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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by M.D. Anderson Cancer Center
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT02152943
First received: May 29, 2014
Last updated: July 17, 2014
Last verified: July 2014
  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.


Condition Intervention Phase
Breast Cancer
Solid Tumors
Drug: Everolimus
Drug: Trastuzumab
Drug: Letrozole
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of Everolimus, Letrozole and Trastuzumab [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    MTD defined by dose limiting toxicities (DLTs) that occur in the first cycle (4 weeks) (induction phase). Dose-limiting toxicity (DLT) defined as any clinically grade 3 or 4 non-hematologic toxicity as defined in the NCI CTC v4.0.

  • Clinical Benefit Rate (CBR) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Clinical benefit rate defined as percentage of patients with stable disease (SD) ≥ 6 months/partial response (PR)/complete response (CR). The point estimate and the 90% exact confidence interval for the clinical benefit rate will be calculated.


Estimated Enrollment: 42
Study Start Date: July 2014
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Advanced Metastatic Breast Cancer Group

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.

Drug: Everolimus

Escalation Group Starting Dose of Everolimus: 5 mg by mouth daily.

Expansion Group Starting Dose of Everolimus: Maximum tolerated dose from Escalation Group.

Other Names:
  • Afinitor
  • Zortress
  • RAD001
Drug: Trastuzumab

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.

Expansion Group Starting Dose of Trastuzumab: Maximum tolerated dose from Escalation Group.

Other Name: Herceptin
Drug: Letrozole
Escalation Group and Expansion Group Letrozole Dose: 2.5 mg by mouth daily.
Other Name: Femara
Experimental: Solid Tumor Group

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.

Drug: Everolimus

Escalation Group Starting Dose of Everolimus: 5 mg by mouth daily.

Expansion Group Starting Dose of Everolimus: Maximum tolerated dose from Escalation Group.

Other Names:
  • Afinitor
  • Zortress
  • RAD001
Drug: Trastuzumab

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.

Expansion Group Starting Dose of Trastuzumab: Maximum tolerated dose from Escalation Group.

Other Name: Herceptin
Drug: Letrozole
Escalation Group and Expansion Group Letrozole Dose: 2.5 mg by mouth daily.
Other Name: Femara

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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: absolute neutrophil count (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 upper limit of normal (ULN) (</= 5x ULN in patients with liver metastases); c) international normalized ratio (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+);
  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 hepatitis B virus (HBV)-DNA and/or positive HbsAg, quantifiable HCV-RNA); d) known severely impaired lung function (spirometry and diffusing capacity of lung for carbon monoxide (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 corrected QT interval (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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02152943

Contacts
Contact: Jennifer J. Wheler, MD 713-563-1930

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Novartis
Investigators
Principal Investigator: Jennifer J. Wheler, MD M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02152943     History of Changes
Other Study ID Numbers: 2014-0119
Study First Received: May 29, 2014
Last Updated: July 17, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
Breast Cancer
Advanced Metastatic Breast Cancer
Solid Tumors
Advanced Solid Tumors
Everolimus
Afinitor
Zortress
RAD001
Trastuzumab
Herceptin
Letrozole
Femara

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Everolimus
Sirolimus
Letrozole
Trastuzumab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Aromatase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 01, 2014