculated by Calvert formula. Although, originally measured glomerular filtration rate (GFR) was used in the formula, creatinine clearanc...

Definitive concurrent chemoradiotherapy (CRT) for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) using systemic dose carboplatin: A retrospective analysis.

e17538Background: Definitive concurrent CRT is considered the standard of care for organ preservation and is the only potentially curative therapy in surgically unresectable patients (pts) with sta...

Phase I trial of a first-in-class ATR inhibitor VX-970 as monotherapy (mono) or in combination (combo) with carboplatin (CP) incorporating pharmacodynamics (PD) studies.

2504Background: ATR is a regulator of cellular responses to replication stress, where it signals DNA damage repair by homologous recombination. Many cells depend on ATR to survive DNA damage. VX-970 is a potent, selective ATR inhibitor with marked preclinical antitumor activity in combo with chemotherapy. Methods: Patients (pts) with advanced cancers were enrolled in 2 parts. Part A: N=1 pt cohorts received VX-970 QW; 3 + 3 cohorts were commenced if ³ G2 drug-related toxicities occurred. Part B: 3 + 3 pt cohorts received CP on d1 + VX-970 on d2 and 9 in 21-day cycles. Timed pre- and post-VX-970 tumor biopsies were assessed for pS345 CHK1 levels by IHC in part B. Hematologic toxicities were modeled for pts in part B. Results: 26 pts were treated; M/F 10/16, ECOG PS 0/1: 9/17. Median age: 66 yrs (range 49-76 years). VX-970 was generally well tolerated as mono or CP combo with mainly G1-2 toxicities. CP dose delays and reductions occurred in 3/3 pts (B1); 2/2 pts (B2); 0/3 pts (B3); 1/6 pts (B4) due to neutr...

MP83-02 ADDITION OF EMETINE DIHYDROCHLORIDE TO PLATINUM BASED CHEMOTHERAPY INHIBITS BLADDER CANCER CELL PROLIFERATION AND REDUCES THE EFFECTIVE DOSE OF PLATINUM CHEMOTHERAPY

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2016MP83-02 ADDITION OF EMETINE DIHYDROCHLORIDE TO PLATINUM BASED CHEMOTHERAPY INHIBITS BLADDER CANCER CELL PROLIFERATION AND REDUCES THE EFFECTIVE DOSE OF PLATINUM CHEMOTHERAPY Valerie J. Davidson, Robert H. Blackwell, Kimberly E. Foreman, Paul C. Kuo, Robert C. Flanigan, and Gopal N. Gupta Valerie J. DavidsonValerie J. Davidson More articles by this author , Robert H. BlackwellRobert H. Blackwell More articles by this author , Kimberly E. ForemanKimberly E. Foreman More articles by this author , Paul C. KuoPaul C. Kuo More articles by this author , Robert C. FlaniganRobert C. Flanigan More articles by this author , and Gopal N. GuptaGopal N. Gupta More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2184AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Emetine is a natural alkaloid that inhibits protein synthesis at the micromolar level. Decades ago, Phase I and II clinical trials of emetine as a single agent showed modest efficacy against many solid tumors, but these findings were not pursued. We have previously reported that low, nanomolar concentrations of emetine act synergistically with cisplatin to inhibit invasive bladder cancer cell proliferation. Here, we extend these findings to evaluate the addition of emetine to the standard of care chemotherapeutic regimen of cisplatin plus gemcitabine. Because 50% of patients are unfit for cisplatin-based therapies, we also examined the effect of emetine combined with carboplatin and gemcitabine on bladder cancer cell proliferation. METHODS Normal urothelial cells and UMUC3, HT1376, and T24 invasive bladder cancer cell lines were cultured under standard conditions. Cells were treated with gemcitabine, cisplatin, carboplatin, and emetine alone or in combination at concentrations based on the drug's experimentally determined inhibitory concentration-50 (IC50). Proliferation was measured via MTT assay or trypan blue-staining based cell counts. Cell cycle data was obtained via DNA-propidium iodide staining and flow cytometry. RESULTS The addition of emetine to either cisplatin-gemcitabine or carboplatin-gemcitabine significantly decreased cell proliferation in cancer cells. Normal urothelial cells were more resistant with ten-fold higher concentrations of emetine required to observe the same effect on proliferation. Cell cycle analysis revealed the addition of emetine did not cause cell death, but rather induced a G1 growth arrest. This growth arrest was irreversible at cisplatin or carboplatin concentrations at or above the calculated IC50. CONCLUSIONS Addition of emetine to either cisplatin or carboplatin-based chemotherapeutic regimens resulted in a significant decrease in bladder cancer cell proliferation. Our findings suggest the addition of emetine to the current standard of care therapies may benefit patients. Importantly, inclusion of emetine appears to lower the dose of cisplatin or carboplatin required to block cell proliferation. This may allow some patients previously unfit for cisplatin-gemcitabine to qualify for this therapeutic regimen. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1081 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Valerie J. Davidson More articles by this author Robert H. Blackwell More articles by this author Kimberly E. Foreman More articles by this author Paul C. Kuo More articles by this author Robert C. Flanigan More articles by this author Gopal N. Gupta More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract C50: Sensitivity of triple-negative breast cancer cell lines to cytotoxic and targeted agents as a function of molecular subtype

