Carboplatin In Treatment Research Articles

EP08.01-001 Update Analysis of Sintilimab With Two Cycles Chemotherapy for Untreated Advanced Squamous Non-small-Cell Lung Cancer

Most sq-NSCLC patients were aged, heavy somkers, with multiple comorbidities who were considered badly-tolerated to chemotherapy. We designed this multi-center, single arm, phase II study of sintilimab plus two cycles nab-paclitaxel /carboplatin in treatment naïve advanced squamous NSCLC patients, aimed to maximize the antitumor activities with less toxicity.

A Redox-active Mn Porphyrin, MnTnBuOE-2-PyP5+, Synergizes with Carboplatin in Treatment of Chemoresistant Ovarian Cell Line.

We have employed a redox-active MnP (MnTnBuOE-2-PyP5+, Mn(III) meso-tetrakis (N-n-butoxyethylpyridinium-2-yl) porphyrin) frequently identified as superoxide dismutase mimic or BMX-001, to explore the redox status of normal ovarian cell in relation to two ovarian cancer cell lines: OV90 human serous ovarian cancer cell and chemotherapy-resistant OV90 cell (OVCD). We identified that OVCD cells are under oxidative stress due to high hydrogen peroxide (H2O2) levels and low glutathione peroxidase and thioredoxin 1. Furthermore, OVCD cells have increased glycolysis activity and mitochondrial respiration when compared to immortalized ovarian cells (hTER7) and parental cancer cells (OV90). Our goal was to study how ovarian cell growth depends upon the redox state of the cell; hence, we used MnP (BMX-001), a redox-active MnSOD mimetic, as a molecular tool to alter ovarian cancer redox state. Interestingly, OVCD cells preferentially uptake MnP relative to OV90 cells which led to increased inhibition of cell growth, glycolytic activity, OXPHOS, and ATP, in OVCD cells. These effects were further increased when MnP was combined with carboplatin. The effects were discussed with regard to the elevation in H2O2 levels, increased oxidative stress, and reduced Nrf2 levels and its downstream targets when cells were exposed to either MnP or MnP/carboplatin. It is significant to emphasize that MnP protects normal ovarian cell line, hTER7, against carboplatin toxicity. Our data demonstrate that the addition of MnP-based redox-active drugs may be used (via increasing excessively the oxidative stress of serous ovarian cancer cells) to improve cancer patients' chemotherapy outcomes, which develop resistance to platinum-based drugs.

Metronomic oral vinorelbine doublet chemotherapy with carboplatin in treatment of advanced lung cancer: a feasibility and safety study

Background: Non-small cell lung cancer (NSCLC) is globally one of the most common forms of cancer. Palliative treatment is a delicate balance against toxicity and survival. Using small frequent doses of chemotherapy, metronomic regimens have been hypothesized to maintain or even improve efficacy while achieving a lower treatment-related toxicity. The mechanism is thought to result from a more continuous exposure of the tumour cells to the drugs. Treating NSCLC, this study addresses the feasibility and tolerability of carboplatin in combination with 12 weeks of daily metronomic vinorelbine. Method: Patients were included over a period of ten months. All patients had biopsy-verified incurable NSCLC and were candidates for first line chemotherapy (PD-L1<50% and no targetable mutations). This open label, non-randomized prospective safety and feasibility study was investigator initiated. Patients received up-to four cycles of standard dose carboplatin AUC 5 every third week in combination with 12 weeks of metronomic oral daily Navelbine® (20/30 mg). Patients were evaluated by CT scans after end of treatment and then every 8 weeks (+/- 1 week) until progression. Results: A total of 20 patients were included. Male/female-ratio was 4/16. Age ranged from 49-83 with a median of 70.5 years. Majority had adenocarcinoma (95%). Two patients withdrew their consent within a week. 18 patients were included in safety analysis. 13 received all four cycles. Grade 1/2 toxicity was frequently seen and included fatigue 13 (72%), diarrhoea 13 (72%), constipation/congestion 13 (72%). Grade 3 toxicities were dyspnoea 2 (11%), nausea 3 (17%) and fatigue 3 (17%). Two (11%) had grade 4 toxicity with neutropenic fever, both recovered. No grade 5 toxicity was detected. Conclusion: In treatment of NSCLC this study is the first addressing the regimen of carboplatin in combination with daily metronomic vinorelbine. We conclude that doublet chemotherapy with daily vinorelbine is safe and feasible.

