A Phase II Study of Rapamycin and Trastuzumab for Patients With HER-2 Receptor Positive Metastatic Breast Cancer

NCT00411788 | Completed Phase 2 Results

• 1 other identifier: 0605001396
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 2

Brief Summary

Rapamune (generic name: Sirolimus®) is a drug that has been approved by the Food and Drug Administration (government) for use in patients receiving a kidney transplant to prevent the patient's body from rejecting the transplanted kidney. It has shown antitumor effects in the laboratory, but has not been approved at this time for the treatment of cancer. Herceptin is a new form of chemotherapy that has been approved by the Food and Drug Administration for the treatment of breast cancer. This study is designed to evaluate the effect and safety of combining Rapamune and Herceptin on breast cancer. Rapamune and Herceptin are being combined because results from our laboratory studies suggest that the combination of the two drugs is superior to either drug used alone. Results from laboratory studies performed at other institutions suggest that adding Rapamune to Herceptin may also reverse the resistance to Herceptin. Although there has been extensive experience using Herceptin alone and Rapamune alone in human subjects, the combination of Herceptin and Rapamune has not been previously evaluated. In addition, we hope to better understand how these treatments work against an individual woman's tumor by analyzing tissue samples before, and during treatment.

Conditions

Breast Cancer

Keywords

HER-2 positive; breast cancer; HER-2 positive breast cancer

Outcome Measures

Primary Outcomes (1)

• Proportion of Patients Who Are Progression-free (CR, PR and Stable Disease)

  To determine the clinical activity of oral daily rapamycin administered in combination with weekly intravenous trastuzumab in patients with HER2 overexpressing advanced breast cancer, the primary outcome is to determine the proportion of patients who are progression-free at 16 weeks, defined by complete response (CR), partial response (PR), or stable disease (SD).who are progression free at 16 weeks, defined by complete response (CR), partial response (PR), or stable disease (SD). Response objectives assessed using response evaluation criteria (RECIST) 1.0 This primary outcome was reworded from its original format when results were entered.

  16 weeks

Secondary Outcomes (5)

• Objective Response Rate (ORR)

  study completion up to 58 weeks

• Incidence of Cardiac Dysfunction

  study completion up to 58 weeks

• To Determine Pre and Post Therapy Changes in the Levels, Phosphorylation Status and/or Subcellular Localization of the Affected Signal Transduction Molecules HER2, Akt, S6K and 4EBP1 in Blood and Tumor Tissues

  Upon completion of study

• To Determine if Currently Available RNA Expression Profiles Associated With Response to Herceptin Will be Predictably Altered in Tumors Treated With Trastuzumab and Rapamycin, and Will Further Elucidate the Mechanism of Synergy of These Two Agents

  study completion

• To Evaluate the Use of FDG-PET as an Early Predictor of Response to the Combination of Rapamycin and Trastuzumab, be Assessing Changes in Glucose Metabolism and Cell Viability Between Pre- and Post-treatment

  Upon completion of study

Study Arms (1)

sirolimus and trastuzumab

EXPERIMENTAL

Patients received oral sirolimus 6 mg daily in combination with weekly trastuzumab administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg weekly in a 28-day cycle. A subsequent amendment allowed trastuzumab to be administered every 3 weeks for patient convenience, with a loading dose of 8 mg/kg followed by a 6 mg/kg in a 21-day cycle. Sirolimus was administered at a 6 mg oral daily dose. Cycles were repeated on an every 21 or 28-day schedule until disease progression, unacceptable toxicity, or the development of any of the criteria for study removal. Doses were reduced or discontinued based on tolerability.

Drug: Rapamycin; Drug: Trastuzumab

Interventions

Rapamycin DRUG

oral rapamycin 6 mg daily

Also known as: Rapamune, Sirolimus

sirolimus and trastuzumab

Trastuzumab DRUG

Trastuzumab 4 mg/kg will be administered (intravenous) on day 1, and this will be followed by weekly dose of 2 mg/kg starting day 8.

