Clinical Trials /

Lapatinib and RAD-001 for HER2 Positive Metastatic Breast Cancer



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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Unknown status


Phase 2

Trial Eligibility



  • Brief Title: Lapatinib and RAD-001 for HER2 Positive Metastatic Breast Cancer
  • Official Title: Phase II Trial of Lapatinib and RAD-001 for HER2 Positive Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 12418
  • NCT ID: NCT01283789


  • Metastatic Breast Cancer


Lapatinib and RAD-001everolimus, tykerbLapatinib and RAD-001


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.

Trial Arms

Lapatinib and RAD-001ExperimentalRAD-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.
  • Lapatinib and RAD-001

Eligibility Criteria


          -  Females > 18 years of age

          -  Histologically proven adenocarcinoma of breast in primary or metastatic setting.
             Stage: Locally advanced (inoperable) or metastatic

          -  HER2 positive breast cancer (IHC 3+ or FISH ratio of > 2.0)

          -  ECOG Performance status 0-2

          -  Up to four prior chemotherapy regimens and anti-HER2 agents in metastatic setting
             allowed. Must have progressed on at least one HER2 targeted therapy (lapatinib or
             Herceptin) for metastatic breast cancer.

          -  Women of childbearing potential must have negative urine or serum pregnancy test
             within 7 days prior to administration of Everolimus. If barrier contraceptives are
             used, they must be continued throughout trial by both sexes. Hormonal contraceptives
             not acceptable as a sole method of contraception.

          -  Adequate kidney function: serum creatinine of < 1.5 mg/dl and/or creatinine clearance
             of > 60 mL/min

          -  Adequate hepatic function: transaminases < 2.5 x upper limit of normal (up to 5 x ULN
             in patients with liver metastases) and total bilirubin < 1.5 mg/dL. Adequate
             coagulation: INR ≤ 2.0 and PTT < 1.5 X the upper limit of institution normal range.
             Oral anticoagulants, eg, warfarin are CYP2C9 substrates and, as such, no interaction
             with Everolimus is expected. Anticoagulation with Coumadin is allowed if target INR is
             ≤ 2.0 and stable for > 2weeks. Anticoagulation with LMW is allowed.

          -  Must be informed of investigational nature of study, and must sign an informed consent

          -  Pretreatment lab values (must be performed within 14 days of patient registration
             unless otherwise specified. Other baseline studies must be performed within 30 days of

          -  Patients will have baseline CT chest, abdomen and pelvis within 30 days of

          -  Adequate cardiac function (LVEF ≥ 50% as measured by echocardiogram or MUGA scan).

          -  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, patient may be
             included after initiation of appropriate lipid lowering medication with approval from
             the principal investigator.

          -  Must have measurable or non-measurable disease by RECIST criteria (version 1.1), with
             radiologic scans performed within 30 days of registration. Baseline scans can include:

               -  CT Scan or MRI and Bone Scan OR

               -  PET/CT provided it is performed with both IV and oral contrast and the CT is
                  acquired with 5mm or less slice thickness. If IV contrast administration is
                  contraindicated, patients should have CT scan without contrast and bone scan or
                  MRI and bone scan.

               -  MRI of brain will be used for baseline assessment and tumor response assessment
                  for CNS lesions.

               -  Patients with CNS progression without systemic progression will be allowed to
                  remain on the protocol. Local treatment, radiation, surgery, and SRS will be
                  allowed while on protocol as deemed necessary by the treating physician.

               -  Baseline imaging method(s) should be used to determine tumor response throughout
                  course of study.

               -  Measurable disease: lesions with clearly defined margins that can be accurately
                  measured in at least one diameter (longest diameter to be recorded) with a
                  minimum size of:

                    -  10mm by CT scan (CT scan slice thickness no greater than 5mm)

                    -  10mm caliper measurement by clinical exam (lesions which cannot be
                       accurately measured with calipers should be recorded as non-measurable)

                    -  20mm by chest xray

                    -  Malignant lymph nodes: to be considered pathologically enlarged and
                       measurable. Lymph node must be > 15mm in short axis when assessed by CT
                       scan. At baseline and in follow-up, only short axis will be measured and

               -  Non-measurable disease: all other lesions including small lesions (longest
                  diameter < 10mm or pathological lymph nodes with > to <15 mm (short axis), and
                  masses with margins not clearly defined. Lesions that are considered
                  non-measurable include:

                    -  Bone lesions

                    -  Leptomeningeal disease

                    -  Ascites

                    -  Pleural/pericardial effusion

                    -  Inflammatory breast disease

                    -  Abdominal masses that are not confirmed and followed by imaging techniques

                    -  Cystic lesion

                    -  Lymphangitic involvement of skin or lung

          -  The following pre-study tests should be obtained within 14 days prior to registration
             in accordance with good medical practice. Results of these tests do not determine
             eligibility and minor deviations are acceptable if they do not impact patient safety
             in the judgment of the treating physician:

               -  ANC > 1,000/mm3

               -  platelet count > 100,000/mm3

               -  hemoglobin > 9 g/dL

        Exclusion Criteria:

          -  Patients who have received prior lapatinib for metatastic breast cancer will be

          -  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.

          -  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).

          -  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)

          -  Pregnant and lactating women. Women of reproductive potential not using or unwilling
             to use effective birth control methods throughout the trial.

          -  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.

          -  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.

          -  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.

          -  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.

          -  Patients should not receive immunization with attenuated live vaccines within one week
             of study entry or during study period.

          -  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.

          -  Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN.

          -  Active (acute or chronic) or uncontrolled severe infections.

          -  Known history of HIV seropositivity.

          -  Active, bleeding diathesis.

          -  Patients who have received prior treatment with an mTOR inhibitor (eg, sirolimus,
             temsirolimus, everolimus).

          -  Known hypersensitivity to Everolimus or other rapamycins (eg, sirolimus, temsirolimus)
             or to its excipients.

          -  Active Hepatitis B or C infection.

          -  Life expectancy of < 2 months.

          -  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.

          -  Prior investigational anti-cancer therapy within 4 weeks prior to Day 1.

          -  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.

          -  Other malignancies within past 3 years except for adequately treated carcinoma of
             cervix or basal or squamous cell carcinomas of the skin.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Assess the effectiveness of the combination of RAD-001 and lapatinib
Time Frame:6 months
Safety Issue:
Description: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

Measure:Overall benefit of combination
Time Frame:6 months
Safety Issue:
Description: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.


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Unknown status
Lead Sponsor:University of Kansas Medical Center

Trial Keywords

  • breast
  • cancer
  • metastatic
  • metastasis

Last Updated

February 8, 2017