Lapatinib and RAD-001 for HER2 Positive Metastatic Breast Cancer
- Registration Number
- NCT01283789
- Lead Sponsor
- University of Kansas Medical Center
- Brief Summary
By doing this study, researchers hope to learn the effectiveness of the combination of Lapatinib and RAD-001 for treating patients who have progressed on previous therapies.
- Detailed Description
Twenty to twenty five percent of Human Breast Cancers are HER2 positive. HER2 positivity confers a poor prognosis in the absence of HER2 targeted therapies (trastuzumab and lapatinib). With these targeted agents often combined with chemotherapy, the treatment of HER2 positive breast cancer has improved greatly, both in metastatic and adjuvant settings. However most patients with metastatic HER2 positive breast cancer will eventually develop resistance to these agents and succumb to their disease. Therefore, there is a need to test new agents and new combinations that can increase the efficacy of HER2 targeted therapy and/or prevent resistance to HER2 targeted therapies.
A unique feature of HER2 positive breast cancers is a rather high incidence of brain metastasis in this population. Brain metastases develop in one third to one half of patients with advanced HER2+ breast cancer and CNS is a frequent site of trastuzumab failure. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Compared to trastuzumab, which has no CNS activity, lapatinib, an epidermal growth factor receptor/HER2 inhibitor, has modest CNS activity. In a study of more than 200 patients by Lin et al, 21% of patients experienced a 20% volumetric reduction in their CNS lesions on lapatinib. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a 20% volumetric reduction in their CNS lesions. Mammalian target of Rapamycin (mTOR) is a serine/threonine kinase that regulates key functions associated with cell growth, survival and angiogenesis. mTOR is activated by HER signaling, PI3K oncogenic mutation and loss of PTEN function. In vitro data suggests that activation of mTOR by PTEN loss and PI3K mutation induces trastuzumab resistance. Preclinical studies have shown that mTOR inhibition enhances the efficacy of trastuzumab and reverses trastuzumab resistance caused by PTEN loss. This preclinical finding was confirmed in 2 recent Phase 1 studies where addition of mTOR inhibitor (RAD-001) to trastuzumab and chemotherapy reversed the resistance to Trastuzumab in patients with heavily pretreated metastatic HER2 positive breast cancer. Thus, mTOR inhibition would be an attractive modality to add to HER2 targeted therapy for improving outcomes in women with HER2 positive breast cancer. Everolimus (RAD001), a rapamycin analogue, is an orally administered inhibitor of mTOR. Everolimus has shown promising activity in solid tumors. PK data in mouse models indicated that penetration of rapamycin and Everolimus into the CNS is substantial. Everolimus brain levels are approximately one-third that of systemic levels at 48 hours after a dose.
A small molecule inhibitor of HER2, lapatinib is clinically active in women with advanced HER2-positive breast cancer who have progressed on trastuzumab treatment. However, the effectiveness of this class of agents is limited by either primary resistance or acquired resistance. Using an unbiased genetic approach, Eichhorn et al performed a genome wide loss-of-function short hairpin RNA screen to identify novel modulators of resistance to lapatinib. Tumor suppressor PTEN was identified as a modulator of lapatinib sensitivity in vitro and in vivo. In addition, they show that two dominant activating mutations in PI3K pathway which are prevalent in breast cancer, also confer resistance to lapatinib. They also showed that PI3K-induced lapatinib resistance could be abrogated through the use of NVP-BEZ235, a dual inhibitor of PI3K/mTOR. This suggests that deregulation of the PI3K pathway leads to lapatinib resistance, which can be effectively reversed by inhibition of PI3K/mTOR pathway.
