A phase II study of paclitaxel for the treatment of ovarian stromal tumors: An NRG Oncology/ Gynecologic Oncology Group Study

To estimate the probability of complete clinical response and toxicity of paclitaxel as second-line chemotherapy in measurable disease patients with malignant tumors of the ovarian stroma, and to evaluate the value of inhibin for predicting response

A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study

PURPOSE: Cediranib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This phase II study was conducted to assess activity and tolerability of single-agent cediranib in recurrent/persistent endometrial cancer. PATIENTS AND METHODS: Eligible patients had recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group (GOG) performance status of ≤2 (≤1 if two prior cytotoxic regimens given). Cediranib 30mg orally daily for a 28daycycle was administered until disease progression or prohibitive toxicity. Microvessel density (MVD) was measured in tumor tissue from initial hysterectomy specimens and correlated with clinical outcome. Primary endpoints were tumor response and surviving progression-free for six months without subsequent therapy (6-month event-free survival [EFS]). RESULTS: Of 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5 years, 52% of patients had received prior radiation, and 73% of patients received only one prior chemotherapy regimen. A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65 months and median overall survival (OS) 12.5 months. No grade 4 or 5 toxicities were observed. A trend towards improved PFS was found in patients whose tumors expressed high MVD. CONCLUSION: Cediranib as a monotherapy treatment for recurrent or persistent endometrial cancer is well tolerated and met protocol set objectives for sufficient activity to warrant further investigation. MVD may be a useful biomarker for activity

Patient clinical characteristics and family history.

<p>Patient clinical characteristics and family history.</p

Patient 3 pedigree.

<p>This pedigree represents the family history of cancer in patient number 3. The proband, or original patient, is denoted by the arrow. The type of cancer each relative has a history of is denoted below their pedigree symbol. If a relative had genetic testing and was found to carry the known familial <i>BRCA1</i> mutation, this is also denoted below their pedigree symbol. If a relative tested negative for the known familial <i>BRCA1</i>mutation, this is also denoted below their pedigree symbol. The proband had full gene sequencing and deletion/duplication analysis of the <i>BRCA1/2</i> genes; therefore, ‘<i>BRCA1/2-</i>‘ is listed below their pedigree symbol. The proband was also found to carry a variant of uncertain significance in <i>MSH2</i>.</p

<i>BRCA</i> phenocopy hypothesis.

<p>A. Maternal-fetal microchimerism. B. Tetragametic chimerism. C. A woman with <i>BRCA</i>-mutant chimeric cells.</p

Mutation primer sequences.

<p>Primers used to detect point mutations by sequence specific PCR, Inner primers end on the indicated variant bases. The size of the resulting product of the extended inner primer and its opposite outer primer will indicate the mutation status.</p

Molecular testing in tumor tissue.

<p><b>A.</b> The <i>BRCA1</i> 187del AG deletion heterozygote (families 1 and 5) is detected as an n-2 product by capillary electrophoresis (left) and by an indicative peak pattern by pyrosequencing (top right). Neither the deletion product nor the mutant peak pattern was detected in the patient tumors (bottom panels). <b>B.</b> The heterozygote detected as a 163 bp product by gel electrophoresis. The synthetic oligomer carrying the mutation confirmed the detection of the mutation by mutation sequence specific primers. This band is not present in the negative control nor family 8 DNA (left four lanes). The 137 bp band specific to the normal A allele was detected by primers specific to that allele in the patient sample. Tumor DNA tested for the familial mutation 5215G>A gave similar results (not shown). <b>C.</b> The <i>BRCA2</i> 8107 A→T mutation was tested by sequence-specific PCR. The 92 bp product (T allele, positive) is not present in the patient’s tissue where only the A allele (80bp) is observed. Reagent blanks for the A and T allele primer sets (Bl A, Bl T) are shown. <b>D.</b> <i>BRCA1</i> 3109 insAA (left), and <i>BRCA2</i> 6794 insA (patients 10 and 11, respectively; right) mutation analysis by PCR-capillary electrophoresis. Amplified products from DNA without (negative control, top) and with (positive control, middle panels) demonstrate the expected right shift in migration for the <i>BRCA1</i> 3109 insAA n+2 product (76 bp) and the <i>BRCA2</i> 6794 insA n+1 product (82 bp)(bottom panels). Patient samples show an unexpected left shift (n-1) product.</p