Symptoms and General Pathology

All Conditions

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Skin and Connective Tissue Diseases

Recurrence

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Breast Neoplasms

Carcinoma, Ductal, Breast

Carcinoma, Ductal

Breast Diseases

Skin Diseases

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Menopause

All Drugs and Chemicals

Antineoplastic Agents

Hormones

Letrozole

Phosphoinositide-3 Kinase Inhibitors

Aromatase Inhibitors

Enzyme Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Patients receive PI3K inhibitor BYL719 PO QD and letrozole PO QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

PI3K inhibitor BYL719

letrozole

laboratory biomarker analysis

pharmacological studies

Ingrid Mayer

This phase I trial studies the side effects and best dose of the PI3K inhibitor BYL719 when given together with letrozole in treating patients with hormone receptor-positive metastatic breast cancer. The PI3K inhibitor BYL719 may stop the growth of tumor cells by blocking some of the proteins needed for cell growth. Hormone therapy using letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving the PI3K inhibitor BYL719 together with letrozole may kill more tumor cells

PRIMARY OBJECTIVE: To determine the safety and tolerability of BYL719 given in combination with endocrine therapy in post-menopausal patients with hormone receptor-positive metastatic breast cancer by determining:

I. Dose limiting toxicities (DLTs) during the first 4 weeks of treatment (cycle 1).

II. Maximum tolerated dose (MTD) of BYL719 (PI3K inhibitor BYL719) given in combination with letrozole.

III. Highest tolerated dose - ability to tolerate BYL719 with letrozole for a total of 8 weeks without development of:

* Hyperglycemia (fasting glucose \> 200 mg/dL) for more than 2 weeks in a row despite optimal medical treatment
* CTC Grade 3 or \> rash for more than 2 weeks in a row despite optimal medical treatment
* CTC Grade 2 or \> GI toxicity for more than 2 weeks in a row despite optimal medical treatment
* CTC Grade 2 or \> serum creatinine, bilirubin, AST, ALT elevation from baseline for more than 2 weeks in a row despite optimal medical treatment

SECONDARY OBJECTIVES: To determine the anti-tumor effect of the combinations of endocrine therapy with BYL719 in post-menopausal patients with hormone receptor-positive metastatic breast cancer by assessing:

I. Progression free survival (PFS). II. Objective response rate (ORR). III. Clinical benefit rate (complete response \[CR\]+partial response \[PR\]+stable disease \[SD\] \>= 6 months).

EXPLORATORY OBJECTIVES:

I. Pharmacokinetics of BYL719 in combination with letrozole: Plasma concentration-time profiles and derived basic pharmacokinetic (PK) parameters of BYL719 and letrozole, including but not limited to area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-tlast), AUC curve to infinite time (AUC0-inf), maximum observed concentration (Cmax), time to peak concentration (Tmax), clearance over bioavailability (CL/F), apparent volume of distribution (Vz/F) and the terminal half-life (t1/2) and other PK parameters if deemed appropriate.

II. Correlation of response with alterations of the PI3K pathway: Mutational analysis of PIK3CA (exons 9 and 20), phosphatase and tensin homolog (PTEN), and AKT1 in formalin-fixed paraffin blocks (FFPB) from previous surgeries or fresh-frozen biopsies (if available) on all patients enrolled in the trial.

OUTLINE: This is an open-label phase Ib dose-escalation study of the PI3K inhibitor BYL719 in combination with letrozole in post-menopausal patients with ER+ metastatic breast cancer.

Patients receive BYL719 orally (PO) once daily (QD) and letrozole PO QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

BYL719 and Letrozole in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer

A Phase Ib Trial of BYL719 (an α-Specific PI3K Inhibitor) in Combination With Endocrine Therapy in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer

Highest dose of BYL719 tested in which a DLT is experienced by 0 out of 3 or 1 of 6 patients, based on the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0

Highest dose of BYL719 without CTC Grade \> 2 hyperglycemia(fasting glucose \> 200 mg/dL) for \> 2 weeks, Grade \> 3 rash for \> 2 weeks , Grade \> 2 gastrointestinal toxicity for \> 2 weeks and Grade \> 2 creatinine, bilirubin, AST, ALT for \> 2 weeks.

Per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1; percentage of patients with complete response (CR) + partial response (PR) + stable disease (SD) for more than 6 months.

Duration from on-study date to date of progressive disease.

Per RECIST version 1.1. number of patients each with CR, PR, SD, and progressive disease (PD) as their best response.

Number of patients with worst-grade toxicity at each of five grades (grade 1, least severe; to grade 5, most severe) following NCI Common Toxicity Criteria 4.0.

