Patient case: 56-year-old female with breast cancer; genetic feature: ERBB2

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

Summary: The goal of this clinical research study is to find the highest tolerable dose of Femara (letrozole) that can be given in combination with Afinitor (everolimus) and Herceptin (trastuzumab) to patients with advanced cancer. The safety of this drug combination will also be studied.

Detailed description: 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.

Eligibility: Inclusion Criteria:
  1. Signed informed consent obtained prior to any screening procedures
  2. Subjects greater than or equal to18 years
  3. Performance status </= 1
  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 </= 2.0 mg/dL; b) ALT and AST </= 2.5x ULN (</= 5x ULN in patients with liver metastases); c) INR </=2
  6. Adequate renal function: serum creatinine </=1.5x ULN
  7. Fasting serum cholesterol </=300 mg/dL OR </=7.75 mmol/L AND fasting triglycerides </= 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)

Relevance to patient case: definitely relevant