Metastatic Breast CancerPhase 2NCT00134680
Letrozole, Herceptin in Her2neu +, Estrogen Receptor [ER] and/or Progesterone Receptor [PR] Positive, MBC
A Phase 2 study testing Letrozole and Trastuzumab in people with Metastatic Breast Cancer, run by Duke University at 4 sites in United States.
Trial summary
The purpose of the study is to investigate the effects (good and bad) that the combination of the drugs letrozole (also called Femara™) and trastuzumab (also called Herceptin®) has on breast cancer. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Metastatic Breast Cancer
- What is being tested?
- Letrozole and Trastuzumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 33 participants
- Where
- 4 sitesUnited States
- Study dates
- Jan 2000to Jul 2005
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Postmenopausal.
- If premenopausal at diagnosis, eligible if undergoes treatment with luteinising hormone-releasing hormone (LHRH) agonist or surgical ovarian ablation before initiating treatment (tx).
- Tumor cell expression of ER and/or PR and ErbB2. Expression can be ascertained on either primary or metastatic site.
- Patient may have received adjuvant and/or neoadjuvant chemotherapy.
- Patient who received adjuvant/neoadjuvant chemotherapy, tx. must have been discontinued for 4 weeks and patient must have recovered from all acute toxicities, except alopecia.
- Prior radiotherapy is permitted as long as it was planned before start of study medication and is completed within 3 weeks of starting trial medication.
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- Prior megestrol acetate or raloxifene therapy is permitted, but must be stopped prior to trial entry.
- Prior tamoxifen therapy.
- At least one bidimensionally measurable lesion.
- ECOG performance status 0-2.
- Patient should have life expectancy of 6 months.
- Patient must have adequate hematologic function: absolute neutrophil count (ANC) 1000/mm3; platelets 75,000/mm3.
- Patient must have adequate renal and liver function, defined as: serum creatinine less than or equal to 1.5 times the upper limit of normal; serum bilirubin less than or equal to 1.5 times the upper limit of normal (three times the upper limit of normal for patients with hereditary benign hyperbilirubinaemia); transaminases (ALT, AST) less than or equal to 2.5 times the upper limit of normal in patients without liver metastasis, or less than or equal to 5 times the upper limit of normal in patients with liver metastasis.
- Ejection fractions by multiple-gated acquisition (MUGA) scan or echocardiogram greater than 50%
- Patient must give written informed consent prior to initiation of any invasive study-related procedures that would otherwise not be performed, and must be able to comply with scheduled visits and evaluations.
- Treatment with bisphosphonates during the trial is permitted.
Who cannot join
- Prior exposure to any aromatase inhibitor (aminoglutethimide, formestane anastrozole, letrozole or exemestane) for more than 28 days. Patients that have already started on aromatase inhibitors (AIs) will be eligible for the protocol if they meet all other eligibility requirements and receive loading dose of trastuzumab not more than 28 days after starting AI therapy. Patients who initially received anastrozole or exemestane will be switched to letrozole.
- Prior treatment with trastuzumab
- Prior anthracycline exposure in adjuvant setting > 360 mg/m2.
- Patients with central nervous system (CNS) involvement with metastatic breast cancer or life threatening lymphangitic or large volume lung or liver disease.
- Patient's only qualifying lesions have been previously irradiated or are scheduled for irradiation following study entry.
- Severe or uncontrolled concomitant disease from other causes.
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- More than 1 prior course of chemotherapy for metastatic disease. If patient has received one course of palliative chemotherapy, acute toxicities must have resolved and patient must be experiencing progressive disease at time of enrollment.
- ECOG performance status 3 or 4.
- Patient has previous malignancies other than breast cancer except:
- adequately treated in situ carcinoma of cervix;
- localized basal or squamous cell carcinoma of skin; or
- any previous malignancy treated with curative intent with recurrence risk of less than 30%.
- Patient is unable to understand informed consent or is unlikely to be compliant with protocol.
Trial locations and contacts
4 sites in 1 country.
United States4 sites
Dana Farber Cancer Institute
Boston, Massachusetts, 02115
Duke University Medical Center
Durham, North Carolina, 27710
Siteman Cancer Center, Washington University
St Louis, Missouri, 63110
Lombardi Cancer Institute, Georgetown University Medical Center
Washington D.C., District of Columbia, 20007
About this study
Official title: Phase II Trial of the Combination of Letrozole 2.5 mg Daily and Trastuzumab 2 mg/kg Weekly in ErbB2 Positive and Estrogen Receptor and/or Progesterone Receptor Positive Metastatic Breast Cancer
The purpose of the study is to investigate the effects (good and bad) that the combination of the drugs letrozole (also called Femara™) and trastuzumab (also called Herceptin®) has on breast cancer. The United States (US) Food and Drug Administration has approved both letrozole and Herceptin for the treatment of advanced breast cancer. Doctors hope that the combination will work better than either drug alone.
