paywalled: Epigenetic Resensitization to Platinum in Ovarian Cancer (low-dose decitabine/carboplatin)

Epigenetic Resensitization to Platinum in Ovarian Cancer
  
 "Together, the results of this study suggest that low-dose decitabine altered DNA methylation of genes and cancer pathways, restoring sensitivity to carboplatin in patients with heavily pretreated ovarian cancer and resulting in a high RR and prolonged PFS."

Abstract

Preclinical studies have shown that hypomethylating agents reverse platinum resistance in ovarian cancer. In this phase II clinical trial, based upon the results of our phase I dose defining study, we tested the clinical and biologic activity of low-dose decitabine administered before carboplatin in platinum-resistant ovarian cancer patients. Among 17 patients with heavily pretreated and platinum-resistant ovarian cancer, the regimen induced a 35% objective response rate

Medscape: Bevacizumab Benefits Patients With Recurrent Ovarian Cancer (bevacizumab plus carboplatin and gemcitabine followed by bevacizumab)

Bevacizumab Benefits Patients With Recurrent Ovarian Cancer

Add-on bevacizumab slows progression of recurrent ovarian cancer - - ModernMedicine

Add-on bevacizumab slows progression of recurrent ovarian cancer - - ModernMedicine


(from Reuters) "....Dr. Aghajanian and colleagues note that overall survival data from the trial are not yet available; information on clinicaltrials.gov indicates a predicted study completion date of October 2013.
For now, say the researchers, "The data from OCEANS demonstrate that the addition of BV (bevacizumab) to GC (gemcitabine and carboplatin) can improve outcomes, and ongoing studies will assess whether this ability to add benefit is universal to other platinum-based combinations."
OCEANS is supported by Genentech, which markets bevacizumab as Avastin.

Carboplatin/Taxol/Ridaforolimus in Endometrial, Ovarian and Solids - Full Text View - ClinicalTrials.gov

Carboplatin/Taxol/Ridaforolimus in Endometrial, Ovarian and Solids - Full Text View - ClinicalTrials.gov

This study is currently recruiting participants.

Verified April 2012 by H. Lee Moffitt Cancer Center and Research Institute

First Received on December 1, 2010.   Last Updated on April 20, 2012   History of Changes

abstract: Effects on the immune system and toxicity of carboplatin/paclitaxel combination chemotherapy in patients with stage III-IV ovarian and non small cell lung cancer and its role in survival and toxicity.

 
Effects on the immune system and toxicity of carboplatin/paclitaxel combination chemotherapy in patients with stage III-IV ovarian and non small cell lung cancer and its role in survival and toxicity.


Abstract
 
Purpose:
To examine the impact of paclitaxel and carboplatin combination chemotherapy on the parameters of the immune system in patients with non small cell lung cancer (NSCLC) and with ovarian cancer before, during and after chemotherapy, and the effect of this combination on the overall patient survival.

Methods:
24 patients with NSCLC and 20 with ovarian cancer (all in stage IIIb-IV) treated with 6 courses of paclitaxel and carboplatin combination chemotherapy were separated into two groups according to their survival group A: long survival (> 12 months for NSCLC; > 30 months for ovarian cancer) group B: short survival (<12 months for NSCLC; <30 months for ovarian cancer).

At the same time we studied some immunological parameters (CD3, CD4, CD8, CD56, CD34, IL-3, IFN-γ) in relation with the induced toxicity during chemotherapy. The results were analysed using the ANOVA method.

Results: 
We observed a statistically significant difference of CD4 and CD4/CD8 after chemotherapy between groups A and B (p<0.001 and p< 0.006 respectively), implying that the further increase of T-helper cells after chemotherapy had a positive impact on survival. In addition, statistically interesting was the difference in values of IFN-γ between patients of groups A and B before and after chemotherapy (p< 0.039 and p< 0.027, respectively). Patients with high IL-3 had little chance of toxicity.

Conclusion:
Our findings support that with carboplatin/ paclitaxel combination chemotherapy, important parameters of the immune system (IFN-γ, CD4, CD4/CD8) can be used as prognostic factors for survival, while others (IL-3) as indicators of toxicity.

abstract: A phase II evaluation of belinostat and carboplatin in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal carcinoma: A gynecologic oncology group study

A phase II evaluation of belinostat and carboplatin in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal carcinoma: A gynecologic oncology group study:

Background
Patients with recurrent ovarian cancer have limited options, especially in the context of relapse less than six months from primary platinum-based therapy. This Gynecologic Oncology Group (GOG) study was conducted to evaluate the impact of the histone deacetylase inhibitor, belinostat, in combination with carboplatin in women with platinum-resistant ovarian cancer.