Study on the Effect of Nano Albumin Paclitaxel Combined with Carboplatin in the Treatment of Lung Squamous Cell Carcinoma.

This study aims to compare the efficacy and side effects of albumin-binding paclitaxel plus carboplatin (NAB PC) and paclitaxel plus carboplatin (PC) in the first-line treatment of advanced non-small cell lung cancer (NSCLC). A total of 60 patients with advanced NSCLC diagnosed by histopathology or cytology were randomly divided into nab PC group (albumin-binding paclitaxel 130 mg/mL, D1, D; carboplatin AUC = 6, D1) and PC group (paclitaxel 175 mg/mL, D1; carboplatin AUC = 6, D1), one cycle every three weeks. RECIST 1.1 standard was used to evaluate the short-term objective efficacy, and who acute and subacute toxicity classification standard was used to evaluate the toxicity. The total effective rate (RR) and disease control rate (DCR) of NAB PC group were 40.0% and 80.0%, respectively, which were higher than 23.3% and 60.0% of the PC group, respectively. This difference was statistically significant (p < 0.05). In squamous cell carcinoma, the RR of NAB PC group and PC group were 57.1% (8/14) and 23.1% (3/13) respectively, with a statistically significant difference (p < 0.05); in non-squamous cell carcinoma, the RR of the two groups were 25.0% (4/16) and 23.3% (4/17) without statistical significance (p > 0.05). The median progression free survival time of the NAB PC group and PC group was 6.5 and 5.9 months, respectively, with no significant difference (p>0.05). No significant difference arose in the incidence of grade III-IV toxicity between the two groups (p > 0.05). The incidence of neutropenia in the NAB PC group was higher than that in the PC group (p < 0.05). The therapeutic effect of paclitaxel combined with carboplatin in the treatment of advanced NSCLC is better, the effect of paclitaxel combined with carboplatin is better, and the side effects can be tolerated, which is worthy of clinical application. Patients are more satisfied with their care.

A pilot study of docetaxel and carboplatin for treatment of patients with mCRPC containing biallelic inactivation of genes in the BRCA1/2 pathway.

127 Background: Despite new treatments, metastatic castration resistant prostate cancer (mCRPC) remains ultimately lethal. Upwards of 25% of mCRPC tumors have alterations in homologous recombination DNA repair (HRD) genes, most frequently BRCA2. Retrospective data suggest addition of the DNA damaging agent carboplatin to standard docetaxel for patients with mCRPC whose tumors have biallelic inactivation of BRCA2 may be effective. Methods: In this prospective, pilot single-arm phase 2 study, we assess response to the combination of docetaxel 60mg/m2 and carboplatin AUC 5 IV q21 days in patients with mCRPC whose tumors have evidence of biallelic inactivation of BRCA1, BRCA2 or ATM and have progressed after any prior treatment, including prior docetaxel and/or PARP inhibitor (PARPi). The primary endpoint is rate of ≥50% PSA decline from baseline (PSA50). With H0 of PSA50 of 26%, 14 patients will provide 80% power to conclude H1 of PSA50 of 60% based on Simon's 2-stage design with 1-sided α = 5%. Secondary endpoints include PSA30, response duration, time to progression and correlative studies. Biallelic inactivation of other HRD-related genes were included at investigators’ discretion. Results: The study opened in Jan 2016 and has enrolled 8/14 (57%) of patients plus 5 patients with other HRD-related genes. 6/13 (46%) treated pts had grade 3 expected AEs, and no grade 4-5 AEs were observed. To date, 7/8 (88%) of pts with biallelic inactivation of BRCA1, BRCA2 and ATM (Table) and 10/13 (77%) of all pts achieved a PSA50 (other HRD-related genes include CDK12, CHD1, MRE11A and PALB2). Updated results will be reported at final presentation. Conclusions: Addition of carboplatin to docetaxel appears to be well-tolerated and effective for patients with mCRPC whose tumors have biallelic inactivation in selected HRD genes such as BRCA2, including those with prior treatment with PARP inhibitor. Clinical trial information: NCT02598895. [Table: see text]