Abstract Triple-negative breast cancer is a heterogeneous disease with no approved targeted therapies. The disease course is very aggressive, characterized by relapse within 3 years of treatment and metastases to the viscera, including the brain. The prognosis in the setting of distant metastases is grim, as median survival is less than one year. Recently, insight into the molecular complexity of TNBC was provided by gene expression analysis, which identified six unique subtypes with distinct gene ontologies that differ with respect to drug sensitivity. These subtypes, each enriched in unique molecular components and pathways, suggest target-based strategies for treatment. A multiplicity of targeted drugs has entered clinical trials for the potential treatment of TNBC, but no uncontested victor has emerged that can appreciably extend overall survival. For instance, one of the most promising experimental drugs is iniparib, which significantly improved outcomes in a Phase II clinical trial of metastatic TNBC when combined with carboplatin/gemcitabine; however, overall survival was still unacceptably short at ~1 year. Therefore, there remains a dire need to identify novel therapeutic modalities for TNBC. A promising research strategy towards this goal is to determine the differential sensitivities of the TNBC molecular subtypes to combinations of cytotoxic and targeted drugs. We are determining the responses of a panel of TNBC cell lines representing different molecular subtypes, including the basal-like 1 (HCC1143 and MDA-MB-468), basal-like 2 (HCC1806 and HCC70), immunomodulatory (HCC1187), mesenchymal stem-like (MDA-MB-436, MDA-MB-231, and MDA-MB-157), and luminal androgen receptor (MFM-223) subtypes, to variable doses of carboplatin, capecitabine, cyclophosphamide, docetaxel, and everolimus, used alone and in combination. These drugs were chosen because they target molecular regulators of prominent signaling pathways specific to certain TNBC molecular subtypes, so we expect to find that sensitivity to these drugs is a function of subtype. The results of this study will enable characterization of TNBC subtypes in finer detail and provide a preclinical framework for the development of subtype-dependent regimens for TNBC treatment. Citation Format: Heather Colley, Roopali Saxena, Angela Ogden, Guilherme Cantuaria, Michelle D. Reid, Xiaoxian (Bill) Li, Uma Krishnamurthy, Padmashree CG Rida, Ritu Aneja. Sensitivity of triple-negative breast cancer cell lines to cytotoxic and targeted agents as a function of molecular subtype. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C50.

Abstract S2-04: Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto)