In summary, the combination of Everolimus and lapatinib needs to be studied in women with metastatic breast cancer who have progressed on at least one prior anti-HER2 therapy. If RAD-001 is able to overcome resistance to anti-HER2 therapies, a very desirable response rate and prolongation in TTP can be expected. Moreover, both lapatinib and Everolimus appear to be able to cross the blood brain barrier, and this combination may prove to be effective in controling CNS metastases in this population. The investigators hypothesize that combining mTOR inhibitor Everolimus with lapatinib will be an effective strategy for patients who have progressed on a prior anti-HER2 therapy, both systemically and within the CNS.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- Female
- Target Recruitment
- 23
Not provided
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Patients who have received prior lapatinib for metatastic breast cancer will be excluded.
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Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics or psychiatric illness/social situations that would limit compliance with study requirements.
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GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (eg, Crohn's, ulcerative colitis).
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Current active hepatic or biliary disease (exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
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Pregnant and lactating women. Women of reproductive potential not using or unwilling to use effective birth control methods throughout the trial.
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Severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study such as:
- Symptomatic congestive heart failure of NYHA Class III or IV
- unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
- liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C). Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.
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Patients with symptomatic brain metastases who have not completed radiation therapy and/or are receiving systemic steroid therapy. Patients with leptomeningeal disease will be excluded.
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Patients with CNS progression during the trial will be allowed to receive local treatment for CNS metastases and will remain on protocol. Trial medications will be held during hte time patients are receiving radiation therapy as dictated by their treating physicians.
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Patients receiving chronic, systemic treatment with corticosteroids (of more than 4mg/day or equivalent of dexamethasone. Doses of dexamethasone of up to 8mg/day may be administered for less than 2 weeks) or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
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Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period.
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Severely impaired lung function defined as spirometry and DLCO that is < 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air.
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Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN.
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Active (acute or chronic) or uncontrolled severe infections.
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Known history of HIV seropositivity.
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Active, bleeding diathesis.
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Patients who have received prior treatment with an mTOR inhibitor (eg, sirolimus, temsirolimus, everolimus).
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Known hypersensitivity to Everolimus or other rapamycins (eg, sirolimus, temsirolimus) or to its excipients.
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Active Hepatitis B or C infection.
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Life expectancy of < 2 months.
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Prior anti-cancer therapy (eg, biologic or other targeted therapy, chemotherapy, hormonal therapy) within 2 weeks prior to Day 1 if the patient has recovered from all AEs to grade 1 except for alopecia.
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Prior investigational anti-cancer therapy within 4 weeks prior to Day 1.
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Patients who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, have not recovered from side effects of any major surgery (defined as requiring general anesthesia) or may require major surgery during the course of study.
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Other malignancies within past 3 years except for adequately treated carcinoma of cervix or basal or squamous cell carcinomas of the skin.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Lapatinib and RAD-001 Lapatinib and RAD-001 RAD-001 will be administered orally as a once-daily dose of 5 mg (one 5 mg tablet) continuously from study day 1 until progression of disease or unacceptable toxicity. Patients will be instructed to take RAD-001 in the morning, at the same time each day. Lapatinib will be administered orally as a once-daily dose of 1250 mg (five 250 mg tablets) continuously from study day 1 until progression of disease or unacceptable toxicity. Patients will be instructed to take lapatinib at bedtime, at the same time each day. Lapatinib should be taken by the patient in a fasting state.
- Primary Outcome Measures
Name Time Method Assess the effectiveness of the combination of RAD-001 and lapatinib 6 months To assess the effectiveness of the combination of RAD-001 and lapatinib as measured by the six-month Overall Response Rate in women with MBC who have progressed on trastuzumab and/or lapatinib based therapies.
- Secondary Outcome Measures
Name Time Method Overall benefit of combination 6 months * Six-month Progression Free Survival.
* Safety and Tolerability of the combination.
* Six-month Objective CNS response rate in patients with CNS metastases.
* Six-month Clinical benefit rate of systemic disease.
* Six-month Clinical benefit rate in the CNS.
* Rate of development of Brain Metastases on six months of therapy.
Trial Locations
- Locations (1)
University of Kansas Medical Centner
🇺🇸Kansas City, Kansas, United States