Read the detailed description
Since ER function is regulated by peptide growth factor signaling, the phenotype of ER positive tumors may be influenced by the expression of growth factors and growth factor receptors. A potential interaction between ErbB2 (HER2/neu) expression and the success of endocrine therapy has been examined. ErbB2 expression was shown to correlate with resistance to hormone therapy.
An inverse relationship between endocrine therapy responsiveness and ErbB2 expression has not been observed in all studies. This may be due to discordant ER status between the primary tumor and metastatic sites. ER status can be discordant in approximately 20% of cases, with a tendency for metastatic disease to become ER negative with time. Data concerning ErbB2 is more limited, but there may be similar lack of concordance between primary tumor and metastases.
Inhibition of ErbB2 signaling may slow the development of resistance to estrogen deprivation therapy by inhibiting a pathway that promotes estrogen independent growth. The ErbB2 signal transduction pathway bypasses the requirement for estrogen for breast epithelial cell growth. When ErbB2 is activated in ER positive breast cancer cells in vitro, ER becomes phosphorylated and capable of stimulating transcription without estrogen. Chronic activation with heregulin, a ligand for the ErbB family of receptors, leads to ER down-regulation and the acquisition of an ER negative phenotype.
Estrogen deprivation therapy with selective aromatase inhibitors (SAIs) has become the standard of care for postmenopausal women with tamoxifen-resistant advanced breast cancer. About 1/3 of patients benefit from this therapy. There is interest in treating endocrine therapy refractory breast cancer with the recombinant DNA-derived humanized monoclonal antibody trastuzumab. When given alone, trastuzumab has an endocrine therapy-like risk benefit ratio. Trastuzumab targets ErbB2 (HER2/neu). Some breast cancers may coexpress ER and ErbB2.
Letrozole (Femara™) is a highly selective oral non-steroidal aromatase inhibitor. According to in vitro data, letrozole is 170-fold more potent in inhibiting aromatase than aminoglutethimide (AG) and 19-fold more active than anastrozole. Letrozole effectively inhibits intratumoral aromatase according to in vitro and in vivo data. It is indicated for the treatment of advanced breast carcinoma in post-menopausal women who have failed prior anti-estrogen therapy. Final FDA approval was granted in 1997. In two randomized phase IIb/III studies in patients previously treated with an antiestrogen, 19.5% and 23.6% of patients achieved an objective response with letrozole 2.5 mg/day compared with 12.4% receiving AG and 16.4% of patients receiving megace. Median overall survival was increased in the letrozole 2.5 mg/day group by 8 months compared to AG and by 3 months compared to megace. The lower 0.5 mg/day dose of letrozole was associated with poorer response rates and overall survival in both studies.
Trastuzumab (Herceptin®) was approved in 1998. A trial of trastuzumab as a single agent for first line treatment of advanced disease has been reported. Response rate in the first 62 patients was 24%.
The primary objective of this trial is to determine the proportion of patients with ER and/or PR positive, ErbB2 positive tamoxifen resistant metastatic breast cancer who achieve complete remission or partial remission or no significant change in lesion size for > 24 weeks from a combination of letrozole and trastuzumab. The study will also determine duration of response and median time to progression, evaluate toxicity, generate a tumor and serum bank, and analyze ErbB2 expression on circulating malignant cells during treatment.
The study will enroll 35 patients
- Conditions
- Metastatic Breast Cancer
- Being tested
- Letrozole, Trastuzumab
- Keywords
- estrogen receptor positive, progesterone receptor positive, ErbB2 positive, metastatic breast cancer
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LetrozoleDrug
Also called Femara
Letrozole tablets 2.5 mg by mouth daily
TrastuzumabDrug
Also called Herceptin
Weekly trastuzumab (4 mg/kg loading dose given by IV over 90 minutes folowed by 2 mg/kg given by IV weekly over 30 minutes, provided the previous dose was well tolerated.
| Study group | Role | What they receive |
|---|---|---|
| Letrozole & Trastuzumab | Experimental | Letrozole 2.5 mg tablets daily and Trastuzumab 2 mg/kg by IV weekly Receives: Drug: Letrozole; Drug: Trastuzumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
To determine the proportion of patients with ER and/or PR positive, ErbB2 positive tamoxifen resistant metastatic breast cancer who achieve complete remission (CR)
or partial remission (PR)
or no significant change in lesion size for greater than 24 weeks
Secondary outcomes (4)
To determine duration of response and median time to progression with letrozole plus trastuzumab treatment
To evaluate the clinical adverse experience during treatment with letrozole plus trastuzumab treatment
To generate a tumor and serum bank from patients receiving combination trastuzumab and letrozole treatment
To analyze ErbB2 expression on circulating malignant cells during treatment with letrozole and trastuzumab
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Aug 2005 (estimated)
- Study startJan 2000
- Primary completionJan 2005
- Study completionJul 2005
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Metastatic Breast CancerStudies of the same condition, open and under way.