Abstract Introduction Addition of carboplatin to anthracycline/taxane-based neoadjuvant chemotherapy has shown to improve pathological complete response (pCR; ypT0 ypN0) rates in patients with triple-negative breast cancer in two large phase II studies (GeparSixto: von Minckwitz et al. Lancet Oncol 2014; CALGB 40603: Sikov et al. J Clin Oncol 2015). Participants of the GeparSixto study with triple-negative tumors showed an improvement of pCR rate from 36.9 to 53.2% by the addition of carboplatin (p=0.005); however, no statistically significant difference in pCR rate was observed in the HER2-positive subgroup (36.8 vs 32.8%, respectively). A greater benefit with carboplatin was observed in patients with BRCA mutations or a high homologous recombination deficiency (HRD score) in the tumor (pCR rate of 30% compared to 10% for patients without HRD). So far, it is unknown whether these effects on pCR translate into a survival benefit for the patients. We here report an early survival analysis of the GeparSixto study. Patients and Methods In the GeparSixto trial (NCT01426880), patients were treated for 18 weeks with paclitaxel 80mg/m2 q1w and non-pegylated-liposomal doxorubicin (NPLD) 20mg/m2 q1w. Patients with TNBC (N=315) received concurrently bevacizumab 15mg/kg i.v. q2w until surgery. Patients with HER2+ disease (N=273) received concurrently trastuzumab 6(8)mg/kg q3w and lapatinib 750mg daily. All patients were randomized 1:1 to receive concurrently carboplatin AUC 1.5-2.0 q1w vs no carboplatin, stratified by subtype (HER2+ vs TNBC). Carboplatin dose was reduced from AUC 2.0 to 1.5 by an amendment after 330 patients. Primary objective was pCR rate (ypT0 ypN0). Loco-regional invasive recurrence free survival (LRRFS), distant-disease- free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS) were secondary objectives. Results 595 patients were recruited (8/2011 - 12/2012) in 51 German centers. 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. So far, 82 events have been reported after a median of 28 months follow-up. Analysis of updated events by treatment arm in the full study population as well as in the TNBC and HRD subgroups will be presented. Conclusion Even if the GeparSixto study was not powered to show carboplatin effects on survival, the expected results will help to assess the overall benefit of carboplatin in TNBC and the power of pCR to predict for DFS and OS. Citation Format: von Minckwitz G, Loibl S, Schneeweiss A, Salat CT, Rezai M, Zahm D-M, Klare P, Blohmer J-U, Tesch H, Khandan F, Fasching PA, Jakisch C, Nekljudova V, Untch M. Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-04.

SUCCESSFUL REGISTRATION OF DOMESTIC BIOANALOGUE OF BEVACIZUMAB – NEW OPPORTUNITIES FOR EFFECTIVE TREA TMENT OF PATIENTS WITH NON-SQUAMOUS CELL NON-SMALL CELL LUNG CANCER

Comparison of the efficacy and safety of drugs Avegra® and Avastin® used in combination with paclitaxel and carboplatin as first-line therapy in patients with locally inoperable or metastatic NSCLC. The study included 138 patients, male and female aged 18 to 75 years with newly diagnosed inoperable or widespread metastatic NSCLC (except squamous cell NSCLC), relevant eligibility criteria. After passing screening, patients were centrally randomized in one of the study groups in a 1:1 ratio. Treatment was carried out according to the following scheme: Avegra® or Avastin®, 15 mg/kg intravenously over 90 minutes immediately after carboplatin on day 1 of each 3‑week cycle + paclitaxel 175 mg/m² intravenously over 3 hours on day 1 of each 3‑week cycle + carboplatin dose required to achieve AUC 6 mg/ml×min, intravenously over 15–30 minutes, immediately following paclitaxel, on the first day of each three-week cycle. The treatment lasted for six cycles of three weeks or until progression or until the development of intolerable toxic effects. Based on CT scan assessment performed by an independent specialist, the overall response rate (ORR, partial response rate + complete response rate) defined as a primary endpoint was 42.59% (95% CI 30.33–55.83%) in Avegra® arm and 39.29% (95% CI 27.58–52.27%) in Avastin® arm, respectively. The difference in ORR between study drug and comparator was 3.30% with 95% CI –14.96–21.40% (р =0.874, the Pearson x² test with Yates correction). The lower limit of calculated 95% CI (-14.96%) exceeds the specified non-inferiority margin and it is indicating the non-inferiority of Avegra® efficacy compared to Avastin®. During the study period the incidence of adverse events, including severe adverse events (grade 3–4 according to CTCAE) related with the investigational drugs, did not have statistically significant differences in both study arms. The drug Avegra® in direct comparison to Avastin® demonstrated equal efficacy, similar safety and immunogenicity profile, equal pharmacokinetic characteristics. Based on the results of the clinical study the first biosimilar of bevacizumab — drug Avegra® was successfully registered in Russian Federation in November 2015 and can be recommended for use in clinical practice.