PEGylated poly(amidoamine) dendrimers-based drug loading vehicles for delivering carboplatin in treatment of various cancerous cells

The fourth generation (G4) of poly(amidoamine) dendrimer was PEGylated and then physically incorporated with carboplatin to develop the new drug delivery carrier. The proton nuclear magnetic resonance (1H NMR) and Fourier-transform infrared spectroscopy (FTIR) were utilized to confirm the successful synthesis and incorporation. The PEGylation leads to increase the particle dimension of G4 dendrimer to 4.04 to 30.67 nm that was still in the effective range for killing cancerous cells. The cytotoxicity on L929 fibroblasts demonstrated that the PEGylation of G4 could eliminate the toxic caused by amine surrounding groups of G4. Three cancerous cells including the cervical cancer cell line (HeLa), the adenocarcinomic human alveolar basal epithelial cells (A549), and the human breast cancer cell line (MCF7) were treated with G4-PEG@CAR as a function of CAR concentrations. The results of resazurin test and live/dead assay indicated that the killing effect of G4-PEG@CAR on three representative cells were achieved and increased following the enhancement of CAR concentration. Furthermore, the better effectiveness of G4-PEG@CAR was achieved on Hela.

Treatment of metastatic melanoma with pazopanib: A report of five patient cases

Metastatic melanoma has a median length of survival after diagnosis of 6-9 months. Unfortunately, the National Comprehensive Cancer Network clinical practice guidelines for treating stage IV, unresectable, metastatic melanoma are limited with regard to treatment options. Pazopanib (Votrient™) is FDA-approved for advanced soft tissue sarcoma and advanced renal cell carcinoma. Limited research exists for using pazopanib in the treatment of metastatic melanoma. We present five cases in which pazopanib was used in combination with paclitaxel ± carboplatin for treatment of unresectable, metastatic melanoma.

An audit of adjuvant carboplatin in patients with stage I testicular seminoma (Anglian Germ Cell Cancer Group, UK).

366 Background: Patients with stage I testicular seminoma can be managed by surveillance or treated with adjuvant radiotherapy or chemotherapy. Concerns of second malignancies induced by radiotherapy have led to a preference for adjuvant chemotherapy. The TE19 trial demonstrated the non-inferiority of a single cycle of carboplatin, given within 8 weeks of orchidectomy, to adjuvant para-aortic radiotherapy in terms of reduction in recurrence rate. This study also suggested a lower relapse rate if GFR estimation was radionuclide based. Methods: A review of case records of germ cell tumor patients within the Anglian Germ Cell Cancer Group between 10/01/2005 and 31/12/2012 was conducted to identify patients with stage I testicular seminoma who received a single cycle of adjuvant carboplatin. Tumor characteristics, clinical management, and patient outcomes were assessed. Results: A total of 336 patients with stage I seminoma who received adjuvant carboplatin were identified. The median age of diagnosis was 38 (range 21 to 78). Median tumor size was 40mm. The rete testis was involved in 131 cases (39%). A radionuclide based estimation of GFR was used in 318 patients (94.6%), the remaining patients GFR was estimated by the Cockcroft-Gault equation. The median time from orchidectomy to receiving chemotherapy was 46 days. Of the 336 patients, 22 relapsed (6.5%), with nine relapsing after 2 years (seven between 24 and 36 months, and wo after 36 months). The median time to relapse was 18 months. There was a trend towards lower progression free survival in patients whose chemotherapy was dosed based on GFR estimation by the Cockcroft-Gault equation. All relapsed patients were successfully treated with combination chemotherapy. Conclusions: These results demonstrate a higher rate of relapse for stage I seminoma patients treated with adjuvant carboplatin compared with the published data from the TE19 study. In addition they confirm that adjuvant carboplatin for treatment of stage I testicular seminoma leads to excellent outcomes in terms of long-term cure. The use of radionuclide based estimation of GFR is advised. Relapses beyond 2 years are not rare and routine cross-sectional imaging beyond this point should be considered.

