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.

Medical News: ECCO-ESMO: Spikes in Liver Enzymes Common in Ovarian Cancer Tx (Trabectedin / Yondelis)

Action Points

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• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.



• Explain that liver transaminase abnormalities in patients with advanced ovarian cancer who received trabectedin did not impact outcomes, including response rate.



• Note that liver transaminase abnormalities were seen in 63% of patients studied.

abstract: The activity of trabectedin (Yondelis)as a single agent or in combination with everolimus for clear cell carcinoma of the ovary

Note: in research (lab)

NICE Unable To Recommend Ovarian Cancer Drug In Final Guidance Due To Lack Of Appropriate Evidence (trabectedin (Yondelis)

Docetaxel plus trabectedin appears active in recurrent or persistent ovarian and primary peritoneal cancer after up to three prior regimens: A phase II study of the Gynecologic Oncology Group

CONCLUSIONS: This combination was well tolerated and appears more active than the historical control of single agent taxane therapy in those with recurrent ovarian and peritoneal cancer after failing multiple lines of chemotherapy. Further study is warranted

full free access: New developments in treatment of ovarian carcinoma: focus on Trabectedin

Note: click on 'pdf' for full free access to paper

Trabectedin (Yondelis) plus pegylated liposomal doxorubicin in relapsed ovarian cancer delays third-line chemotherapy and prolongs the platinum-free interval (full access)

Trabectedin (Yondelis) plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 6–12 months) subpopulation of OVA-301 phase III randomized trial — Ann Oncol (full free access)

repost: abstract: (Yondelis) Trabectedin Plus Pegylated Liposomal Doxorubicin in Recurrent Ovarian Cancer. BJ Monk et al

Note: Reposted from June 9th to coincide with Editorial from JCO; multinational study plus: JCO link

Regulator to reject ovarian cancer treatment approve Trabectedin (Yondelis)

18th June 2010 - The health regulator, "The National Institute for Health and Clinical Excellence (NICE), says a new treatment for ovarian cancer is not recommended for the NHS because the manufacturer did not submit sufficient evidence that the medication benefits patients more than the most widely-used treatments.

NICE is appraising trabectedin (Yondelis) in combination with pegylated liposomal doxorubicin (PLDH) for the treatment of relapsed ovarian cancer that is sensitive to platinum-based therapies.

Its independent advisory found that the evidence submitted by the manufacturer was not robust because it did not compare trabectedin against a current ‘gold-standard’ treatment for relapsed ovarian cancer: paclitaxel in combination with platinum-based chemotherapy. This meant NICE couldn’t confirm whether or not the treatment extends patients’ lives for longer than one of the more effective and commonly-used treatments...."

Trabectedin Plus Pegylated Liposomal Doxorubicin in Recurrent Ovarian Cancer. (multinational study)

Note: Trabectedin is also known as Yondelis PURPOSE The objective of this study was to compare the efficacy and safety of trabectedin plus pegylated liposomal doxorubicin (PLD) with that of PLD alone in women with recurrent ovarian cancer after failure of first-line, platinum-based chemotherapy CONCLUSION When combined with PLD, trabectedin improves PFS and ORR over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer.

Health Canada Approves Trabectedin for Relapsed Ovarian Cancer (Trabectedin//Yondelis)

May 26, 2010 — Health Canada has approved trabectedin (Yondelis; PharmaMar SA [Zeltia SA], marketed by Centocor Ortho Biotech Products, LP) in combination with pegylated liposomal doxorubicin (PLD) for the treatment of relapsed platinum-sensitive ovarian cancer.

The treatment is indicated for patients who have failed (blogger comment - ho hum!)  first-line platinum-based chemotherapy regimen, including adjuvant therapy, and who are not expected to benefit from, are ineligible for, or are unwilling to undergo additional platinum-based chemotherapy.

Approval was based on radiologic data from a multinational phase 3 clinical study (n = 672) showing that administration of trabectedin (1.1 mg/m²) plus doxorubicin (30 mg/m²) in 3-week cycles significantly increased progression-free survival by 21% compared with PLD alone (50 mg/m²) given every 4 weeks (7.3 months vs 5.8 months; hazard ratio [HR], 0.79; P = .019).

These findings were confirmed by an independent radiologic assessment that considered clinical as well as radiologic imaging data in assessing tumor progression (HR, 0.72; P = .0008). These study results were presented at the 2008 European Society for Medical Oncology Congress, and reported by Medscape Oncology during the conference.

In July 2009, the FDA declined approval of trabectedin for ovarian cancer, citing the potential for variations in radiologic data assessment and questioning whether the 6-week increase in progression-free survival offset an increased risk for toxicity, as previously reported by Medscape Oncology.

Trabectedin previously was approved in the European Union for the treatment of platinum-sensitive ovarian cancer and soft tissue sarcoma.

PharmaMar Presents New Clinical Trials With Three Marine-Based Drugs at the American Association for Cancer Research Convention - yondelis/Trabectedin

Two trials provided new data on Yondelis(R) (trabectedin), a marine-based anti-tumor drug currently produced by chemical synthesis. Yondelis(R) (trabectedin) has European Commission approval for advanced and metastatic soft tissue sarcoma (STS) and for recurrent platinum-sensitive ovarian cancer in combination with Doxil/Caelyx