Safety Study of Preoperative Sunitinib and Radiation in Soft Tissue Sarcoma

NCT ID: NCT01498835

Last Updated: 2017-08-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 9 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-02-29
• Study Completion Date: 2015-02-28

Brief Summary

To evaluate the toxicity of sunitinib concurrently given with irradiation for preoperative treatment of locally advanced or recurrent soft tissue sarcoma.

Detailed Description

Although the introduction of multimodal treatment of soft tissue sarcoma resulted in great progress in STS treatment, local failure still occurs in 10-20% of STS patients. Therefore further improvement of local and systemic treatment is needed in order to achieve tumor control and limb salvage. The proposed study treatment will combine external beam radiation and orally administered sunitinib.

Sunitinib is a multiple receptor tyrosine kinase (RTK) inhibitor with anti-angiogenic and anti-tumoral properties. For their key role in tumor development, RTKs are regarded as excellent targets for cancer chemotherapy. External beam radiation is widely used as neoadjuvant treatment for locally advanced soft tissue sarcoma.

The concurrent application of anti-angiogenic sunitinib appears reasonable, since STS are highly vascularized tumors and overexpression of VEGFR and other RTKs has been shown for various histologic soft tissue sarcoma subtypes. At first sight, the combination of antiangiogenic treatment and radiation seems to be contradictory, since anti-angiogenic treatment attacks tumor vasculature and radiation effects are decreased by hypoxia. Yet, in animal studies the concurrent application of radiation with tyrosine kinase inhibitors such as sunitinib or other antiangiogenic agents resulted in additive, if not synergistic antitumoral effects. These results can be explained by the superiority of the anti-tumoral activity of antiangiogenic agents over their hypoxia related, radiation weakening effects; or by the hypothesis of vascular normalization. It is well known that tumor vasculature is immature and ineffective in means of blood supply and oxygenation. In preclinical models, antiangiogenic agents balanced pro- and anti-angiogenic effectors which may result in maturation of tumor vasculature with improvement of blood flow and oxygen supply.

The combination of sunitinib as an anti-angiogenic and anti-proliferative agent thus might not only add the therapeutic effects of the RTK-inhibitor and external beam radiation but might additionally lead to a radiosensitizing effect due to tumor vessel normalization. The Purpose of this study is to assess the toxicity of the combined treatment and to gather preliminary data on treatment efficacy.

Conditions

Soft Tissue Sarcoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Combined Sunitinib and irradiation

Patients with locally advanced or recurrent soft tissue sarcoma will receive Sunitinib and irradiation as neoadjuvant treatment. Restaging and tumor resection will be performed 6 weeks after completion of sunitinib and irradiation.

Group Type: EXPERIMENTAL

Sunitinib

Intervention Type: DRUG

Patients will receive Sunitinib daily for 2 weeks prior to and then concurrently with irradiation as neoadjuvant treatment. Radiotherapy will be given as intensity modulated radiation therapy with a total dose of 50.4Gy in 28 fractions to each patient (5 1/2 weeks).

Sunitinib will be given in two dose levels. The first dose level will be 25mg Sunitinib per os daily. The second dose level will be 37.5mg sunitinib per os daily. A dose modification schedule according to a 3+3 design will be applied for patient accrual.

Interventions

Sunitinib

Patients will receive Sunitinib daily for 2 weeks prior to and then concurrently with irradiation as neoadjuvant treatment. Radiotherapy will be given as intensity modulated radiation therapy with a total dose of 50.4Gy in 28 fractions to each patient (5 1/2 weeks).

Sunitinib will be given in two dose levels. The first dose level will be 25mg Sunitinib per os daily. The second dose level will be 37.5mg sunitinib per os daily. A dose modification schedule according to a 3+3 design will be applied for patient accrual.

Intervention Type: DRUG

Other Intervention Names

Radiation therapy

Eligibility Criteria

Inclusion Criteria

• histologically proven soft tissue sarcoma of any histology but GIST, Angiosarcoma, dermatofibrosarcoma protuberans, Ewing Sarcoma or Embryonal Rhabdomyosarcoma
• patients with primary tumors OR with local recurrences who did not receive prior radiation therapy OR with solitary metastatic lesions may be included
• complete resection after neoadjuvant treatment is expected
• age of 18 or older
• ECOG performance score 0 or 1
• normal organ and bone marrow function
• ability to give written informed consent

Exclusion Criteria

• medication with inhibitors or inducers of CYP3A4
• prior therapy with tyrosine kinase inhibitors or conventional chemotherapy within 4 weeks before study inclusion
• history of myocardial infarction, stroke or thromboembolic events
• clinical signs of heart failure (NYHA 3 or 4)
• anticoagulation with Vitamin K antagonists
• acquired or hereditary coagulopathy
• uncontrolled hypertension
• uncontrolled intercurrent illness
• women who are pregnant or breastfeeding

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

German Research Foundation

OTHER

Sponsor Role: collaborator

Heidelberg University

OTHER

Sponsor Role: lead

Responsible Party

Peter Hohenberger

MD PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Peter Hohenberger, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Heidelberg University

Locations

Helios Klinikum Bad Saarow

Bad Saarow, , Germany

University Medical Center Mannheim

Mannheim, , Germany

Countries

Germany

References

Jakob J, Simeonova A, Kasper B, Ronellenfitsch U, Rauch G, Wenz F, Hohenberger P. Combined sunitinib and radiation therapy for preoperative treatment of soft tissue sarcoma: results of a phase I trial of the German interdisciplinary sarcoma group (GISG-03). Radiat Oncol. 2016 Jun 3;11:77. doi: 10.1186/s13014-016-0654-2.

Reference Type: DERIVED

PMID: 27255678 (View on PubMed)

Jakob J, Rauch G, Wenz F, Hohenberger P. Phase I trial of concurrent sunitinib and radiation therapy as preoperative treatment for soft tissue sarcoma. BMJ Open. 2013 Sep 18;3(9):e003626. doi: 10.1136/bmjopen-2013-003626.

Reference Type: DERIVED

PMID: 24048627 (View on PubMed)

Other Identifiers

2007-002864-87

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GISG 03

Identifier Type: -

Identifier Source: org_study_id