Also known as: Herceptin

sirolimus and trastuzumab

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed HER2 overexpressing (IHC 3+ and/or FISH +) metastatic breast cancer with measurable disease. Patients with either HER2 3+ positive tumors by immunohistochemistry (Dako Herceptest®) or gene amplification (\> 2 copies) by fluorescence in-situ hybridation (FISH) are eligible.
• Progression following at least 8 weeks of standard doses of Herceptin or a Herceptin containing regimen.
• Off Herceptin for a minimum of 2 weeks.
• Patients must have measurable disease as defined by RECIST guidelines (the lesion that will be biopsied on study cannot be the only measurable lesion).
• Life expectancy \> 3 months
• Age ≥18 years
• ECOG performance status ≤2
• Adequate bone marrow function as indicated by the following:
• ANC ≥1500/µL
• Platelets ≥100,000/µL
• Hemoglobin ≥9 g/dL
• Adequate liver function, as indicated by bilirubin ≤1.5 x ULN, AST or ALT \<2x ULN.
• Adequate renal function, as indicated by creatinine \<1.5 x upper limit of normal (ULN)
• Ability to understand and the willingness to sign a written informed consent.
• Adequate birth control: Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and must have a negative serum or urine pregnancy test within 1 week prior to beginning treatment on this trial. Pregnant and nursing patients are excluded because the effects of the combination of Rapamycin on a fetus or nursing child are unknown. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

You may not qualify if:

• Active infection or treatment for systemic infections within 14 days of enrollment
• Patients with active brain metastases requiring treatment, inclusive but not limited to surgery, radiation, and corticosteroids (patients with asymptomatic non- progressing brain metastasis who have completed treatment ≥30 days before enrollment and without evidence of progression on a post treatment MRI may be considered for the study).
• Pregnant or lactating women
• Prior chemotherapy within the last 4 weeks (last 6 weeks for nitrosureas/mitomycin)
• Prior radiation therapy within the last 4 weeks; prior radiation therapy to indicator lesion (unless objective disease recurrence or progression within the radiation portal has been documented since completion of radiation).
• Prior therapy with rapamycin, rapamycin analogs, or experimental agents targeting mTOR.
• Concomitant malignancies or previous malignancies within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
• Ejection fraction \<50% or below the lower limit of the institutional normal range, whichever is lower
• Hypersensitivity to trial medications
• Patients may not be receiving any other investigational agents within 30 days before enrollment.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because the investigational agents may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated.
• HIV-positive patients are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy and the potential pharmacokinetic interaction between antiretroviral therapy and the investigational agents.
• Use of all herbal and alternative medications within 4 weeks. All herbal and alternative medications should be discontinued while on study, these include but not limited to: Hydrastis canadensis (goldenseal) - Uncaria tomentosa (cat's claw) - Echinacea angustifolia roots - trifolium pratense (wild cherry) - matricaria chamomila (chamomile) - Glycyrrhiza glabra (licorice) - dillapiol - naringenim.
• Use of any of these medications within 4 weeks; cyclosporine, diltiazen, ketoconazole, rifampin, fluconazole, delavirdine, nicardipine, pioglitazone, and sulfonamides, erythromycin, clarithromycin, itraconazole, erythromycin, metoclopramide, nevirapine, phenobarbital, phenytoin, indinavir, fosamprenavir, nefazadone, St Johns Wort.

Sponsors & Collaborators

• Yale University: lead
• Genentech, Inc.: collaborator

Study Sites (2)

Bridgeport Hospital

Bridgeport, Connecticut, 06610, United States

Location

Yale Comprehensive Cancer Center at Yale University School of Medicine

New Haven, Connecticut, 06519, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Sirolimus; Trastuzumab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

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: Abu-Khalaf, Maysa
• Organization: Yale University

maysa.abu-khalaf@yale.edu

(203) 785-4095

Study Officials

• Maysa Abu-Khalaf, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2006
• First Posted: December 15, 2006
• Study Start: December 1, 2006
• Primary Completion: May 1, 2010
• Study Completion: May 1, 2010
• Last Updated: September 21, 2016
• Results First Posted: September 21, 2016

Record last verified: 2016-08

Locations

US (2)