Phase I Study of Olaparib with Irinotecan and/or Temozolomide in Adolescent and Adult Patients with Recurrent/Metastatic Ewing Sarcoma or Rhabdomyosarcoma following failure of prior chemotherapy

Protocol # :
Ewing Sarcoma
Disease Sites
Bones and Joints
Principal Investigator
Choy, Edwin
Site Investigator
Demetri, George, D.
Dubois, Steven
Site Research Nurses
Anderson, Barbara, M.
Anderson, Barbara, M.
Aste, Marie, Francesca
Carrozza, Susan, J.
Cavanaugh, Kerri, Lynn
Diorio, RN, Michele
Gurski, Carol
Hohos, Melissa
Leonard, Emily
Limor, Sora
Morley, Mark, G.

Trial Description

This research study is a Three 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/or
irinotecan may help kill Ewing sarcoma or rhabdomyosarcoma cells.

In this research study, the investigators are looking for the highest dose of the combination
of olaparib and irinotecan and/or temozolomide that can be given safely. The investigators
will also begin to collect information about the effects of the combination on Ewing sarcoma
and rhabdomyosarcoma.

Eligibility Requirements

Inclusion Criteria:

- Histologically confirmed Ewing's sarcoma

- Ewing's sarcoma must have progressed following at least one standard prior
chemotherapy regimen

- Life expectancy of at least 16 weeks

- Willing to comply with the protocol for the duration of the study including pre- and
post-treatment biopsies, undergoing treatment, scheduled visits and examinations
including follow up

- Presence of measurable disease

- Prior approval from insurance company to obtain oral temozolomide for the duration of
the study

Exclusion Criteria:

- Involvement in the planning and/or conduct of the study

- Previous enrollment in the present study

- Participation in another clinical study with an investigational product during the 21
days prior to first dose of olaparib and temozolomide

- Receiving any systemic chemotherapy, radiotherapy (except for palliative reasons),
within 2 weeks from the last dose prior to study treatment

- Concurrent use of the following classes of inhibitors of CYP3A4: azole antifungals,
macrolide antibiotics, protease inhibitors

- Persistent clinically significant toxicities caused by previous cancer therapy

- Previously documented diagnosis of myelodysplastic syndrome (or any dysplastic
leukocyte morphology suggestive of MDS) or acute myeloid leukemia

- Symptomatic uncontrolled brain metastases

- Major surgery within 14 days of starting study treatment

- Considered a poor medical risk due to a serious, uncontrolled medical disorder,
non-malignant systemic disease or active, uncontrolled infection

- Unable to swallow orally administered medication and subjects with gastrointestinal
disorders likely to interfere with absorption of study medication

- Pregnant or breastfeeding

- Known to be serologically positive for HIV and receiving antiviral therapy

- Subjects with known active hepatitis B or C

- Known hypersensitivity to olaparib or any of the excipients of the product

- Uncontrolled seizures

- Need to continue treatment with any prohibited medications or have not completed the
appropriate washout period for a prohibited medication