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

NCT02152943 | Completed Phase 1 FDA Drug

• 3 other identifiers: 2014-0119NCI-2014-01615P30CA016672
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Advanced Malignant Solid Neoplasm; Estrogen Receptor Positive; HER2/Neu Positive; Postmenopausal; Premenopausal; Progesterone Receptor Positive; Recurrent Breast Carcinoma; Refractory Breast Carcinoma; Refractory Hormone Receptor Positive Breast Carcinoma; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose and/or recommended phase II dose

  Defined as the highest dose at which no more than 1 of 6 patients has had dose-limiting toxicity.

  21 days

• Clinical benefit rate

  Defined as the percentage of patients with stable disease \>= 6 months/partial response/complete response. The point estimate and the 90% exact confidence interval for the clinical benefit rate will be calculated.

  Up to 4 years

Study Arms (1)

Treatment (everolimus, letrozole, trastuzumab)

EXPERIMENTAL

Patients receive everolimus PO QD and letrozole PO QD. Patients also receive trastuzumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Everolimus; Other: Laboratory Biomarker Analysis; Drug: Letrozole; Biological: Trastuzumab

Interventions

Everolimus DRUG

Given PO

Also known as: 42-O-(2-Hydroxy)ethyl Rapamycin, Afinitor, Certican, RAD 001, RAD001, Votubia, Zortress

Treatment (everolimus, letrozole, trastuzumab)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (everolimus, letrozole, trastuzumab)

Letrozole DRUG

Given PO

Also known as: CGS 20267, Femara

Treatment (everolimus, letrozole, trastuzumab)

Trastuzumab BIOLOGICAL

Given IV

Also known as: ABP 980, Anti-c-ERB-2, Anti-c-erbB2 Monoclonal Antibody, Anti-ERB-2, Anti-erbB-2, Anti-erbB2 Monoclonal Antibody, Anti-HER2/c-erbB2 Monoclonal Antibody, Anti-p185-HER2, c-erb-2 Monoclonal Antibody, HER2 Monoclonal Antibody, Herceptin, Herceptin Biosimilar PF-05280014, Herceptin Trastuzumab Biosimilar PF-05280014, MoAb HER2, Monoclonal Antibody c-erb-2, Monoclonal Antibody HER2, Ogivri, PF-05280014, rhuMAb HER2, RO0452317, Trastuzumab Biosimilar ABP 980, Trastuzumab Biosimilar HLX02, Trastuzumab Biosimilar PF-05280014, Trastuzumab-dkst

Treatment (everolimus, letrozole, trastuzumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (5)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MD Anderson in Katy

Houston, Texas, 77094, United States

Location

MD Anderson League City

Nassau Bay, Texas, 77058, United States

Location

MD Anderson in Sugar Land

Sugar Land, Texas, 77478, United States

Location

MD Anderson in The Woodlands

The Woodlands, Texas, 77384, United States

Location

Related Publications (1)

• Ballhausen A, Wheler JJ, Karp DD, Piha-Paul SA, Fu S, Pant S, Tsimberidou AM, Hong DS, Subbiah V, Holley VR, Huang HJ, Brewster AM, Koenig KB, Ibrahim NK, Meric-Bernstam F, Janku F. Phase I Study of Everolimus, Letrozole, and Trastuzumab in Patients with Hormone Receptor-positive Metastatic Breast Cancer or Other Solid Tumors. Clin Cancer Res. 2021 Mar 1;27(5):1247-1255. doi: 10.1158/1078-0432.CCR-20-2878. Epub 2020 Oct 28.

  PMID: 33115815 DERIVED

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Everolimus; Letrozole; Trastuzumab; PF-05280014; Ogivri; trastuzumab biosimilar HLX02

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Nitriles; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Filip Janku

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 29, 2014
• First Posted: June 2, 2014
• Study Start: July 17, 2014
• Primary Completion: December 14, 2020
• Study Completion: December 14, 2020
• Last Updated: December 19, 2020

Record last verified: 2020-12

Locations

US (5)