Breast CancerPhase 1/2NCT00458237
Dose Escalation Followed by Study of RAD001 in Combination With Trastuzumab in HER2-Positive Metastatic Breast Cancer
A Phase 1/2 study testing Everolimus and Trastuzumab in people with Breast Cancer, run by Beth Israel Deaconess Medical Center at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Everolimus 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
- 11 participants
- Where
- 2 sitesUnited States
- Study dates
- Apr 2007to Apr 2010
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 11Show fewer
- Patients may have received hormonal therapy in the adjuvant or metastatic setting
- 18 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
Who cannot join
- 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
Show all 15Show fewer
- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Dana-Farber Cancer Institute
Boston, Massachusetts, 02115
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
About this study
Official title: A Brief Dose Escalation Followed by a Phase 2 Study of RAD001 in Combination With Trastuzumab in HER2-Positive Metastatic Breast Cancer
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.
Read the detailed description
- Since we are looking for the dose of RAD001 that can be given safely in combination with trastuzumab, not everyone will receive the same amount of RAD001. Small groups of participants will be enrolled at a certain dose of RAD001 and if they tolerate the medications well, the next small group will receive a higher dose. This will continue until the optimal dose of RAD001 that can be given in combination with trastuzumab is found.
- Blood will be drawn on days 1, 2, 8, and 15 of the first cycle of treatment and then once at every 4 cycles for everolimus pharmacokinetics analysis.
- There is an optional tissue biopsy component to this study asking for 2 biopsies performed pre-treatment and after the cycle one.
- We will keep track of the participants medical condition for the next three years by calling them on the telephone twice a year to see how they are doing.
OBJECTIVES:
Primary
- To assess the safety and tolerability of RAD001 in combination with trastuzumab in HER2-positive metastatic breast cancer
Secondary
- To evaluate the activity of RAD001 plus trastuzumab, as defined by objective response rate, in patients with progression on a trastuzumab-containing regimen
- To evaluate changes in signaling molecules in response to trastuzumab and RAD001 in circulating tumor cells and tumor tissue
- To evaluate the pharmacokinetics of RAD001 in combination with trastuzumab.
STATISTICAL DESIGN:
This Phase I study followed a standard 3+3 dose escalation design with two dose levels of everolimus in combination with trastuzumab to be evaluated. The DLT observation period was cycle one (first 21 days of treatment). There is a 20 patient expansion cohort treated at the MTD. The regimen would be considered promising if at least 2 objective responses are observed out of 20 treated patients. If the true but unknown response rate is 15% then the probability of observing at least 2 responses is 82% but if the true rate is 5% this probability reduces to 26%.
- Conditions
- Breast Cancer
- Being tested
- Everolimus, Trastuzumab
- Keywords
- HER2 positive, metastatic breast cancer, RAD001, Herceptin
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EverolimusDrug
Also called RAD001
Everolimus is being administered orally 7 days per week.
TrastuzumabDrug
Also called Herceptin
Trastuzumab is being administered at a dose of 6 mg/kg intravenously once every 21 days.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: Everolimus; Drug: Trastuzumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Cycle One (first 21 days of treatment)
Secondary outcomes (1)
Clinical Response Rate
Best response on treatment was based on RECIST 1.0 criteria with overall clinical response defined as achieving stable disease (SD), partial response (PR) or complete response (CR). Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no fewer than 4 weeks after the response. SD is neither CR/PR or progressive disease (PD). PD is at least a 20% increase in sum LD, takings as reference smallest sum LD since treatment started.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Apr 2007 (estimated)
- Study startApr 2007
- Primary completionApr 2010
- Study completionApr 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by Beth Israel Deaconess Medical CenterThe 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 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- Beth Israel Deaconess Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis Pharmaceuticals, Dana-Farber Cancer Institute
- Responsible party
- Principal investigator, Gerburg Wulf, MD, PhD, Dana-Farber Cancer Institute
- Investigators
- Gerburg Wulf, MD, PhD, Principal investigator, Beth Israel Deaconess Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00458237
- Sponsor's protocol ID
- 06-124
- Status last verified
- Oct 2016
- First submitted
- 9 Apr 2007
- Last updated
- 20 Oct 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 21730275
Study at a glance
From the registry record, last updated by the sponsor on 20 Oct 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Brief Dose Escalation Followed by a Phase 2 Study of RAD001 in Combination With Trastuzumab in HER2-Positive Metastatic Breast Cancer
- ClinicalTrials.gov ID
- NCT00458237
- Acronym / sponsor ID
- 06-124
- Conditions
- Breast Cancer
- Keywords
- HER2 positive, metastatic breast cancer, RAD001, Herceptin
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 11 participants (actual)
- Lead sponsor
- Beth Israel Deaconess Medical CenterUniversity, hospital or other
- Collaborators
- Novartis Pharmaceuticals, Dana-Farber Cancer Institute
- Study start
- Apr 2007
- Primary completion
- Apr 2010 (actual)
- Study completion
- Apr 2010 (actual)
- First posted
- 10 Apr 2007 (estimated)
- Results
- Posted 10 Mar 2016
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 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.
