Treatments and/or Procedures

Study Criteria

Inclusion Criteria:

  -  Signed informed consent obtained prior to any screening procedures

  -  Performance status =< 1

  -  Absolute neutrophil count (ANC) >= 1 x 10^9/L

  -  Platelets >= 75 x 10^9/L

  -  Hemoglobin (Hb) > 8 g/dL

  -  Total serum bilirubin =< 2.0 mg/dL

  -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper
     limit of normal (ULN) (=< 5 x ULN in patients with liver metastases)

  -  International normalized ratio (INR) =< 2

  -  Serum creatinine =< 1.5 x ULN

  -  Fasting serum cholesterol =< 300 mg/dL or =< 7.75 mmol/L and fasting triglycerides =<
     2.5 x ULN; Note: in case one or both of these thresholds are exceeded, the patient can
     only be included after initiation of appropriate lipid lowering medication

  -  Histologically confirmed advanced solid tumors with HR-positivity defined as > 1% on
     immunohistochemistry (estrogen receptor-positive with or without positivity for the
     progesterone receptor) and HER2/neu positivity (3+ on IHC and/or 2+ on IHC and FISH
     amplified, or by v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2
     [ERBB2] mutation on next generation sequencing)

  -  Must have measurable or evaluable disease

  -  At least 4 weeks since the last dose of chemotherapy, immunotherapy, surgery, or
     radiation therapy (exception: patients may have received palliative low dose radiation
     therapy one week before treatment provided it is not given to the only targeted
     lesions); at least 6 weeks for therapy which is known to have delayed toxicity
     (nitrosoureas, mitomycin-C, and liposomal doxorubicin); at least 4 weeks (or 5
     half-lives, whichever is shorter) since treatment with biologic/targeted therapies; at
     least 2 weeks since last hormonal therapy

  -  Female patients must either be: post-menopausal women as defined by a) age >= 60 years
     of age; b) prior bilateral oophorectomy; c) age < 60 with at least 12 months of
     spontaneous amenorrhea or post-menopausal range follicle stimulating hormone (FSH) and
     estradiol levels or premenopausal women receiving a gonadotropin-releasing hormone
     agonist

  -  Patient may have had any number of prior chemotherapy regimens in the
     adjuvant/neoadjuvant and/or metastatic setting (including none)

  -  Patient may have had any number of prior treatments with anti-HER2 strategies in the
     adjuvant/neoadjuvant and/or metastatic setting (including none)

  -  Patient may have had any number of prior hormonal therapies in the
     adjuvant/neoadjuvant and/or metastatic setting (including none)

  -  Breast cancer patients in the expansion cohort must be hormone sensitive or have
     refractory disease

Exclusion Criteria:

  -  Patients currently receiving anticancer therapies or who have received anticancer
     therapies within 4 weeks of the start of everolimus (including chemotherapy, radiation
     therapy, antibody based therapy, etc.)

  -  Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g.
     sirolimus, temsirolimus)

  -  Known impairment of gastrointestinal (GI) function or GI disease that may
     significantly alter the absorption of oral everolimus

  -  Uncontrolled diabetes mellitus as defined by glycated hemoglobin (HbA1c) > 8% despite
     adequate therapy; patients with a known history of impaired fasting glucose or
     diabetes mellitus (DM) may be included, however blood glucose and antidiabetic
     treatment must be monitored closely throughout the trial and adjusted as necessary

  -  Patients who have any severe and/or uncontrolled medical conditions such as:

       -  Unstable angina pectoris, symptomatic congestive heart failure, myocardial
          infarction 6 months prior to start of everolimus, serious uncontrolled cardiac
          arrhythmia, or any other clinically significant cardiac disease

       -  Symptomatic congestive heart failure of New York Heart Association class III or
          IV

       -  Active (acute or chronic) or uncontrolled severe infection, liver disease such as
          cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable
          hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] and/or positive hepatitis B
          surface antigen [HbsAg], quantifiable hepatitis C virus [HCV]-ribonucleic acid
          [RNA])

       -  Known severely impaired lung function (spirometry and diffusion capacity of the
          lungs for carbon monoxide [DLCO] 50% or less of normal and oxygen [O2] saturation
          88% or less at rest on room air)

       -  Active, bleeding diathesis

  -  Chronic treatment with corticosteroids or other immunosuppressive agents; topical or
     inhaled corticosteroids are allowed

  -  Known history of human immunodeficiency virus (HIV) seropositivity

  -  Patients who have received live attenuated vaccines within 1 week of start of
     everolimus and during the study; patient should also avoid close contact with others
     who have received live attenuated vaccines; examples of live attenuated vaccines
     include intranasal influenza, measles, mumps, rubella, oral polio, bacillus
     Calmette-Guérin (BCG), yellow fever, varicella and TY21a typhoid vaccines

  -  Patients who have a history of another primary malignancy, with the exceptions of:
     non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from
     which the patient has been disease free for >= 3 years

  -  Patients with a history of non-compliance to medical regimens or who are considered
     potentially unreliable or will not be able to complete the entire study

  -  Patients who are currently part of or have participated in any clinical investigation
     with an investigational drug within 1 month prior to dosing

  -  Pregnant or nursing (lactating) women

  -  Women of child-bearing potential (WOCBP), defined as all women physiologically capable
     of becoming pregnant, must use highly effective methods of contraception during the
     study and 8 weeks after; highly effective contraception methods include combination of
     any two of the following:

       -  Use of oral, injected or implanted hormonal methods of contraception or

       -  Placement of an intrauterine device (IUD) or intrauterine system (IUS)

       -  Barrier methods of contraception: condom or occlusive cap (diaphragm or
          cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository

       -  Total abstinence or

       -  Male/female sterilization

  -  Women are considered post-menopausal and not of child-bearing potential if they have
     had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
     (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral
     oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior
     to randomization; in the case of oophorectomy alone, only when the reproductive status
     of the woman has been confirmed by follow up hormone level assessment is she
     considered not of child-bearing potential

  -  Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate
     contraception, during the study and for 8 weeks after the end of treatment

  -  History of allergic reactions or hypersensitivity to compounds similar to trastuzumab
     and/or letrozole

  -  Left ventricular ejection fraction (LVEF) < 50%

  -  Patients with corrected QT (QTc) interval > 0.47 seconds

  -  Prior exposure to more than 360 mg/m^2 doxorubicin, more than 120 mg/m^2 mitoxantrone,
     or more than 90 mg/m^2 idarubicin, or elevated baseline cardiac troponin I

  -  Drugs with potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)
     inhibitors and inducers should be avoided during the course of treatment

  -  Patients with active central nervous system (CNS) metastasis and/or carcinomatous
     meningitis; however, patients with CNS metastasis (except leptomeningeal disease) who
     have completed a therapy and are clinically stable for 3 weeks as defined as: (1) no
     evidence of new or enlarging CNS metastasis and (2) off steroids and/or
     anticonvulsants may be eligible

  -  Patient is known to be hepatitis B or hepatitis C-positive (these tests are not
     required)

  -  Patients with current active hepatic or biliary disease (with exception of patients
     with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic
     liver disease)