Methods 
Eligible patients had measurable, recurrent disease within six months of their last dose of a platinum-based combination. Belinostat was dosed at 1000mg/m² daily for five days with carboplatin AUC 5 on day three of 21-day cycles. The primary endpoint was overall response rate (ORR), using a two-stage design.

Results
Twenty-nine women enrolled on study and 27 were evaluable. The median number of cycles given was two (range 1–10). One patient had a complete response and one had a partial response, for an ORR of 7.4% (95% CI, .9%–24.3%). Twelve patients had stable disease while eight had increasing disease. Response could not be assessed in five (18.5%). Grade 3 and 4 events occurring in more than 10% of treated patients were uncommon and limited to neutropenia (22.2%), thrombocytopenia (14.8%), and vomiting (11.1%). The median progression-free survival (PFS) was 3.3months and overall survival was 13.7months. PFS of at least six months was noted in 29.6% of patients. Due to the lack of drug activity, the study was closed after the first-stage.

Conclusions 
The addition of belinostat to carboplatin had little activity in a population with platinum-resistant ovarian cancer.

abstract: Regimens with intraperitoneal cisplatin plus intravenuous cyclophosphamide and intraperitoneal carboplatin plus intravenuous cyclophosphamide are equally effective in second line intraperitoneal chemotherapy for advanced ovarian cancer.

Regimens with intraperitoneal cisplatin plus intravenuous cyclophosphamide and intraperitoneal carboplatin plus intravenuous cyclophosphamide are equally effective in second line intraperitoneal chemotherapy for advanced ovarian cancer.:


Abstract
Purpose:
We compared response, survival and side effects of regiments with intravenous cyclophosphamide followed by intraperitoneal cisplatin versus intravenous cyclophosphamide followed by intraperitoneal carboplatin as second line treatment in one center retrospective study.

Material and Methods:
Inclusion criteria were: relapse or recurrence of the disease after surgery and first line treatment; stage III histologicaly documented serous epithelial ovarian cancer after one or more prior regiments of chemotherapy. Recurrence were confirmed throughout restaging laparotomy or second look laparotomy. Patients from one of the groups received 90mg/m2 cisplatin on the first day and 750mg/m2 cyclophosphamide intravenously, while the second group members AUC 6 carboplatin intraperitoneally and 750mg/m2 cyclophosphamide intravenously. Four courses were administrated for each patient.

Results: 

Of the 49 patients in the cisplatin group the response rates were 21 (43%), 10 (20%) and 18 (37%) in the groups of pathologic complete response, pathologic partial response and progressive disease, respectively. The median survival from the initiation of intraperitoneal chemotherapy was 59 months.

Of the 25 patients in the carboplatin group the response rates were 10 (40%), 4 (16%) and 11 (44%) respectively. The median survival -51 months.

The differences between the groups were not statistically significant p 0.05 either in response or in toxicity.

Conclusions: 
The results of our research including relatively long survival from intraperotoneal chemotherapy initiation confirm that carboplatin treatment is as good as cisplatin in second line intraperitoneal chemotherapy for ovarian cancer.

abstract: Predictors of severe and febrile neutropenia during primary chemotherapy for ovarian cancer

Predictors of severe and febrile neutropenia during primary chemotherapy for ovarian cancer.


Abstract

OBJECTIVE: 
To identify factors that increase the risk of neutropenic events in women with advanced ovarian carcinoma receiving initial chemotherapy.

METHODS: 
Multi-center retrospective study of women with FIGO stage III-IV epithelial ovarian cancer treated postoperatively with multi-agent intravenous chemotherapy 1995-2008.......

CONCLUSION:
While SN is fairly common, FN occurs infrequently in women with EOC undergoing taxane and platin-based chemotherapy and primary prophylactic growth factor support is not indicated. However, women older than 60 years of age receiving non-carboplatin containing regimens are at higher risk for FN and warrant closer surveillance.

A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study

A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study


Objective 
To define the maximum tolerated dose (MTD) and assess the feasibility of intravenous (IV) paclitaxel, intraperitoneal (IP) carboplatin, and IP paclitaxel in women with newly diagnosed Stages II–IV ovarian, fallopian tube, or primary peritoneal carcinoma.

