Dose Escalation Followed by Study of RAD001 in Combination With Trastuzumab in HER2-Positive Metastatic Breast Cancer

NCT00458237 | Completed Phase 1 Results DMC

• 1 other identifier: 06-124
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this research study is to determine the safety of RAD001 and the highest dose of this drug that can be given to people with HER2-positive metastatic breast cancer safely in combination with trastuzumab. RAD001 has been used in patients with severe rheumatoid arthritis, in recipients of solid-organ transplants, healthy volunteers and experiments with animals, and information from those other research studies suggest that this RAD001 may help to stop cancer cells from growing abnormally.

Conditions

Breast Cancer

Keywords

HER2 positive; metastatic breast cancer; RAD001; Herceptin

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD)

  The MTD is determined by the number of patients who experience a dose limiting toxicity (DLT). The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached. Dose Limiting Toxicities (DLTs) were defined as follows (CTCAE v4.0): * Any grade 4 hematologic toxicity, excluding anemia. * Any grade 3 or 4 nonhematologic toxicity, except for nausea, vomiting, diarrhea, or hyperlipidemia that responds promptly (within 24 hours for nausea, vomiting, and diarrhea and within 1 week for hyperlipidemia) to appropriate treatment, and except for cardiac toxicity which will be assessed after 12 weeks of treatment. * Need to hold \>1 dose of trastuzumab or \> 7 doses of RAD001 within the first 3 weeks because of the presence of toxicity.

  Cycle One (first 21 days of treatment)

Secondary Outcomes (1)

• Clinical Response Rate

  Disease assessments occurred every 9 weeks (3 cycles) on treatment. Treatment continued until disease progression or unacceptable toxicity. Median duration of treatment was 2.4 months.

Study Arms (3)

Ph I: Everolimus L1 + Trastuzumab

EXPERIMENTAL

Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus 5 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.

Drug: Everolimus; Drug: Trastuzumab

Ph I: Everolimus L2 + Trastuzumab

EXPERIMENTAL

Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus 10 mg by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.

Drug: Everolimus; Drug: Trastuzumab

PhII: Everolimus MTD + Trastuzumab

EXPERIMENTAL

Cycle duration is 21 days. Participants receive trastuzumab 6 mg/kg \[8 mg/kg loading dose\] IV once every three weeks and take everolimus at the MTD by mouth daily on days 1-21. Participants are treated until disease progression or unacceptable toxicity.

Drug: Everolimus; Drug: Trastuzumab

Interventions

Everolimus DRUG

Everolimus is being administered orally 7 days per week.

Also known as: RAD001

Ph I: Everolimus L1 + Trastuzumab; Ph I: Everolimus L2 + Trastuzumab; PhII: Everolimus MTD + Trastuzumab

Trastuzumab DRUG

Trastuzumab is being administered at a dose of 6 mg/kg intravenously once every 21 days.

Also known as: Herceptin

Ph I: Everolimus L1 + Trastuzumab; Ph I: Everolimus L2 + Trastuzumab; PhII: Everolimus MTD + Trastuzumab

Eligibility Criteria

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

You may qualify if:

• Histologically or cytologically confirmed invasive breast cancer, with stage IV disease
• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as greater than or equal to 20mm with conventional techniques or as greater than or equal to 10mm with spiral CT scan.
• Primary tumor or metastasis must overexpress HER2
• Patient must have received 1-2 prior chemotherapeutic regiments for metastatic breast cancer and must have been off treatment for at least three weeks.
• Patient must have received and progressed on at least 1 prior trastuzumab-containing regimen, but not more than 2, in the metastatic setting.
• Patients may have received prior radiation therapy
• Patients may have received hormonal therapy in the adjuvant or metastatic setting
• years of age or older
• Life expectancy of greater than 6 months
• Normal organ and marrow function as defined in the protocol
• Left ventricular ejection fraction (LVEF) greater than or equal to the institutional lower limit of normal

You may not qualify if:

• Treatment with any investigational drug within 4 weeks
• Long-term treatment, over 3 months, with a systemic steroid or another immunosuppressive agent
• Other malignancies within the past 3 years, except for adequately treated carcinoma of teh cervix or basal-or squamous-cell carcinoma of the skin
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001
• An active, bleeding diathesis or an oral anti-vitamin K medication
• Prior treatment with an mTOR inhibitor
• History of non-compliance with medical regimens
• Unwillingness or inability to comply with the protocol
• Major surgery within 2 weeks before study entry
• Patients with active brain metastases or leptomeningeal carcinomatosis
• Patients who have experienced grade 1 or grade 2 hypersensitivity reactions to prior trastuzumab therapy are eligible ONLY IF these reactions did not prevent further administration
• Severe and/or uncontrolled intercurrent medical condition, psychiatric illness or a social situation that could limit their ability to comply with the study requirements.
• Pregnant or breast-feeding women
• HIV positive patients
• Known hypersensitivity to RAD001 (everolimus) or other rapamycins

Sponsors & Collaborators

• Beth Israel Deaconess Medical Center: lead
• Novartis Pharmaceuticals: collaborator
• Dana-Farber Cancer Institute: collaborator

Study Sites (2)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Morrow PK, Wulf GM, Ensor J, Booser DJ, Moore JA, Flores PR, Xiong Y, Zhang S, Krop IE, Winer EP, Kindelberger DW, Coviello J, Sahin AA, Nunez R, Hortobagyi GN, Yu D, Esteva FJ. Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol. 2011 Aug 10;29(23):3126-32. doi: 10.1200/JCO.2010.32.2321. Epub 2011 Jul 5.

  PMID: 21730275 RESULT

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Everolimus; Trastuzumab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Gerburg Wulf
• Organization: Beth Israel Deaconess Medical Center

gwulf@bidmc.harvard.edu

(617) 667-1910

Study Officials

• Gerburg Wulf, MD, PhD

  Beth Israel Deaconess Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 9, 2007
• First Posted: April 10, 2007
• Study Start: April 1, 2007
• Primary Completion: April 1, 2010
• Study Completion: April 1, 2010
• Last Updated: October 20, 2016
• Results First Posted: March 10, 2016

Record last verified: 2016-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)