Endocrine Therapy + OSI-906 With or Without Erlotinib for Hormone-Sensitive Metastatic Breast Cancer

• Safety Profile Based on Number of Patients With Each Worst-grade Toxicity [ Time Frame: Every 4 weeks up to 24 weeks ] [ Designated as safety issue: Yes ]
  According to National Cancer Institute Common Toxicity Criteria for Adverse Events with 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening/disabling, and 5 = death.
• Number of Participants With Tumor Response Per RECIST [ Time Frame: Every 12 weeks to tumor progression ] [ Designated as safety issue: No ]
  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
• Correlative Studies [ Time Frame: < or = to 2 weeks before initiation of Phase II study treatment period ] [ Designated as safety issue: No ]
  Biomarkers associated with response to OSI-906 + Erlotinib + Letrozole + Goserelin

• Safety of OSI-906 given in combination with erlotinib and endocrine therapy in patients with hormone-sensitive metastatic breast cancer [ Time Frame: During treatment ] [ Designated as safety issue: Yes ]
• Response rates (RR) of OSI-906 and erlotinib given in combination with endocrine therapy in patients with hormone-sensitive metastatic breast cancer [ Time Frame: Every 3 cycles ] [ Designated as safety issue: No ]
• Correlative studies [ Time Frame: Prior to treatment ] [ Designated as safety issue: No ]

Erlotinib attacks a part of cancer cells that helps them live and grow. Studies done in human beings show that this drug can make a difference in the way anti-estrogens work in hormone-sensitive breast cancers. OSI-906 attacks a different part of the cancer cell that helps them live and grow. Studies done in the laboratory show that OSI-906 can make a difference in the way anti-estrogens work in hormone-sensitive breast cancers.

The safety run component of this trial is to determine the safety profile of the OSI-906, erlotinib and anti-endocrine treatment combination. The phase II component evaluates the antitumor activity of the combination OSI-906, erlotinib and endocrine therapy.

• Drug: OSI-906

  In a pill form by mouth, twice a day (12 hours apart)

  During the safety run portion of the study"

  • Dose level 2 = 150 mg twice a day
  • Dose level 1 = 100 mg twice a day
  • Dose level -1 = 100 mg twice a day
  • Dose level -2 = 100 mg twice a day
• Drug: Erlotinib

  During the safety run phase of the study:

  • Dose Level 2 = 100 mg/d
  • Dose Level 1 = 100 mg/d
  • Dose Level -1= 75 mg/d
  • Dose Level -2 = 50 mg/d
• Drug: Letrozole
  In a pill form, by mouth, once per day at 2.5 mg/d.
• Drug: Goserelin
  For pre-menopausal patients only. Given as an injection once a month at 3.6 mg/month.

Inclusion Criteria:

• Patients must provide informed written consent.
• Patients must be ≥18 years of age.
• ECOG performance status 0-1.
• Patients with clinical stage IV invasive mammary carcinoma, previously documented by histological analysis, which is ER-positive and/or PR-positive by immunohistochemistry (IHC), which had previous endocrine therapy in the metastatic setting or had metastatic recurrence within 6 months of adjuvant endocrine therapy. Patients may have either measurable or non-measurable disease, both are allowed.
• Patients whose breast cancers are also HER2-overexpressed (IHC 3+ or FISHpositive) need to have had previous treatment exposure to trastuzumab (Herceptin®)
• Life expectancy ≥ 6 months

• Patients must have adequate hematologic, hepatic, and renal function. All tests must be obtained less than 2 weeks from study entry. This includes:

  • ANC ≥1250/mm3
  • Platelet count ≥100,000/mm3
  • Creatinine ≤1.5X upper limits of normal
  • Bilirubin, SGOT, SGPT ≤ 1.5 X upper limits of normal if no liver metastasis present*
  • Bilirubin, SGOT, SGPT, alkaline phosphatase ≤ 3 X upper limits of normal if liver metastasis present* *for patients with Gilbert's syndrome, direct bilirubin will be measured instead of total bilirubin
• Able to swallow and retain oral medication.
• Pre-menopausal patients must have a negative pregnancy test prior to participating in the study. Women of childbearing age and their male counter parts should use a barrier method of contraception during and for 3 months following protocol therapy.

• Post-menopausal female subjects should be defined prior to protocol enrollment by any of the following:

  • Subjects at least 55 years of age;

  • Subjects under 55 years of age and amenorrheic for at least 12 months or follicle-stimulating hormone (FSH) values ≥40 IU/L and estradiol levels

    ≤20 IU/L;

  • Prior bilateral oophorectomy or prior radiation castration with amenorrhea for at least 6 months.
• Patients may receive concurrent radiation therapy to painful bone metastases or areas of impending bone fracture as long as radiation therapy is initiated prior to study entry. Patients who have received prior radiotherapy must have recovered from any toxicity induced by this treatment (toxicity grade ≤ 1).
• Patients must be disease-free of prior invasive cancers for > 5 years with the exception of basal or squamous cancer of the skin or cervical carcinoma in situ.
• Subjects must complete all screening assessments as outlined in the protocol.
• Patients must have available tissue (archived formalin-fixed paraffin embedded blocks (FFPB) or fresh frozen tissue from original diagnosis or metastatic setting)for correlative studies. Tissue needs to be sent to VUMC (see Appendix E) at the time of registration. Patients will not be able to start study drugs without tissue availability.

Exclusion Criteria:

• Locally recurrent resectable breast cancer.
• Pregnant or lactating women.
• Patients must not have had > than 4 prior chemotherapy treatments in the metastatic setting. This restriction does not include endocrine therapies or single agent biologic therapies.
• Use of CYP3A4 and CYP1A2 modifiers or drugs that prolong QTcF with high risk for Torsade de Pointes (see Appendix A)
• Any kind of malabsorption syndrome significantly affecting gastrointestinal function.
• History of other malignancy within 5 years prior to enrollment. Subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinomas are eligible.
• Patients with baseline QTcF> 450 msec
• Patients with diabetes, glucose > 160 mg/dL or receiving ongoing antihyperglycemic therapies

• Uncontrolled intercurrent illness including, but not limited to:

  • ongoing or active infection requiring parenteral antibiotics
  • impairment of lung function (COPD > grade 2, lung conditions requiring oxygen therapy)
  • symptomatic congestive heart failure (class III or IV of the New York Heart Association classification for heart disease)
  • unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months
  • uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg, found on two consecutive measurements separated by a 1-week period despite adequate medical support)
  • clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment [National Cancer Institute -Common Terminology Criteria for Adverse Events, Version 4.0, grade 3]
  • psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary
• Patients with symptomatic brain metastases (patients with a history of brain metastases must be clinically stable for more than 3 weeks from completion of radiation treatment and not taking steroids or therapeutic anticonvulsants that are CYP3A4 modifiers)
• Patients with asymptomatic brain metastasis on prophylactic anticonvulsants that are CYP3A4 modifiers
• Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, biologic therapy) other than the ones specified in the protocol. Patients must have discontinued the above cancer therapies for 1 week prior to the first dose of study medication, as well as recovered from toxicity (to ≤ than grade 1, except for alopecia, neuropathy, and ANC, which should be ≥ 1250/mm3) induced by previous treatments. Any other investigational drugs should be discontinued 2 weeks prior to the first dose of study medication.
• Prior therapy with an IGF-1R inhibitor