- More trials run by Duke UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 33 participants (actual)
Sponsor and investigators
- Lead sponsor
- Duke University
- Sponsor type
- University, hospital or other
- Collaborators
- Genentech, Inc., Novartis Pharmaceuticals
- Responsible party
- Sponsor
- Investigators
- Paul K Marcom, MD, Principal investigator, Duke UniversityMatthew J Ellis, MB, PhD, Study director, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00134680
- Sponsor's protocol ID
- 1144
- Other IDs
- 1144-05-6R5
- Status last verified
- Oct 2012
- First submitted
- 24 Aug 2005
- Last updated
- 16 Sep 2014
- Results posted
- No
- Data monitoring committee
- No
Publications
Marcom PK, Isaacs C, Harris L, Wong ZW, Kommarreddy A, Novielli N, Mann G, Tao Y, Ellis MJ. The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers. Breast Cancer Res Treat. 2007 Mar;102(1):43-9. doi: 10.1007/s10549-006-9307-8. Epub 2006 Aug 8.
PubMed 16897431
Study at a glance
From the registry record, last updated by the sponsor on 16 Sep 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Trial of the Combination of Letrozole 2.5 mg Daily and Trastuzumab 2 mg/kg Weekly in ErbB2 Positive and Estrogen Receptor and/or Progesterone Receptor Positive Metastatic Breast Cancer
- ClinicalTrials.gov ID
- NCT00134680
- Acronym / sponsor ID
- 1144
- Conditions
- Metastatic Breast Cancer
- Keywords
- estrogen receptor positive, progesterone receptor positive, ErbB2 positive, metastatic breast cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 33 participants (actual)
- Lead sponsor
- Duke UniversityUniversity, hospital or other
- Collaborators
- Genentech, Inc., Novartis Pharmaceuticals
- Study start
- Jan 2000
- Primary completion
- Jan 2005 (actual)
- Study completion
- Jul 2005 (actual)
- First posted
- 25 Aug 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of the study is to investigate the effects (good and bad) that the combination of the drugs letrozole (also called Femara™) and trastuzumab (also called Herceptin®) has on breast cancer. The United States (US) Food and Drug Administration has approved both letrozole and Herceptin for the treatment of advanced breast cancer. Doctors hope that the combination will work better than either drug alone.
Detailed description
Since ER function is regulated by peptide growth factor signaling, the phenotype of ER positive tumors may be influenced by the expression of growth factors and growth factor receptors. A potential interaction between ErbB2 (HER2/neu) expression and the success of endocrine therapy has been examined. ErbB2 expression was shown to correlate with resistance to hormone therapy.
An inverse relationship between endocrine therapy responsiveness and ErbB2 expression has not been observed in all studies. This may be due to discordant ER status between the primary tumor and metastatic sites. ER status can be discordant in approximately 20% of cases, with a tendency for metastatic disease to become ER negative with time. Data concerning ErbB2 is more limited, but there may be similar lack of concordance between primary tumor and metastases.
Inhibition of ErbB2 signaling may slow the development of resistance to estrogen deprivation therapy by inhibiting a pathway that promotes estrogen independent growth. The ErbB2 signal transduction pathway bypasses the requirement for estrogen for breast epithelial cell growth. When ErbB2 is activated in ER positive breast cancer cells in vitro, ER becomes phosphorylated and capable of stimulating transcription without estrogen. Chronic activation with heregulin, a ligand for the ErbB family of receptors, leads to ER down-regulation and the acquisition of an ER negative phenotype.
Estrogen deprivation therapy with selective aromatase inhibitors (SAIs) has become the standard of care for postmenopausal women with tamoxifen-resistant advanced breast cancer. About 1/3 of patients benefit from this therapy. There is interest in treating endocrine therapy refractory breast cancer with the recombinant DNA-derived humanized monoclonal antibody trastuzumab. When given alone, trastuzumab has an endocrine therapy-like risk benefit ratio. Trastuzumab targets ErbB2 (HER2/neu). Some breast cancers may coexpress ER and ErbB2.