Evaluation of the impact of treatment delays and dose reductions in human ovarian cancer orthotopic mouse models

The primary objective of this study was to quantify the impact of treatment delay and dose reductions in an in vivo orthotopic ovarian cancer model. In addition, this study evaluated the role of growth factors in achieving “full dose on time”. HeyA-8 and SKOV3.ip1ovarian cancer orthotopic mouse models were used determine the effect of paclitaxel/carboplatin treatment delays or dose reductions on tumor response and overall survival. The addition of growth factor support with pegfilgrastim and darbepoetin was also evaluated in treatment control arm. The results indicated that full dose of paclitaxel (20 mg/kg) and carboplatin (50 mg/kg) delivered on time (every 21 days) achieved better tumor response in both aggressive (HeyA-8) and metastatic (SKOV3.ip1) human ovarian tumors compared to treatment delay or dose reduction arms. In the HeyA-8 orthotopic model treatment delay (P<0.05) resulted in a significant reduction in overall survival compared to on time, full dose treatment control arm and the dose reduction decreased overall survival but was not statistically significant. However, in the SKOV3.ip1orthotopic model a treatment delay (P<0.01) or dose reduction (P<0.05) both resulted in a significant reduction in overall survival compared to on time, full dose treatment control arm. In both orthotopic models, the addition of pegfilgrastim (1000 µg/kg) and darbepoetin (10 µg/kg) delayed the onset of ascites formation and was associated with an improved overall survival rate. Treatment delays and dose reductions had a negative impact on tumor response and overall survival compare with on-time, full dose treatment controls. In addition, use of growth factor agents improved overall survival and tumor responses.

Best treatment option for clinical stage I seminoma patients.

In the present cross sectional study comprising 106 patients, the authors compared a risk adapted therapeutic strategy in patients with CSI seminoma [1]. The patients were distributed to active surveillance (AS) (n = 84) and adjuvant chemotherapy (ACT) (n = 22) with single dose carboplatin groups. The relapse rates between the 2 groups were similar. The authors advocated AS for patients with low risk of relapse and, on the other hand, ACT for those with high risk of relapse. The current management options for CSI seminomas include adjuvant radiotherapy (ART), AS, and ACT. ART has been the preferred treatment modality for a long time, but concerns regarding its side effects, such as risks of cardiovascular disease and secondary malignancies, resulted in a significant change in the concept of ART. Thus, the option of ART has been removed from the current guidelines [2, 3]. Surveillance avoids overtreatment in approximately 85% of patients when appropriate follow-up protocols are used [4]. However, identifying the 15% who may harbor micrometastatic disease should be of utmost importance in patients under AS. Surveillance requires highly compliant patients willing to have multiple abdominal CT scans. The radiation from abdominal CT is not benign, with a lifetime attributable risk of secondary malignancy from 4 scans for an 18 year old patient calculated at 0.64% [5]. ACT has been shown to be non-inferior to ART [6]. In the largest series of ACT, a 4.1% relapse rate was demonstrated with a median time to relapse of 22.7 months among 517 patients [7]. A recent study which investigated the practice patterns for adjuvant therapies for CSI seminoma in the US population has demonstrated that ART has been largely replaced by ACT, rather than AS [8]. However, the authors concluded that the lack of an increase in AS in their cohort might represent overtreatment of the population. Proponents of AS consider ACT a potentially harmful and unnecessary intervention. However, in recent studies, especially low risk patients were selected for AS, whereas high risk patients were given ACT [9]. Due to this reason, such series may possibly be flawed by selection bias in favor of AS, whereas predominantly low risk patients were included rather than high risk ones [10]. The long term side effects of single dose ACT remain unclear; moreover, the use of ACT does not obviate the need for abdominal CT scans, which has been proposed as a concern against AS. A risk adapted treatment strategy seems to be logical for CSI seminoma patients. Although rete testis invasion and primary tumor >4 cm were reported to be independent prognostic factors for relapse, these data have not been validated in prospective studies [11]. Currently, AS has been recognized as the treatment of choice of CSI seminomas in the EAU and American Society of Clinical Oncology guidelines [2, 3].

Selective Inner Hair Cell Dysfunction in Chinchillas Impairs Hearing-in-Noise in the Absence of Outer Hair Cell Loss.

Poorer hearing in the presence of background noise is a significant problem for the hearing impaired. Ototoxic drugs, ageing, and noise exposure can damage the sensory hair cells of the inner ear that are essential for normal hearing sensitivity. The relationship between outer hair cell (OHC) loss and progressively poorer hearing sensitivity in quiet or in competing background noise is supported by a number of human and animal studies. In contrast, the effect of moderate inner hair cell (IHC) loss or dysfunction shows almost no impact on behavioral measures of hearing sensitivity in quiet, when OHCs remain intact, but the relationship between selective IHC loss and hearing in noise remains relatively unknown. Here, a moderately high dose of carboplatin (75mg/kg) that produced IHC loss in chinchillas ranging from 40 to 80% had little effect on thresholds in quiet. However, when tested in the presence of competing broadband (BBN) or narrowband noise (NBN), thresholds increased significantly. IHC loss >60% increased signal-to-noise ratios (SNRs) for tones (500-11,300Hz) in competing BBN by 5-10dB and broadened the masking function under NBN. These data suggest that IHC loss or dysfunction may play a significant role in listening in noise independent of OHC integrity and that these deficits may be present even when thresholds in quiet are within normal limits.