Cyclooxygenase Inhibitor Associated with Carboplatin in Treatment of Metastatic Nasal Carcinoma in Dog

A 10-year-old, intact male, pinscher was presented with unilateral bloodstained nasal discharge, sneezing, dyspnea, zygomatic arch deformity, submandibular lymph node increase, blindness in right eye, and exophthalmia. After clinical examination, it was found that the animal presented with upper respiratory tract dyspnea origin, possibly caused by an obstructive process. Complete blood count (CBC), ocular ultrasonography, thoracic radiographs, mandibular lymph node, and nasal sinus fine needle aspiration were performed. The right mandibular lymph node excisional biopsy was conducted and a tumor sample was obtained through the nasal fistula at hard palate. The material was processed, paraffin embedded, sectioned, and stained with hematoxylin and eosin. Immunohistochemical staining for cytokeratin (AE1/AE3), vimentin, and COX-2 was performed. After histopathological evaluation nasal carcinoma diagnosis was obtained. Chemotherapy was established with carboplatin 300 mg/m2intravenously—four cycles with intervals of 21 days—and firocoxib 5 mg/kg orally every 24 hours for 7 months. After 7 months the treatment started, the animal presented with ataxia, vocalization, hyperesthesia, and anorexia. Due the clinical condition presented, the animal owner opted for performing euthanasia. The chemotherapy protocol was effective causing the disease stagnation, minimizing the clinical signs, and extending patient survival and quality of life.

Potent therapeutic activity of folate receptor-targeted liposomal carboplatin in the localized treatment of intraperitoneally grown human ovarian tumor xenograft

Intraperitoneal (IP) therapy with platinum (Pt)-based drugs has shown promising results clinically; however, high locoregional concentration of the drug could lead to adverse side effects. In this study, IP administration was coupled with a folate receptor-targeted (FRT) liposomal system, in an attempt to achieve intracellular delivery of the Pt-based drug carboplatin in order to increase therapeutic efficacy and to minimize toxicity. In vitro and in vivo activity of FRT carboplatin liposomes was compared with the activity of free drug and nontargeted (NT) carboplatin liposomes using FR-overexpressing IGROV-1 ovarian cancer cells as the model. Significant reduction in cell viability was observed with FRT liposomes, which, compared with the free drug, provided an approximately twofold increase in carboplatin potency. The increase in drug potency was correlated with significantly higher cellular accumulation of Pt resulting from FRT liposomal delivery. Further evaluation was conducted in mice bearing intraperitoneally inoculated IGROV-1 ovarian tumor xenografts. A superior survival rate (five out of six animals) was achieved in animals treated with FRT carboplatin liposomes, injected intraperitoneally with a dose of 15 mg/kg and following a schedule of twice-weekly administration for 3 weeks. In contrast, no survivors were observed in the free drug or NT carboplatin liposome groups. The presence of cancer cells in lung and liver tissues was observed in the saline, free carboplatin, and NT carboplatin liposome groups. However, there was no sign of cancer cells or drug-related toxicity detected in tissues from the animals treated with FRT carboplatin liposomes. The results of this study have demonstrated for the first time that the approach of coupling IP administration with FRT liposomal delivery could provide significantly improved therapeutic efficacy of carboplatin in the treatment of metastatic ovarian cancer.

