Everolimus, Letrozole and Trastuzumab in HR- and HER2/Neu-positive Patients

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of trastuzumab and everolimus based on when you join this study. Up to 5 dose levels of
trastuzumab and everolimus will be tested. Up to 3 participants will be enrolled at each dose
level. The first group of participants will receive the lowest dose level. Each new group
will receive a higher dose than the group before it, if no intolerable side effects were
seen. This will continue until the highest tolerable dose of trastuzumab and everolimus is
found.

All participants will receive the same dose level of letrozole.

After the 4th cycle is completed, you may be considered for treatment at a dose level that is
higher than the dose to which you were first assigned. In order for you to be treated at a
higher dose level, you must have tolerated the lower dose for at least 4 cycles of therapy.
Also, the new, higher dose that you will receive must be the same or below the highest
tolerated dose seen in this study so far.

Once the highest tolerated dose of the drug combination is found, 2 groups of 12 participants
will be enrolled in expansion groups. One group will include participants with breast cancer
and the other group will include participants with any solid tumor.

Study Drug Administration:

You will take letrozole and everolimus by mouth 1 time every day at the same time. Both drugs
should be taken either with or without food every time.

You will receive trastuzumab by vein on Day 1 of every 21-day cycle

Study Visits:

On Day 1 of every Cycle:

- You will have a physical exam.

- Blood (about 3 teaspoons) will be drawn for routine tests and to test for hepatitis B.

- If you can become pregnant, you will have a urine pregnancy test.

Every 2 cycles, you will have a CT scan or MRI to check the status of the disease. If the
doctor thinks it is needed, they will be performed more often.

At the end of Cycle 4 and every 4 cycles after that, you will have an ECHO or a MUGA scan to
check your heart function.

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drugs if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after you have completed the end-of-study and
follow-up visits.

End-of-Study Visit:

After your last dose of study drugs, you will have an end-of-study visit. At this visit:

- You will have a physical exam.

- Blood (about 3 teaspoons) and urine will be collected for routine tests.

This is an investigational study. Letrozole is FDA approved and commercially available for
the treatment of certain kinds of breast cancer. Everolimus is FDA approved to treat advanced
renal cell carcinoma. Trastuzumab is FDA approved for certain kinds of gastric and breast
cancer. The combination of these drugs is considered investigational.

Up to 42 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Signed informed consent obtained prior to any screening procedures

2. Subjects greater than or equal to18 years

3. Performance status
4. Adequate bone marrow function as shown by: ANC >/= 1 x 10^9/L, Platelets >/= 75 x
10^9/L, Hb >8 g/dL

5. Adequate liver function as shown by: a) Total serum bilirubin and AST
6. Adequate renal function: serum creatinine
7. Fasting serum cholesterol 2.5x 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

8. 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 ERBB2 mutation on next generation sequencing);

9. Must have measurable or evaluable disease

10. 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

11. 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 FSH and estradiol levels OR
Premenopausal women receiving a gonadotropin-releasing hormone agonist

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

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

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

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

Exclusion Criteria:

1. 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.)

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

3. Known impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral Everolimus

4. Uncontrolled diabetes mellitus as defined by 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

5. Patients who have any severe and/or uncontrolled medical conditions such as: a)
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; b) Symptomatic congestive heart
failure of New York heart Association Class III or IV; c) active (acute or chronic) or
uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver
disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg,
quantifiable HCV-RNA); d) known severely impaired lung function (spirometry and DLCO
50% or less of normal and O2 saturation 88% or less at rest on room air); e) active,
bleeding diathesis

6. Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or
inhaled corticosteroids are allowed

7. Known history of HIV seropositivity

8. 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, BCG, yellow fever,
varicella and TY21a typhoid vaccines

9. 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

10. 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

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

12. Pregnant or nursing (lactating) women

13. 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: a) Use of oral, injected or implanted hormonal methods of
contraception or; b) Placement of an intrauterine device (IUD) or intrauterine system
(IUS); c) Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository; d)
Total abstinence or; e) Male/female sterilization.

14. continued #13) 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.

15. 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

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

17. Left ventricular ejection fraction (LVEF) < 50%

18. Patients with QTc interval > 0.47 seconds

19. Prior exposure to more than 360 mg/m2 doxorubicin, more than 120 mg/m2 mitoxantrone,
or more than 90 mg/m2 idarubicin, or elevated baseline cardiac troponin I

20. Drugs with potent CYP3A4 inhibitors and inducers should be avoided during the course
of treatment

21. Patients with active 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

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

23. 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)