Adjuvant Carboplatin Treatment in 115 Patients With Stage I Seminoma: Retrospective Multicenter Survey

BackgroundThe administration of carboplatin AUC 7 has become a standard adjuvant option for patients undergoing orchiectomy for stage I seminoma, in alternative to radiotherapy on retroperitoneal lymphnodes or surveillance. The toxicity of AUC 7 carboplatin appeared manageable in the pivotal trial of Oliver et al, but dose ranges were not reported. Fear of toxicity may induce arbitrary dose reductions, which may potentially compromise patients' outcome. Patients and MethodsWe reviewed adjuvant carboplatin administration in 115 stage I seminoma patients followed in 11 Italian medical oncology centers since 2005. Clinical and pathological data, modality of carboplatin dose calculation, dose reductions, toxicities, and relapses were recorded. ResultsMedian age was 35 years (range, 18-65 years), adverse prognostic factors were either T ≥ 4 cm (17.4%) or rete testis invasion (28.7%), both of them (35.7%), none or unspecified (18.3%). GFR was estimated mainly by Cockroft-Gault formula (55.7%) or Jeliffe formula (26.1%), with a median of 105 mL/min (range, 75-209 mL/min). The median dose of carboplatin was 900 mg (range, 690-1535 mg). A dose reduction > 10% was applied to 14 patients. Toxicities were mild fatigue, moderate nausea/vomiting, 5.2% of grade 3 to 4 thrombocytopenia. After a median follow-up of 22.1 months, 5.2% of patients have relapsed in the retroperitoneal lymph nodes. None of the patients that relapsed were treated with reduced dose. All but one achieved complete remission with salvage chemotherapy. ConclusionsAdjuvant AUC 7 carboplatin reduce relapses of stage I seminoma patients to 5.2%, with manageable toxicities. Dose reductions should be proscribed.

High-Dose Melphalan Versus Busulfan, Cyclophosphamide As Conditioning Regimens for Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma

Introduction: Autologous stem cell transplantation after high dose chemotherapy has been shown to increase survival in patients with multiple myeloma. Studies have shown prolongation of median overall survival by 12 months. The standard conditioning regimen is high-dose Melphalan (HDM) at a dose of 200 mg/m2. Melphalan was shown to be superior to Thiotepa when given with total body irradiation. Other regimens include high dose Carboplatin with Etoposide and Cyclophosphamide or Cyclophosphamide, Carmustine and Etoposide. No regimen has shown marked superiority over others. Patients of I. Brodsky Associates at Hahnemann University Hospital were treated with autologous transplant with either high-dose Melphalan (HDM) or Busulfan and Cyclophosphamide (BuCy) as the conditioning regimens. To date, no studies comparing these two preparative regimens have been published. Thus the purpose of our chart review was to compare progression free survival of the two regimens.Hypothesis: The objective of the study is to determine if there is a difference in progression free survival and side effects in autologous stem cell transplant patients receiving either Melphalan or Busulfan and Cyclophosphamide as conditioning regimens.Methods: This study is a retrospective chart review of 94 patients, who underwent HSCT for multiple myeloma at Hahnemann University Hospital between December, 1989 and March, 2012. 47 patients received BuCy (Busulfan 16mg/kg and Cyclophosphamide 120mg/kg) and 49 patients received Melphalan 200 mg/m2. The primary end points were progression free survival (PFS) at 6 months, one year and overall PFS. Data was analyzed using the Kaplan Meier method with the WINKS SDA6 statistical software. Survival curves were compared using the Mantel-Haenszel comparison. Secondary study endpoints included safety profile.Results: Median age was 56 and 60 for the BuCy and HDM groups, respectively. The BuCy group had 68% males while the HDM group had 53% males. Patients in both groups received peripheral stem cell transplants with the exception of 4 in the BuCy group who had bone marrow transplants. As compared with BuCy, HDM treatment increased median progression free survival (37.3 vs. 18.1 months; P=0.014). There was a significantly higher rate of 6 month progression free survival (94% vs. 75%; P=.011) and 12 month progression free survival (82% vs 57%; P=0.006) in the HDM group compared to the BuCy group. The safety profile was as follows comparing BuCy and HDM, respectively: Moderate/severe mucositis (55% vs 48%), VOD (2 of 49 vs 1 of 47), hemorrhagic cystitis (2 of 49 vs. 1 of 47), infection within 100 days of transplant (28% vs 18%), mean peak T. Bilirubin ( 0.75 vs. 0.89), mean peak Alkaline phosphatase (127 vs. 90), mean peak AST (37.5 vs. 35), mean peak Cr (1.0 vs 1.2), mean days to ANC of 1000 (11.9 vs. 12.5), mean days to platelets > 20K (11.3 vs. 9.9), mean days to platelets > 50K (13.5 vs. 12.9).Conclusion: Our study showed that median progression free survival was longer with the HDM group compared to the BuCy group overall and at 6 and 12 months. Overall, patients treated with HDM had a median improvement in DFS of 1.5 years (37.3 months vs. 18.1 months, p=0.014). This data supports the use of HDM as the effective first line regimen for high dose chemotherapy and autologous stem cell transplant for patients with multiple myeloma. A limitation to our study is incomplete data regarding maintenance therapy post-transplant for the two groups. There was one patient in the BuCy group who relapsed at 236 months. Such prolonged disease free survival was not apparent in the HDM group but the median time to follow up for BuCy is longer by up to 13 years. BuCy was associated with more infections and more severe mucositis, while metabolic and hematologic toxicities were similar in both groups. DisclosuresNo relevant conflicts of interest to declare.

