Clinical Trials /

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

NCT02152943

Description:

This phase I trial studies the side effects and best dose of everolimus and trastuzumab when given together with letrozole in treating patients with hormone receptor-positive and human epidermal growth factor (EGF) receptor 2 (HER2)-positive breast cancer or other solid tumors that have spread to other places in the body. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by blocking the use of estrogen by tumor cells. Immunotherapy with monoclonal antibodies, such as trastuzumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving everolimus, letrozole, and trastuzumab together may be a better treatment for breast cancer and other solid tumors than everolimus alone.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Everolimus</span>, Letrozole and <span class="go-doc-concept go-doc-intervention">Trastuzumab</span> in HR- and <span class="go-doc-concept go-doc-biomarker">HER2</span>/Neu-positive Patients

Title

  • Brief Title: Everolimus, Letrozole and Trastuzumab in HR- and HER2/Neu-positive Patients
  • Official Title: Combination Treatment With Everolimus, Letrozole and Trastuzumab in Hormone Receptor and HER2/Neu-positive Patients With Advanced Metastatic Breast Cancer and Other Solid Tumors: Evaluating Synergy and Overcoming Resistance
  • Clinical Trial IDs

    NCT ID: NCT02152943

    ORG ID: 2014-0119

    NCI ID: NCI-2014-01615

    Trial Conditions

    Breast Cancer

    Solid Tumors

    Trial Interventions

    Drug Synonyms Arms
    Everolimus Afinitor, Zortress, RAD001 Advanced Metastatic Breast Cancer Group, Solid Tumor Group
    Trastuzumab Herceptin Advanced Metastatic Breast Cancer Group, Solid Tumor Group
    Letrozole Femara Advanced Metastatic Breast Cancer Group, Solid Tumor Group

    Trial Purpose

    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.

    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.

    Trial Arms

    Name Type Description Interventions
    Advanced Metastatic Breast Cancer Group Experimental Everolimus and Letrozole should be administered orally once daily at the same time every day, either consistently with or consistently without food. Trastuzumab will be administered intravenously (IV) once every 3 weeks. A cycle will be considered 21 days. Escalation Group Starting Dose of Everolimus: 5 mg by mouth daily. Escalation Group Starting Dose of Trastuzumab: 4 mg/Kg loading dose by vein every 3 weeks, then 2 mg/Kg maintenance dose by vein every 3 weeks. Escalation Group and Expansion Group Letrozole Dose: 2.5 mg by mouth daily. Expansion Group Starting Dose of Everolimus and Trastuzumab: Maximum tolerated dose from Escalation Group. Everolimus, Trastuzumab, Letrozole
    Solid Tumor Group Experimental Everolimus and Letrozole should be administered orally once daily at the same time every day, either consistently with or consistently without food. Trastuzumab will be administered intravenously (IV) once every 3 weeks. A cycle will be considered 21 days. Escalation Group Starting Dose of Everolimus: 5 mg by mouth daily. Escalation Group Starting Dose of Trastuzumab: 4 mg/Kg loading dose by vein every 3 weeks, then 2 mg/Kg maintenance dose by vein every 3 weeks. Escalation Group and Expansion Group Letrozole Dose: 2.5 mg by mouth daily. Expansion Group Starting Dose of Everolimus and Trastuzumab: Maximum tolerated dose from Escalation Group. Everolimus, Trastuzumab, Letrozole

    Eligibility Criteria

    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)

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum Tolerated Dose (MTD) of Everolimus, Letrozole and Trastuzumab

    Clinical Benefit Rate (CBR)

    Secondary Outcome Measures

    Trial Keywords

    Breast Cancer

    Advanced Metastatic Breast Cancer

    Solid Tumors

    Advanced Solid Tumors

    Everolimus

    Afinitor

    Zortress

    RAD001

    Trastuzumab

    Herceptin

    Letrozole

    Femara