Methods 
Patients received escalating doses of paclitaxel IV and carboplatin IP on day 1 and paclitaxel IP 60mg/m² on day 8. A standard 3+3 design was used in the escalation phase. A two-stage group sequential design with 20 patients at the MTD was used in the feasibility phase. Patient-reported neurotoxicity was assessed pre and post treatment.

Results 
Patients were treated with paclitaxel 175mg/m² IV and carboplatin IP from AUC 5–7 on day 1 and paclitaxel 60mg/m² IP on day 8. The MTD was estimated at carboplatin AUC 6 IP and 25 patients enrolled at this dose level. Within the first 4cycles, seven (35%) of twenty evaluable patients had dose-limiting toxicities (DLTs) including grade 4 thrombocytopenia (1), grade 3 neutropenic fever (3), >2week delay due to ANC recovery (1), grade 3 LFT (1), and grade 3 infection (1). De-escalation to paclitaxel 135mg/m² IV was given to improve the safety. After six evaluable patients completed 4 cycles without a DLT, bevacizumab was added and six evaluable patients completed 4cycles with one DLT (grade 3 hyponatremia).

Conclusions 
Paclitaxel at 175mg/m² IV, carboplatin AUC 6 IP day 1 and paclitaxel 60mg/m² IP day 8 yield 18–56% patients with DLTs. The tolerability of the regimen in combination with bevacizumab was indicated in a small cohort.

abstract: Phase I clinical and pharmacokinetic study of trabectedin and carboplatin in patients with advanced solid tumors (including OC)

Phase I clinical and pharmacokinetic study of trabectedin and carboplatin in patients with advanced solid tumors.

Investigational new Drugs [2012, 30(2):616-28]

Purpose
This study intended to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RD) of trabectedin combined with carboplatin in patients with advanced solid tumors.

Patients and methods
Carboplatin-pretreated patients received carboplatin AUC 4 (Group 1), whereas carboplatin-naïve patients received carboplatin AUC 5 (Group 2) as a 1-h i.v. infusion followed by trabectedin at dose range from 0.5-1.2 mg/m(2) in the schedule of 3-h/every-3-weeks. Pharmacokinetic (PK) sampling was performed in the first 2 cycles.

Results
Forty-four patients were treated and evaluable for safety and dose-limiting toxicities (DLTs). In Group 1, at trabectedin 1.0 mg/m(2), cumulative hematological toxicity was found in all patients and 1/10 patients had DLTs. The RD was considered trabectedin 0.8 mg/m(2) combined with carboplatin AUC 4. Although no DLT occurred at this dose level, frequent dose delays (28.6%) and the 4-week cycle re-scheduling (66.7%) were required. In Group 2, DLTs occurred at trabectedin 0.8 mg/m(2) (3/8 patients), 1.0 mg/m(2) (3/10 patients) and 1.2 mg/m(2) (2/2 patients) with cumulative hematological toxicity associated with an important number of transfusions. In this group, neither the MTD nor the RD were established. Promising antitumor activity was found for this carboplatin/trabectedin combination; especially in patients with advanced ovarian cancer and soft tissue sarcoma. No significant PK drug-drug interaction occurred.

Conclusions
This study established a trabectedin dose of 0.8 mg/m(2) combined with carboplatin AUC 4 and given every 4 weeks as the most feasible schedule in carboplatin-pretreated patients. Dose and cycle recommendations for carboplatin-naïve patients warrant further evaluation.

abstract: Health-related quality of life in recurrent platinum-sensitive ovarian cancer—results from the CALYPSO trial

Background: In the CALYPSO trial, carboplatin–pegylated liposomal doxorubicin (CD) demonstrated superior therapeutic index versus carboplatin–paclitaxel (CP) in patients with recurrent ovarian cancer. This paper reports the health-related quality of life (HRQoL) findings.

Conclusions: These patient-reported outcomes confirm the overall lower toxicity of CD versus CP. The improved disease-related outcomes achieved with CD were not at the expense of QoL.

A Risk-Adapted Strategy of Adjuvant Paclitaxel/Carboplatin in Early-Stage Ovarian Cancer: Time-Dependent Effect of 4 versus 6 Cycles on Outcome.

Abstract

Objective:
We investigated the efficacy of risk-adapted adjuvant paclitaxel/carboplatin chemotherapy in early-stage ovarian carcinoma.

