Last updated on September 2018

Olaparib Cediranib Maleate and Wee1 Inhibitor AZD1775 in Treating Patients With Recurrent Refractory or Metastatic Endometrial Cancer


Brief description of study

This randomized phase II trial studies how well olaparib, cediranib maleate, and Wee1 inhibitor AZD1775 work in treating patients with endometrial cancer that has come back, does not respond to treatment, or has spread to other places in the body. Olaparib, cediranib maleate, and Wee1 inhibitor AZD1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Study Description

PRIMARY OBJECTIVES:

I. To compare the efficacy of either single-agent olaparib, the combination of olaparib and cediranib and the combination of olaparib and WEE1 inhibitor AZD1775 (AZD1775) versus single agent cediranib maleate (cediranib) as measured by progression free survival (PFS), in patients with recurrent, persistent or metastatic endometrial cancer.

SECONDARY OBJECTIVES:

I. To compare the efficacy of single-agent olaparib, the combination of olaparib and cediranib and the combination of olaparib and AZD1775 versus single-agent cediranib as measured by overall survival (OS) in patients with recurrent, persistent or metastatic endometrial cancer.

II. To compare the efficacy of single-agent olaparib, the combination of olaparib and cediranib and the combination of olaparib and AZD1775 versus single-agent cediranib as measured by response rate in patients with recurrent, persistent or metastatic endometrial cancer.

III. To assess the safety and tolerability of agent single-agent cediranib, single-agent olaparib, the combination of olaparib and cediranib and the combination of olaparib and AZD1775.

TERTIARY OBJECTIVES:

I. To compare the efficacy of the combination of olaparib and cediranib and the combination of olaparib and AZD1775 versus single agent olaparib as measured by PFS, response rate and OS, if and only if each combination is superior to the single-agent cediranib arm.

II. To assess if loss of function of ARID1A assessed by immunohistochemistry (IHC) and mutational profile is predictive of response to olaparib alone or in combination with cediranib or AZD1775.

III. To assess if mutations in deoxyribonucleic acid (DNA) homologous repair genes are predictive of response to olaparib alone or in combination with cediranib or in combination with AZD1775.

IV. To assess if phosphatase and tensin homolog (PTEN) loss as assessed by IHC is predictive of response to olaparib alone or in combination with cediranib or in combination with AZD1775.

V. To assess if microsatellite instability (MSI) as assessed by loss of DNA mismatch repair (MMR) proteins is associated with response to olaparib alone or in combination with cediranib or in combination with AZD1775.

VI. To assess if TP53 mutation status and p53 expression as assessed by IHC is associated with response to the combination of olaparib and AZD1775.

VII. To assess if markers of angiogenesis determined by IHC including VEGFA, VEGF R1, VEGFR2, and microvessel density (e.g., CD31) are associated with response to cediranib alone or in combination with olaparib.

VIII. To assess if mutations in Wee1-related genes (KRAS, MYC, Cyclin E, CDKN2A, cyclin D3 in addition to p53 HRD genes) are associated with response to AZD1775.

IX. To assess if surrogate markers for the TCGA molecular subgroups p53 IHC, MSI, and mutational status of the exonuclease domain of polymerase-epsilon (POLE) are associated with response to treatment in all arms.

OUTLINE: Patients are randomized into 1 of 4 arms.

ARM I: Patients receive cediranib maleate orally (PO) once daily (QD). Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

ARM II: Patients receive olaparib PO twice daily (BID). Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

ARM III: Patients receive olaparib PO BID and cediranib maleate PO QD. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

ARM IV: Patients receive olaparib PO BID and Wee1 inhibitor AZD1775 PO. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Clinical Study Identifier: NCT03660826

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Helen J. Mackay

NRG Oncology
Philadelphia, PA United States
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