Pharmacokinetics of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in cerebrospinal fluid (CSF) of a patient with breast cancer with carcinomatous meningitis.

e13559 Background: Triple-negative breast cancer (TNBC) carries a high risk for brain metastasis and is associated with poor survival. A key role has emerged for PARP1 in the repair of DNA damage, particularly in cancers associated with BRCA1 dysfunction, including TNBC. BSI-201, a small molecule inhibitor of PARP1, has demonstrated significant antitumor activity when added to gemcitabine and carboplatin in treatment of metastatic TNBC. BSI- 201 was provided through a single patient IND to a patient with metastatic TNBC who developed carcinomatous meningitis as the only site of initial relapse. Methods: The patient had an Omaya reservoir inserted to facilitate intrathecal (IT) chemotherapy. The patient received IT methotrexate, which was switched to liposomal-cytarabine due to arachnoiditis. The patient received BSI-201 (5.6 mg/kg IV, biweekly) throughout IT treatment. CSF was sampled via the Omaya reservoir, and BSI-201 and its metabolites were measured prior to dosing and up to 2 hours post-infusion. Results: BSI-201 exposure in the CSF was ∼120 ng/mL at end-of-infusion. BSI-201 was rapidly eliminated from the CSF (t1/2 ∼ 10 min), with a longer-lived metabolite (t1/2 ∼ 21min). Overall exposure of the CNS was estimated to be ∼8% of the total systemic AUC for BSI-201, and Cmax in CSF was ∼7.5% of plasma Cmax. The patient responded to treatment for 5 months before developing disease progression in the bone and a second primary breast cancer. The burden of tumor cells in the CSF was reduced by > 95% throughout treatment. No evidence of systemic or neurologic toxicity from BSI-201 beyond what is normally observed with chemotherapy occurred. Conclusions: BSI-201 and its key metabolites cross the blood-brain barrier with BSI-201 AUC and Cmax in CSF of ∼10% of plasma values. This observation provides a basis for further examination of the role of BSI-201 in the treatment of this metastatic complication. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration BiPar Sciences

Efficacy of docetaxel plus carboplatin combination chemotherapy for advanced non-small cell lung cancer

Chemotherapy is one of the important treatment methods for advanced non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the efficacy of docetaxel combined with carboplatin in treatment of advanced NSCLC. Sixty-four stage IIIB/IV NSCLC patients were treated with docetaxel (75 mg/m² intravenously, on day 1) and carboplatin (AUC=5 intravenously, on day 2). The overall response rate (RR) was 42.6%, median survival time (MST) was 14 months, and 1-year survival rate was 45.23%. In initial treatment group, 1-year survial rate was 48.84% and MST was 14 months, and 37.89% and 12 months respectively in retreatment group (P=0.0233). The 1-year survial rate and MST of stage IIIB patients were 44.86% and 15 months, and 39.75% and 12 months respectively in stage IV patients (P=0.0354). There was no significant difference in efficacy between squamous cell carcinoma and adenocarcinoma patients. The major adverse effects were granulopenia, fatigue, nausea, vomiting and alopecia. The combination of docetaxel and carboplatin has a high response rate and tolerable side effects in treatment of advanced NSCLC, which can be adopted as both the first-line and second-line treatment.

Phase II study on the combination carboplatin-celecoxib in heavily pre-treated recurrent ovarian carcinoma patients