Detailed description
- Since we are looking for the dose of RAD001 that can be given safely in combination with trastuzumab, not everyone will receive the same amount of RAD001. Small groups of participants will be enrolled at a certain dose of RAD001 and if they tolerate the medications well, the next small group will receive a higher dose. This will continue until the optimal dose of RAD001 that can be given in combination with trastuzumab is found.
- Blood will be drawn on days 1, 2, 8, and 15 of the first cycle of treatment and then once at every 4 cycles for everolimus pharmacokinetics analysis.
- There is an optional tissue biopsy component to this study asking for 2 biopsies performed pre-treatment and after the cycle one.
- We will keep track of the participants medical condition for the next three years by calling them on the telephone twice a year to see how they are doing.
OBJECTIVES:
Primary
- To assess the safety and tolerability of RAD001 in combination with trastuzumab in HER2-positive metastatic breast cancer
Secondary
- To evaluate the activity of RAD001 plus trastuzumab, as defined by objective response rate, in patients with progression on a trastuzumab-containing regimen
- To evaluate changes in signaling molecules in response to trastuzumab and RAD001 in circulating tumor cells and tumor tissue
- To evaluate the pharmacokinetics of RAD001 in combination with trastuzumab.
STATISTICAL DESIGN:
This Phase I study followed a standard 3+3 dose escalation design with two dose levels of everolimus in combination with trastuzumab to be evaluated. The DLT observation period was cycle one (first 21 days of treatment). There is a 20 patient expansion cohort treated at the MTD. The regimen would be considered promising if at least 2 objective responses are observed out of 20 treated patients. If the true but unknown response rate is 15% then the probability of observing at least 2 responses is 82% but if the true rate is 5% this probability reduces to 26%.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Ph I: Everolimus L1 + Trastuzumab | Experimental | Drug: Everolimus, Drug: TrastuzumabCycle 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. |
| Ph I: Everolimus L2 + Trastuzumab | Experimental | Drug: Everolimus, Drug: TrastuzumabCycle 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. |
| PhII: Everolimus MTD + Trastuzumab | Experimental | Drug: Everolimus, Drug: TrastuzumabCycle 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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.
Key exclusion criteria (15 listed)
- 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
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 |
|---|---|---|
| EverolimusAlso: RAD001Everolimus is being administered orally 7 days per week. | Drug | Ph I: Everolimus L1 + Trastuzumab, Ph I: Everolimus L2 + Trastuzumab, PhII: Everolimus MTD + Trastuzumab |
| TrastuzumabAlso: HerceptinTrastuzumab is being administered at a dose of 6 mg/kg intravenously once every 21 days. | Drug | Ph I: Everolimus L1 + Trastuzumab, Ph I: Everolimus L2 + Trastuzumab, PhII: Everolimus MTD + Trastuzumab |
Primary outcome
Maximum Tolerated Dose (MTD)
Time frame: Cycle One (first 21 days of treatment)
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.
1 secondary outcome
Clinical Response Rate
Time frame: 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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Oct 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 21730275Morrow 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.
- Individual participant dataSharing planned: No
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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.
Gerburg Wulf, MD, PhD principal investigator
Beth Israel Deaconess Medical Center
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Everolimus and Trastuzumab in people with Breast Cancer, run by Beth Israel Deaconess Medical Center at 2 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 11 inclusion and 15 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 20 Oct 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Yes. Results are posted in the registry (first posted 10 Mar 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Maximum Tolerated Dose (MTD) (time frame: Cycle One (first 21 days of treatment)). 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 NCT00458237, 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 20 Oct 2016.