Phase 2, Endocrine Therapy + OSI-906 With or Without Erlotinib for Hormone-sensitive Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole +/- goserelin (the latter for pre-menopausal women only) may fight breast cancer by lowering the amount of estrogen the body makes. OSI-906 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether hormone therapy and OSI-906 are more effective when given with or without erlotinib hydrochloride in treating hormone-sensitive metastatic breast cancer. PURPOSE: This phase II trial is studying how well giving hormone therapy together with OSI-906 with or without erlotinib hydrochloride works in treating hormone-sensitive patients with metastatic breast cancer.

Detailed Description
-----------------
OBJECTIVES: Primary To determine the antitumor activity of letrozole +/- goserelin (the latter for pre-menopausal women only) in combination with IGF-1R inhibitor OSI-906 with or without erlotinib hydrochloride, measured by time to progression, in patients with hormone-sensitive metastatic breast cancer. Secondary To determine the safety of these regimens in these patients. To determine the response rate in patients treated with these regimens. To measure circulating C-peptide, IGF-1, and IGFBP-3 levels in patients treated with these regimens. To correlate the expression of IGF-IR, EGFR, HER2, Y1316 and Y1131 pIGF-1R, PTEN, S473 pAkt, pMAPK, S118 (MAPK site), and S167 (Akt and S6 site) pER in formalin-fixed paraffin blocks (FFPB) with clinical outcome and luminal A vs. luminal B subtypes of breast cancer. To correlate the mutational status of PI3K (E542K, E545K, H1047R) in DNA extracted from FFPB or fresh biopsy with clinical outcome and luminal A vs. luminal B subtypes of breast cancer OUTLINE: This is a multicenter study. Stratification will be based on previous exposure to endocrine therapy: (Arm I) no previous endocrine therapy or have completed adjuvant therapy > 6 months prior to study enrollment; (Arm II) patients that had previous endocrine therapy in the metastatic setting or had metastatic recurrence within 6 months of adjuvant endocrine therapy. Arm I: Patients receive oral letrozole once daily on days 1-28 +/- subcutaneous goserelin* on day 1 and oral IGF-1R inhibitor OSI-906 twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive oral letrozole +/- subcutaneous goserelin* and IGF-1R inhibitor OSI-906 as in arm I. Patients also receive oral erlotinib hydrochloride once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. NOTE: *Goserelin will only be given to premenopausal patients. Tumor tissue samples from original diagnosis or from fresh biopsy tissue are collected for biomarker analysis and other studies. After completion of study therapy, patients are followed periodically.

Official Title
-----------------
A Phase II Trial of Endocrine Therapy in Combination With OSI-906 (an IGF-1R Inhibitor) With or Without Erlotinib (Tarceva, an EGFR Inhibitor) in Patients With Hormone-sensitive Metastatic Breast Cancer.

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: IGF-1R inhibitor OSI-906
* Drug: erlotinib hydrochloride
* Drug: goserelin
* Drug: letrozole


