Clinical Trial: Phase I Study of Olaprib and Temozolomide for Ewings Sarcoma

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Phase I Study of Olaparib and Temozolomide in Adult Patients With Recurrent/Metastatic Ewing's Sarcoma Following Failure of Prior Chemotherapy

Brief Summary:

This research study is a Two arm Phase I clinical trial, which tests the safety of an investigational drug or combination of drugs and also tries to define the appropriate dose of the combination of investigational drugs to use for further studies. "Investigational" means that the combination of drugs is being studied. It also means that the FDA has not yet approved the combination of drugs for your type of cancer.

Olaparib works by blocking the activity of a protein called poly (ADP-ribose) polymerase (PARP) which is involved in DNA repair. Cancer cells rely on PARP to repair their DNA and enable them to continue dividing. Olaparib has been used in research studies with other cancers. Information from those other research studies suggests that this drug may help to treat patients with Ewing's sarcoma. The investigational drug olaparib is not approved for any use outside of research studies.

Temozolomide (Temodar) is approved by the FDA for the treatment of a type of brain tumor, glioblastoma. It has been studied in Ewing sarcoma in previous research studies. While it is not approved by the FDA for Ewing sarcoma, it is considered part of standard treatment for relapsed disease.

Irinotecan is approved by the FDA for the treatment of gastrointestinal cancers. It has been studied in Ewing sarcoma in previous research studies. While it is not approved by the FDA for Ewing sarcoma, it is considered part of standard treatment for relapsed disease.

Laboratory studies suggest that the combination of olaparib and temozolomide and irinotecan may help kill Ewing sarcoma cells.

In this research study, the investigators are looking for the highest dose of the combination of olap

Detailed Summary:

If the patient agrees to participate in this research study they will be asked to undergo some screening tests and procedures to confirm that they are eligible. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that they do not take part in the research study. If they have had some of these tests and procedures recently, they may or may not have to be repeated. These tests and procedures will include: a medical history, complete physical examination, performance status, tumor assessment, EKG, blood tests, pregnancy test, confirmation of pathology report and obtain insurance approval to receive temozolomide. If these tests show that the patient is eligible to participate in the research study, they will begin the study drug administration. If they do not meet the eligibility criteria, they will not be able to participate in this research study.

Biomarkers are substances such as genes and proteins that are important biological "indicators" that can be measured in tumor tissue. The investigators would like to look at biomarkers before and after patients receive study drug administration. Comparing the biomarkers from tissue collected before and after receiving study treatments may help us find biomarkers that are associated with response to study treatment or lack of response to study drug administration.

Before the patient starts study drug administration, if the investigators determine that the patient is healthy enough for a biopsy, the patient will undergo a biopsy to provide tumor tissue for the research tests described above. (If it is determined that the patient should not have a biopsy, they can still take part in this research study).

The investigators are looking for the highest doses of ola
Sponsor: Massachusetts General Hospital

Current Primary Outcome: Determine MTD of olaparib and irinotecan and/or temozolomide [ Time Frame: 30 days ]

Original Primary Outcome: Determine MTD of olaparib and temozolomide [ Time Frame: 2 years ]

Current Secondary Outcome:

• Evaluate safety and tolerability of olaparib/irinotecan and/or temozolomide combination [ Time Frame: 2 years ]
  Evaluate the safety and tolerability of combination olaparib/temozolomide as defined by CTC version 4.0
• Objective response in tumor dimensions to olaparib/irinotecan and/or temozolomide [ Time Frame: 2 years ]
  Observe objective response in tumor dimensions to olaparib/temozolomide therapy as determined by RECIST 1.1, time of progression free survival (PFS) and overall survival (OS)
• Explore variations in PARP activity and tumor characteristics [ Time Frame: 2 years ]
  Patients will undergo tumor biopsies before and after starting olaparib and temozolomide therapy. Genomic DNA and RNA will be isolated from these samples and slides will be made to identify specific protein levels. The investigators will assess homologous repair status by measuring gammaH2AX and Rad51 focus formation by immunofluorescence. Biomarkers for apoptosis and DNA repair that the investigators plan to analyze include but are not limited to BRCA1, MRE11A, NBS1, TDG, XPA, Rad50, 53BP1, CHEK2, and MK2.

Original Secondary Outcome:

• Evaluate safety and tolerability of olaparib/temozolomide combination [ Time Frame: 2 years ]
  Evaluate the safety and tolerability of combination olaparib/temozolomide as defined by CTC version 4.0
• Objective response in tumor dimensions to olaparib/temozolomide [ Time Frame: 2 years ]
  Observe objective response in tumor dimensions to olaparib/temozolomide therapy as determined by RECIST 1.1, time of progression free survival (PFS) and overall survival (OS)
• Explore variations in PARP activity and tumor characteristics [ Time Frame: 2 years ]
  Patients will undergo tumor biopsies before and after starting olaparib and temozolomide therapy. Genomic DNA and RNA will be isolated from these samples and slides will be made to identify specific protein levels. We will assess homologous repair status by measuring gammaH2AX and Rad51 focus formation by immunofluorescence. Biomarkers for apoptosis and DNA repair that we plan to analyze include but are not limited to BRCA1, MRE11A, NBS1, TDG, XPA, Rad50, 53BP1, CHEK2, and MK2.

Dates:
Date Received: May 8, 2013
Date Started: July 2013
Date Completion: July 2019
Last Updated: May 9, 2017
Last Verified: May 2017