National Cancer Institute (NCI)

Vanderbilt-Ingram Cancer Center

Assistant Professor of Medicine

Digestive System Diseases

Rare Diseases

Carcinoma, Squamous Cell

Stomach Neoplasms

Esophageal Neoplasms

Esophageal Squamous Cell Carcinoma

Disease Attributes

Neoplasms, Squamous Cell

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Stomach Diseases

Head and Neck Neoplasms

Esophageal Diseases

Stomach Cancer

Esophageal Cancer

Camptothecin

Topoisomerase I Inhibitors

Patients receive cyclodextrin-based polymer-camptothecin CRLX101 IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. After the completion of 6 courses, patients achieving stable disease or better may receive treatment for an additional 6 months.

cyclodextrin-based polymer-camptothecin CRLX101

Laboratory biomarker analysis

Pharmacological studies

Joseph Chao

This pilot clinical trial studies cyclodextrin-based nanopharmaceutical CRLX101 in treating patients with advanced or metastatic stomach, gastroesophageal, or esophageal cancer that has progressed through at least one prior regimen of chemotherapy and cannot be removed by surgery. CRLX101 delivers the cytotoxic topoisomerase-1 inhibitor camptothecin into tumor cells and is hypothesized to interrupt the growth of tumor cells.

PRIMARY OBJECTIVES:

I. To evaluate pre- and post-treatment biopsies to assess CRLX101 (cyclodextrin-based polymer-camptothecin CRLX101) nanoparticle and 20(S)-Camptothecin (CPT) uptake in tumor and normal tissue.

SECONDARY OBJECTIVES:

I. To evaluate the safety and toxicity of CRLX101 in this patient population.

II. To examine the antitumor efficacy of CRLX101 in advanced gastric/gastroesophageal junction (GEJ)/esophageal squamous or adenocarcinoma including clinical benefit rate (complete response \[CR\] + partial response \[PR\] + stable disease \[SD\]) at 4 months and overall survival.

OUTLINE:

Patients receive cyclodextrin-based polymer-camptothecin CRLX101 intravenously (IV) over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients achieving stable disease or better, may receive treatment for an additional 6 months.

After completion of study treatment, patients are followed up monthly.

Pilot Trial of CRLX101 in Treatment of Patients With Advanced or Metastatic Stomach, Gastroesophageal, or Esophageal Cancer That Cannot be Removed by Surgery

Pilot Trial of CRLX101 in the Treatment of Patients With Advanced Gastric, Gastroesophageal, or Esophageal Squamous or Adenocarcinoma

Using Fisher's Exact to determine statistical significance in detection of a CPT fluorescence signal posttreatment between tumor and adjacent normal tissue biopsy specimens.

Patients with best response of Complete Response or Partial Response assessed using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Patients with a best response of Complete Response, Partial Response or Stable Disease after at least 4 months of treatment assessed using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), not a CR, PR, Progression or Symptomatic Deterioration; Progression (PD), a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Symptomatic Deterioration, global deterioration of health status requiring discontinuation of treatment without objective evidence of progression. Clinical Benefit (CR + PR +SD≥4months).

Estimated using the product-limit method of Kaplan and Meier.

Incidence of treatment related adverse events graded per NCI CTCAE version 4.03

City of Hope Medical Center

"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.

Patients receive cyclodextrin-based polymer-camptothecin CRLX101 IV over 60 minutes on days 1 and 15 at 15 mg/m\^2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. After the completion of 6 courses, patients achieving stable disease or better may receive treatment for an additional 6 months.

cyclodextrin-based polymer-camptothecin CRLX101: Given IV

Laboratory biomarker analysis: Correlative studies

Pharmacological studies: Correlative studies

Treatment (Cyclodextrin-based Polymer-camptothecin CRLX101)

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Paul Frankel, Ph.D.

CPT signal was observed in the tissue

CPT signal was not observed in the tissue

One patient was not included in the analysis because no tumor tissue was identified in the biopsy samples both pre and post-CRLX101 treatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
BYL719 and Letrozole in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer	NCT01791478	Estrogen Recept... HER2-negative B... Invasive Ductal... Progesterone Re... Recurrent Breas... Stage IV Breast...	PI3K inhibitor ... letrozole laboratory biom... pharmacological...	18 Years -	Vanderbilt-Ingram Cancer Center
Pilot Trial of CRLX101 in Treatment of Patients With Advanced or Metastatic Stomach, Gastroesophageal, or Esophageal Cancer That Cannot be Removed by Surgery	NCT01612546	Adenocarcinoma ... Adenocarcinoma ... Diffuse Adenoca... Intestinal Aden... Mixed Adenocarc... Recurrent Esoph... Recurrent Gastr... Squamous Cell C... Stage IIIB Esop... Stage IIIB Gast... Stage IIIC Esop... Stage IIIC Gast... Stage IV Esopha... Stage IV Gastri...	cyclodextrin-ba... Laboratory biom... Pharmacological...	18 Years -	City of Hope Medical Center

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