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed invasive breast carcinoma Stage IV disease No locally recurrent resectable disease No symptomatic brain metastases History of brain metastases allowed provided the patient is clinically stable for > 3 weeks after completion of radiotherapy AND is not taking steroids or therapeutic anticonvulsants that are CYP3A4 modifiers Hormone receptor status: Estrogen receptor and/or progesterone receptor positive tumor by immunohistochemistry (IHC) PATIENT CHARACTERISTICS: Pre- or post-menopausal ECOG performance status 0-1 Life expectancy ≥ 6 months ANC ≥ 1,250/mm^3 Platelet count ≥ 100,000/mm^3 Creatinine ≤ 1.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN (≤ 3 times ULN if liver metastasis is present) For patients with Gilbert syndrome, direct bilirubin will be measured instead of total bilirubin SGOT and SGPT ≤ 1.5 times ULN (≤ 3 times ULN if liver metastasis is present) Alkaline phosphatase ≤ 1.5 times ULN (≤ 3 times ULN if liver metastasis is present) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for 3 months after completion of study therapy Able to swallow and retain oral medication Baseline QTc ≤ 450 msec No other invasive cancer within the past 5 years except for completely resected basal cell or squamous cell skin cancer or successfully treated cervical carcinoma in situ No malabsorption syndrome significantly affecting gastrointestinal function No diabetes, fasting glucose > 150mg/dL, or receiving ongoing anti-hyperglycemic therapies No concurrent uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection requiring parenteral antibiotics Impaired lung function (i.e., COPD or lung conditions requiring oxygen therapy) Symptomatic congestive heart failure (NYHA class III or IV heart disease) Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within the past 6 months Uncontrolled hypertension, defined as systolic BP > 180 mm Hg or diastolic BP > 100 mm Hg on two consecutive measurements taken ≥ 1 week apart, despite adequate medical support Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, or ventricular tachycardia that is symptomatic or requires treatment) Psychiatric illness and/or social situation that would compromise patient safety or limit compliance with study requirements, including maintenance of a compliance/pill diary PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from prior therapy At least 2 weeks since prior investigational drugs No more than 4 prior chemotherapy treatments in the metastatic setting Does not include endocrine therapy or single-agent biologic therapy No concurrent CYP3A4 or CYP1A2 modifiers No other concurrent anticancer therapy, including chemotherapy, radiotherapy, surgery, immunotherapy, hormonal therapy, or biologic therapy Concurrent radiotherapy to painful bone metastases or areas of impeding bone fracture allowed provided radiotherapy is initiated before study therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Letrozole +/-goserelin, OSI-906 (Arm I )<br>Patients receive oral letrozole once daily on days 1-28 plus subcutaneous goserelin (the latter for pre-menopausal women only) on day 1 and oral IGF-1R inhibitor OSI-906 twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: IGF-1R inhibitor OSI-906<br>* Given orally<br>Drug: goserelin<br>* Given subcutaneously<br>* Other names: Zoladex;Drug: letrozole<br>* Given orally<br>* Other names: Femara;|
| Experimental: Letrozole +/- goserelin, OSI-906, erlotinib (Arm II)<br>Patients receive oral letrozole and subcutaneous goserelin (the latter for pre-menopausal women only) and oral IGF-1R inhibitor OSI-906 as in arm I. Patients also receive oral erlotinib hydrochloride once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: IGF-1R inhibitor OSI-906<br>* Given orally<br>Drug: erlotinib hydrochloride<br>* Given orally<br>* Other names: Tarceva;Drug: goserelin<br>* Given subcutaneously<br>* Other names: Zoladex;Drug: letrozole<br>* Given orally<br>* Other names: Femara;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression | Duration from study enrollment to date of progressive disease (PD) as measured by Response Evaluation in Solid Tumors (RECIST) criteria v. 1.1: measurable lesions: PD is > 20% increase in the sum of the longest diameter of target lesions or appearance of new lesions | from study entry to date of progressive disease | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile of OSI-906 and letrozole +/ goserelin, with and without erlotinib | The number of patients with worst-grade toxicity at each of five grades following NCI Common Toxicity Criteria: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, disabling, 5 = death | at 4 weeks | 
| Response | Per RECIST criteria v. 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions | every 12 weeks to progression | 
| Circulating C-peptide, IGF-1 | Levels of the protein C-peptide and the hormone IGF-1 in the blood | At baseline and on day 1 of each 28-day cycle | 
| Correlation of IGF-IR, EGFR, HER2, Y1316 and Y1131 pIGF-1R, PTEN, S473 pAkt, pMAPK, S118 (MAPK site), and S167 (Akt and S6 site) pER expression with time to progression and molecular classification | The levels of these biomarkers will be measured in breast tumor tissue and compared and contrasted with patient's time to progression and molecular classification (luminal A vs. luminal B) | On receipt of breast tissue: tissue block from prevous surgery or fresh tissue from current surgery | 
| Mutation analysis of PI3K (E542K, E545K, H1047R) | Breast tumor tissue will be examined for mutations in these genes. | On receipt of breast tissue: tissue block from prevous surgery or fresh tissue from current surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, stage IV breast cancer, recurrent breast cancer