15009 Background: Cyclooxygenase-2 (COX-2) has been shown to be involved in several steps of ovarian onset and progression and its overepression is associated with a poor chance of response to chemotherapy and poor prognosis in ovarian cancer. Celecoxib, an orally active selective COX-2 inhibitor, has been tested for its ability to potentiate the activity of carboplatin in treatment of heavily pretreated recurrent ovarian cancer patients. Methods: A phase II study was planned, considering the regimen active if at least 12 responses were observed among the 43 enrolled patients. Celecoxib (400 mg/die), and carboplatin (5 AUC) q28 were administered, until progression or unacceptable toxicity. Response was assessed by RECIST and also by Rustin criteria. Results: 34 pts (median age: 60 yrs, range 28–74) and an ECOG performance status (0/1/2) of (21/12/1), were enrolled. 58.8% of patients were platinum resistant (progressing during or &lt; 6 months from primary treatment). Median number of previous chemotherapy regimens was 3 (range 2–6). Currently 27 patients are evaluable for response. The overall response rate (CR and PR) was 25.9% (2 CR, 5 PR) with stabilization of disease in 8 patients (29.6%). Four responses occurred in platinum sensitive and 3 in platinum resistant group Median time to response was 11 weeks (range 9–19) and median duration of response was 23 weeks (range 12–39). According to Rustin criteria 10 patients out of 25 (40%) were considered responsive to treatment (return of CA125 levels to normal level or &gt;50% reduction). Overall, 143 cycles were administered with a median value of 3 cycles (range = 1–10). Moderate/severe toxicities were as follows: G3 anemia occurred in 2.3% cycles, G3 neutropenia in 4.6% cycles, G3 thrombocytopenia in 1.5% cycles, G3/4 gastrointestinal toxicity occurred in 4.6% cycles. Cutaneous diffuse erithema was observed in 2 patients, in both cases recovered with a short period of antihistaminic treatment; 2 cases of hypertension were documented, G2 hypersensitivity reactions during carboplatin infusion were observed in 4 cases. Conclusions: Celecoxib combined with carboplatin is well tolerated and has promising activity as salvage treatment in heavily pretreated recurrent ovarian cancer patients. No significant financial relationships to disclose.

Superselective intra-arterial carboplatin for treatment of intracranial neoplasms: experience in 100 procedures.

The results of animal studies suggest that superselective intra-arterial infusion allows the permeation of a high concentration of chemotherapeutic agents within intracranial neoplasms. In the present report, we review our clinical experience with the 100 intra-arterial infusions of carboplatin in intracranial neoplasms not responsive to other treatment modalities. Carboplatin was infused in 100 separate sessions (24 patients) as a mean dose of 286+/-60 mg/m2 (range 34-377 mg/m2). RMP-7, a bradykinin analog, was used as an adjunct in 28 sessions (6 patients). The infusions were performed through superselective microcatheterization of the following arteries: internal carotid (n = 39), middle cerebral (n = 61), posterior cerebral (n = 21) and anterior cerebral (n = 10). The frequency of neurological and non-neurological complications, and survival were recorded. In a subset of 10 patients, tumor volume was measured by serial magnetic resonance images to assess therapeutic response to therapy. The mean age of the patients was 44.5 years (range 26-67 years); 13 were men. The tumors were classified as glioblastoma multiforme (n = 12), metastatic tumor (n = 1), high-grade astrocytoma (n = 6), and anaplastic mixed glioma (n = 5). Follow-up was available for 23 patients (mean 22 months, range 2-69 months). Survival beyond 1 year after initiation of intra-arterial carboplatin therapy was documented in 12 of the 23 patients. A total of 13 neurological complications including seizures (n = 7), transient neurological deficits (n = 5), and ischemic stroke (n = 1) were observed in 100 procedures. A lower frequency of complications occurred in men and in patients who received adjunctive RMP-7. Volumetric analysis of serial magnetic resonance images demonstrated tumor mass reduction in 3 out of 10 patients. An increase in tumor mass ranging from 23% to 230% was observed in the other 7 patients over a period ranging from 2.3 to 37.7 months since initiation of carboplatin therapy. Superselective intra-arterial administration of carboplatin appears feasible and was associated with predominantly transient neurological complications. The addition of RMP-7 to carboplatin therapy appears to be at least as safe as the administration of carboplatin alone and requires further investigation as a means of chemotherapeutic dose intensification.

Carboplatin in treatment of patients with bronchogenic carcinoma: Skrickova J, Vorlicek J, Adam Z, Kralovcova D, Hejlova N, Tomiska M et al. Nemocnice Tuberkul. a Resp. Nemoci, NsP Brno-Venkov, Babice nad Svitavou. Klin Onkol 1995;8:16–19

Carboplatin in treatment of patients with bronchogenic carcinoma: Skrickova J, Vorlicek J, Adam Z, Kralovcova D, Hejlova N, Tomiska M et al. Nemocnice Tuberkul. a Resp. Nemoci, NsP Brno-Venkov, Babice nad Svitavou. Klin Onkol 1995;8:16–19