Abstract C2: Clinical safety, pharmacokinetics and early evidence of activity of the oral IAPs inhibitor Debio 1143 in combination with carboplatin and paclitaxel: a phase Ib study

Abstract Background: Resistance to apoptosis is a typical hallmark of cancer. Inhibitor of Apoptosis Proteins (IAPs) block caspase activation, modulate NF-kB signaling pathways, and are involved in resistance to standard chemo and radiation therapies. As such, IAPs antagonism represents an attractive target for therapeutic intervention. Debio 1143 is a potent orally-available monovalent SMAC mimetic antagonist of IAPs currently in clinical development. A previous phase I study showed Debio 1143 was well tolerated up to 900 mg QD as a single agent, with strong evidence of pharmacodynamic (PD) activity and appropriate pharmacokinetic (PK) disposition at doses ≥ 120 mg. [1] This Phase I study defined the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, PK, and PD of Debio 1143 in combination with carboplatin and paclitaxel. Methods: Treatment-naïve and previously treated patients with squamous non-small cell lung cancer (NSCLC), and previously treated patients with triple negative breast cancer (TNBC) and platinum-resistant epithelial ovarian cancer (EOC) were treated with carboplatin (AUC 6) and paclitaxel 175 mg/m2 on day 1 of every 21-day-cycle up to a maximum of 6 cycles, combined with escalating doses of Debio 1143, administered once daily on days 1-5 of every 21-day cycle. The starting dose of Debio 1143 was 200 mg QD. Results: Thirty-one patients were included in the study. Four patients are still on treatment. Hematological DLTs were observed in 2/4 patients in the first two dose levels despite the reduction of Debio 1143 dose to 100 mg. PK data suggested a PK interaction between Debio 1143 and paclitaxel. The study protocol was amended to reduce the doses of carboplatin to AUC 5 and paclitaxel to 135 mg/m2. Afterwards, patients received Debio 1143 doses of 100 mg (n = 2), 125 mg (n = 2), 175 mg (n = 2), 200 mg (n = 7), 225 mg (n = 5), 250 mg (n = 9). DLTs were febrile neutropenia (n = 2) and G3 ALT increase (n = 1). The MTD of Debio 1143 to be combined with carboplatin (AUC 5) and paclitaxel (135 mg/m2) is 250 mg QD. Most common treatment-related AEs reported in ≥ 15% of patients were asthenia (n = 13), decreased appetite (n = 11), diarrhea (n = 9), neutropenia (n = 9), thrombocytopenia (n = 8), anemia (n = 8), nausea (n = 7), fatigue (n = 7), vomiting (n = 4), AST increase (n = 4), hypomagnesaemia (n = 4), myalgia (n = 4),and epistaxis (n = 4). Paclitaxel exposure in patients dosed at 135 mg/m2 in combination with Debio 1143 was similar to historical control dosed at 175 mg/m2 due to a 25 to 40% reduction in clearance. Preliminary evaluation of PD endpoints confirmed Debio 1143-induced cIAP1 degradation in PBMCs at doses starting from 100mg. In line with the expected mechanism of action, modulation of serum PD markers of NF-kB signaling pathways and epithelial apoptosis was also observed during treatment. Twenty-three patients were evaluable for response. Partial responses by RECIST have been observed in 7 patients with EOC (6/17) and TNBC (1/5). Conclusions: The combination of Debio 1143 with carboplatin and paclitaxel is well tolerated, with significant PD activity and hints of activity. The clinical PK interaction between Debio 1143 and paclitaxel is well-controlled and managed in the patients. These findings support a further Phase II program. [1] HI Hurwitz et al., Cancer Chemother Pharmacol (2015) 75:851 Citation Format: Isabelle Ray-Coquard, Christophe Le Tourneau, Nicolas Isambert, Carlos A. Gomez-Roca, Philippe Cassier, Marie Paule Sablin, Bruno Gavillet, Daniela Purcea, Elisabeth Rouits, Claudia Schusterbauer, Claudio Zanna, Pierre Fumoleau, Jean-Pierre Delord. Clinical safety, pharmacokinetics and early evidence of activity of the oral IAPs inhibitor Debio 1143 in combination with carboplatin and paclitaxel: a phase Ib study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C2.

Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial

Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118. Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. Boehringer Ingelheim.

Doxorubicin and carboplatin trials in Tasmanian devils (Sarcophilus harrisii) with Tasmanian devil facial tumor disease

The devil facial tumor disease (DFTD) is having a devastating impact on Tasmanian devils (Sarcophilus harrisii) (devils) in the wild. Only a single study has been published regarding treatment of DFTD, where vincristine was not found to be an effective chemotherapeutic agent. In the current study, devils were treated with escalating dosages of carboplatin (8–26 mg/kg) (n = 13) and doxorubicin (0.75–1.0 mg/kg) (n = 5). Dosages for carboplatin (20 mg/kg) and doxorubicin (1.0 mg/kg) were identified as maximally tolerated dosages. Limiting toxicities for carboplatin were anorexia and weight loss (gastrointestinal signs) and azotemia. Limiting toxicities for doxorubicin were neutropenia, anorexia and weight loss. None of the treated devils responded to either drug, suggesting that, based on the clonality of this tumour, it is unlikely that either drug individually or in combination would be effective treatments for DFTD. These results, however, provide valuable information for practitioners who may choose to treat other neoplastic diseases in the devil or other marsupials. In addition, these results show that even drugs that are metabolized and excreted in the same manner can be tolerated to different degrees by the same species.

Abstract POSTER-THER-1410: Combining small molecule drugs and standard chemotherapy for treatment of granulosa cell tumour cells

Abstract Evasion of apoptosis is a hallmark of cancer, and direct induction of apoptosis without dependence on signaling upstream of Caspase-3 (CASP3) is an attractive target for cancer therapy. CASP3 sits at the hub of apoptotic pathways and it is a primary target for inhibition by anti-apoptotic proteins like the X-linked inhibitor of apoptosis (XIAP). Granulosa cell tumour (GCT) is a rare form of ovarian cancer, highly lethal in the event of recurrence, and has no standard chemotherapy because it is resistant to most common drugs. A recently discovered small-molecule drug, procaspase activating compound-1 (PAC1), has been shown to effectively cleave procaspase-3 into its active form by removal of an inhibitory zinc ion, facilitating autocleavage of the zymogen and direct induction of apoptosis. Initial in vitro experiments in our lab have shown PAC1 capable of significantly reducing viability of GCT cells (represented by the KGN cell line), and combining PAC1 with a drug inhibiting XIAP further increases the killing effect. In addition, combining the small-molecule XIAP inhibitor with carboplatin, a standard chemotherapy agent, displays significant drug interaction while killing GCT cells, in vitro. Results: GCT cell line KGN was treated with various concentrations of PAC1, for 24 and 48 hour time points, and assessed for cell viability using a metabolic assay. Results showed significant reduction of cell viability (p&amp;lt;0.05) in both time and dose-dependent manners. The dose-response curve for these assays indicate an EC50 of ~10 µM PAC1. High-content screening of PAC1-treated GCT cells produced quantified imagery that suggests treatment with PAC1 is, in fact, inducing activation of CASP3-mediated apoptosis and an assay inhibiting CASP3 displayed reduction in PAC1-induced killing. Combining 10 µM PAC1 with selected concentrations of embelin, a monovalent XIAP-inhibitor, showed strong additive effect in initial experiments, indicating it is an area worthy of further research. Combination of embelin with carboplatin also displayed significant drug interaction as well as single drug effect (p&amp;lt;0.05). This presentation suggests that PAC1 reduces viability of GCT cells in a time and dose-dependent manner, in vitro, and the mechanism of that loss of viability is caspase-mediated apoptosis. Furthermore, combining PAC1 with drugs that inhibit XIAP enhances the killing effect. Combining small molecule drugs that promote apoptosis display strong interaction with carboplatin, a standard chemotherapeutic agent, and may have the potential to allow carboplatin dose reduction. Further research to determine activity in animal models and/or primary human GCT explants is warranted and planned. Citation Format: Powel Crosley, Kate Agopsowicz, Michael Weinfeld, Mary Hitt. Combining small molecule drugs and standard chemotherapy for treatment of granulosa cell tumour cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1410.