Letrozole (Femara™) is a highly selective oral non-steroidal aromatase inhibitor. According to in vitro data, letrozole is 170-fold more potent in inhibiting aromatase than aminoglutethimide (AG) and 19-fold more active than anastrozole. Letrozole effectively inhibits intratumoral aromatase according to in vitro and in vivo data. It is indicated for the treatment of advanced breast carcinoma in post-menopausal women who have failed prior anti-estrogen therapy. Final FDA approval was granted in 1997. In two randomized phase IIb/III studies in patients previously treated with an antiestrogen, 19.5% and 23.6% of patients achieved an objective response with letrozole 2.5 mg/day compared with 12.4% receiving AG and 16.4% of patients receiving megace. Median overall survival was increased in the letrozole 2.5 mg/day group by 8 months compared to AG and by 3 months compared to megace. The lower 0.5 mg/day dose of letrozole was associated with poorer response rates and overall survival in both studies.
Trastuzumab (Herceptin®) was approved in 1998. A trial of trastuzumab as a single agent for first line treatment of advanced disease has been reported. Response rate in the first 62 patients was 24%.
The primary objective of this trial is to determine the proportion of patients with ER and/or PR positive, ErbB2 positive tamoxifen resistant metastatic breast cancer who achieve complete remission or partial remission or no significant change in lesion size for > 24 weeks from a combination of letrozole and trastuzumab. The study will also determine duration of response and median time to progression, evaluate toxicity, generate a tumor and serum bank, and analyze ErbB2 expression on circulating malignant cells during treatment.
The study will enroll 35 patients
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Letrozole & Trastuzumab | Experimental | Drug: Letrozole, Drug: TrastuzumabLetrozole 2.5 mg tablets daily and Trastuzumab 2 mg/kg by IV weekly |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Postmenopausal.
- If premenopausal at diagnosis, eligible if undergoes treatment with luteinising hormone-releasing hormone (LHRH) agonist or surgical ovarian ablation before initiating treatment (tx).
- Tumor cell expression of ER and/or PR and ErbB2. Expression can be ascertained on either primary or metastatic site.
- Patient may have received adjuvant and/or neoadjuvant chemotherapy.
- Patient who received adjuvant/neoadjuvant chemotherapy, tx. must have been discontinued for 4 weeks and patient must have recovered from all acute toxicities, except alopecia.
Key exclusion criteria (13 listed)
- Prior exposure to any aromatase inhibitor (aminoglutethimide, formestane anastrozole, letrozole or exemestane) for more than 28 days. Patients that have already started on aromatase inhibitors (AIs) will be eligible for the protocol if they meet all other eligibility requirements and receive loading dose of trastuzumab not more than 28 days after starting AI therapy. Patients who initially received anastrozole or exemestane will be switched to letrozole.
- Prior treatment with trastuzumab
- Prior anthracycline exposure in adjuvant setting > 360 mg/m2.
- Patients with central nervous system (CNS) involvement with metastatic breast cancer or life threatening lymphangitic or large volume lung or liver disease.
- Patient's only qualifying lesions have been previously irradiated or are scheduled for irradiation following study entry.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LetrozoleAlso: FemaraLetrozole tablets 2.5 mg by mouth daily | Drug | Letrozole & Trastuzumab |
| TrastuzumabAlso: HerceptinWeekly trastuzumab (4 mg/kg loading dose given by IV over 90 minutes folowed by 2 mg/kg given by IV weekly over 30 minutes, provided the previous dose was well tolerated. | Drug | Letrozole & Trastuzumab |
Primary outcome
To determine the proportion of patients with ER and/or PR positive, ErbB2 positive tamoxifen resistant metastatic breast cancer who achieve complete remission (CR)
or partial remission (PR)
or no significant change in lesion size for greater than 24 weeks
4 secondary outcomes
To determine duration of response and median time to progression with letrozole plus trastuzumab treatment
To evaluate the clinical adverse experience during treatment with letrozole plus trastuzumab treatment
To generate a tumor and serum bank from patients receiving combination trastuzumab and letrozole treatment
To analyze ErbB2 expression on circulating malignant cells during treatment with letrozole and trastuzumab
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Sep 2014.
- Results publication: PubMed 16897431Marcom PK, Isaacs C, Harris L, Wong ZW, Kommarreddy A, Novielli N, Mann G, Tao Y, Ellis MJ. The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers. Breast Cancer Res Treat. 2007 Mar;102(1):43-9. doi: 10.1007/s10549-006-9307-8. Epub 2006 Aug 8.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paul K Marcom, MD principal investigator
Duke University
Matthew J Ellis, MB, PhD study director
Washington University School of Medicine
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Letrozole and Trastuzumab in people with Metastatic Breast Cancer, run by Duke University at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Sep 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To determine the proportion of patients with ER and/or PR positive, ErbB2 positive tamoxifen resistant metastatic breast cancer who achieve complete remission (CR). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00134680, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Sep 2014.