Methods: Fifty-three patients were treated according to the risk of relapse: patients with stages IA or IB or with grade 1 (low risk) received 4 cycles of paclitaxel and carboplatin; patients with IC/IIA and grade 2 or 3 (high risk) received 6 cycles of chemotherapy. The outcome was compared with that of 95 patients who were all treated with 4 cycles.

Results: Median follow-up was 88, 113 and 42 months for the whole cohort, non-risk-adapted and risk-adapted treatment, respectively.

Five-year relapse-free and disease-specific survival was 86 and 93% for the whole population, 96 and 97% for low-risk and 81 and 91% for high-risk patients.

Risk classification was the only significant prognostic factor for relapse-free (p = 0.011) and disease-specific survival (p = 0.039). Among high-risk patients, the administration of 6 cycles was associated with a significantly lower relapse rate after censoring events, which occurred beyond 2 years (3 vs. 18%; p = 0.013), but this difference was diminished at 5 years (23 vs. 25%; p = 0.797).

Conclusions: Six cycles of chemotherapy reduced the risk of relapse within 2 years, but the benefit from two additional cycles beyond this time is questionable.

currently recruiting: Intraperitoneal Therapy For Ovarian Cancer With Carboplatin Trial - Full Text View - ClinicalTrials.gov

Intravenous/Intraperitoneal Paclitaxel and Intraperitoneal C... : International Journal of Gynecological Cancer

Objective:
This study aimed to evaluate intravenous (IV)/intraperitoneal (IP) paclitaxel and IP carboplatin (TCipTip therapy) feasibility in epithelial ovarian (EOC), fallopian tube (FTC), or peritoneal carcinoma (PC) patients.


Methods:
From December 2007 to August 2010, 20 women with histologically confirmed stage IC to IV EOC, FTC, or PC.....

Phase II Study of Docetaxel Weekly in Combination With Carboplatin Every 3 Weeks as First-Line Chemotherapy in Stage IIB to Stage IV Epithelial Ovarian Cancer

 Objectives: 
The purpose of this study was to assess the response rate, toxicity, progression-free survival, and overall survival in a series of patients with advanced-stage ovarian carcinoma treated with a first-line weekly docetaxel and 3 weekly carboplatin regimen.
 
Conclusions:
The tolerable hematologic toxicity (no need for colony-stimulating factors) and the low rate of neurotoxicity (only grades 1–2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgery make this regimen an interesting alternative in selected patients.

A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study

Highlights

► The maximum tolerated dose and feasibility of IV and IP chemotherapy was assessed.
► The dose limiting toxicity rate for Paclitaxel 175 mg/m² IV, carboplatin AUC 6 IP and paclitaxel IP was 35%.

Combination of two drugs (carboplatin/decitabine) 'can treat ovarian cancer' | International Federation of Gynecology and Obstetrics

Decitabine (duh-sye-tuh-bean)

Trade/other name(s): Dacogen


"...Experts from Indiana University (IU) noted that carboplatin and decitabine, when combined, has a positive effect on the majority of late-stage ovarian cancer patients, even if they had previously developed a resistance to carbolplatin....Further studies will now be conducted to determine whether the drug combination can be rolled out on a wide scale."

Abstract/full free access: Sustained platelet-sparing effect of weekly low dose paclitaxel allows effective, tolerable delivery of extended dose dense weekly carboplatin in platinum resistant/ refractory epithelial ovarian cancer

abstract: Cost-effectiveness of combination versus sequential docetaxel and carboplatin for the treatment of platinum-sensitive, recurrent ovarian cancer

CONCLUSIONS:

Combined weekly cDC (concurrent docetaxel and carboplatin) appeared to be cost-effective compared with sDC (sequential docetaxel and carboplatin ) as treatment strategy for patients with platinum-sensitive ovarian cancer, even when accounting for slightly lower QoL during treatment.

PharmaLive: Topotarget Announces Updates on Belinostat in Two Clinical Trials - NSCLC and Ovarian Cancer (negative study ovarian/Belinostat/Carboplatin)

Ovarian cancer – GOG 0126-T (NCI-driven study)

Preliminary analysis of GOG 0126-T trial has not shown enough activity to enter into second stage. Consequently the study will be ended.

The study

The study is an open-label single-arm phase II trial with belinostat in combination with carboplatin given to patients with ovarian cancer who progress during or shortly after first-line treatment with platinum containing chemotherapy. The trial is sponsored by the GOG with support from the NCI. Belinostat is administered as a 30-minute daily IV infusion on day one through five with carboplatin being administered on day three. Treatment is given every third week and is repeated until disease progression......