Abstract 4457: Novel fatty-acid synthase inhibitor in combination with platinum-based therapy provides increased tumor killing efficacy in luminal breast murine model

Abstract While targeted therapies exist for Her2 and Luminal breast cancers there remains a subset of patients that would benefit from additional therapeutic options when refractory disease emerges. Independent previous studies have shown that Fatty acid synthase (FAS) can inhibit Her2 oncogene expression and has been shown to be effective as a therapeutic target in xenografts. In this abstract we provide evidence for the anti-tumor activity of a novel FAS inhibitor HS-106 in the Mouse mammary tumor virus (MMTV) driven transgenic mice expressing the Her2 rat analog Neu when combined with platinum-based chemotherapeutic agent Carboplatin. Single parous female MMTV-Neu mice (Jackson Labs Strain 002376) were used to test the efficacy of HS106 (15mpk, IP twice weekly) alone and in combination with Carboplatin (50mpk IP once weekly). Mice were monitored for tumor development by palpating them weekly as per UNC Lineberger Comprehensive Cancer Center's Mouse Phase I Unit (MP1U) protocol. Once tumors were observed, the mice were placed on treatment. The tumor-bearing mice were injected weekly with HS106 and/or Carboplatin. HS106 is dosed at 15 milligrams (mg) per 1 kilogram (kg) of mouse weight, using a solution of 5mg per 1 milliliter (ml) of solvent. The solvent for HS106 consists of 50% dimethyl sulfoxide (DMSO)and 50% saline (0.9% sodium chloride solution). Clinical grade Carboplatin was purchased from the UNC Hospital pharmacy. Tumor volume was measured at the time of injection by caliper and width (short diameter) and length (long diameter) in millimeters (mm) were recorded. The volume was calculated using the formula: length x width2 × 0.5. Body composition was assessed and weight measurements (in grams) were taken weekly at the time of injection were recorded and used to determine toxicity. After three weeks, tumor progression was calculated using the formula: (21 day volume - initial volume)/initial volume x 100. This percent change in tumor volume, at 21 days, was used to assess the objective response rate of the therapies. Objective Response Rate (Stable Disease, Partial Responses and Complete Responses) were noted in 7 of 8 mice treated with the combination of HS106 and Carboplatin (Mean tumor regression of 4.5%) compared to 3 of 9 in Carboplatin alone (Mean tumor progression of 103%). The combination was well tolerated with no deaths associated with toxicity The FAS inhibitor HS-106 provides a novel means to homogenize and increase the therapeutic response to Platinum-based therapeutic agents. Additional analyses are underway however pharmacokinetic data suggests that a more frequent dosing schedule could provide additional benefit. Further refinement of the dosing schedule for HS-106 may permit the reduction of Carboplatin dose, leading to lowering Carboplatin related toxicity and adverse effects. Citation Format: David Darr, Yazan Alwarawrah, Lucas Hunter, David Loiselle, Philip Hughes, Timothy Haystead. Novel fatty-acid synthase inhibitor in combination with platinum-based therapy provides increased tumor killing efficacy in luminal breast murine model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4457. doi:10.1158/1538-7445.AM2015-4457