Breast CancerPhase 2NCT00411788
A Phase II Study of Rapamycin and Trastuzumab for Patients With HER-2 Receptor Positive Metastatic Breast Cancer
A Phase 2 study testing Rapamycin and Trastuzumab in people with Breast Cancer, run by Yale University at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Rapamycin 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
- Dec 2006to May 2010
- Phase
- Phase 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
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
- Fasting serum cholesterol <350 mg/d L and triglycerides < 400 mg/ d L.
- Biopsy is required but patients or physicians may opt out of this part of the trial if sufficient justification is provided. Justification must be provided to the PI in writing indicating excessive physical risk or psychological trauma if biopsy is undertaken.
Who cannot join
- 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.
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- 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.
- Consumption of grapefruit juice is prohibited during the study.
- Use of warfarin (Coumadin), immunosuppressive agents or chronic oral, intravenous or topical steroid
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Bridgeport Hospital
Bridgeport, Connecticut, 06610
Yale Comprehensive Cancer Center at Yale University School of Medicine
New Haven, Connecticut, 06519
About this study
Official title: A Phase II Study of Rapamycin (Rapamune, Sirolimus) and Trastuzumab (Herceptin) for Patients With HER-2 Receptor Positive Metastatic Breast Cancer
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
- Being tested
- Rapamycin, Trastuzumab
- Keywords
- HER-2 positive, breast cancer, HER-2 positive 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.
RapamycinDrug
Also called Rapamune, Sirolimus
oral rapamycin 6 mg daily
TrastuzumabDrug
Also called Herceptin
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Rapamycin; Drug: Trastuzumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 16 weeks
Secondary outcomes (5)
Objective Response Rate (ORR)
ORR was determined according to RECIST criteria, duration of response, and time to progression in patients with HER2 overexpressing advanced breast cancer receiving trastuzumab and rapamycin. The objective response rate (ORR) by response evaluation criteria (RECIST) 1.0, duration of response, safety, and pharmacodynamic endpoints.
This secondary outcome measure was reworded from its original submission when results were entered.
Measured: study completion up to 58 weeks
Incidence of Cardiac Dysfunction
This safety measure was used to determine the number of patients treated with the combination of trastuzumab and rapamycin with cardiac dysfunction.
This secondary outcome measure was reworded from its original version when results were entered.
Measured: 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
These data were not collected and analyzed as described here in the initial protocol submission.
Measured: 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
Measured: 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
Measured: Upon completion of study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Dec 2006 (estimated)
- Study startDec 2006
- Primary completionMay 2010
- Study completionMay 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.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by Yale 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
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- Genentech, Inc.
- Responsible party
- Sponsor
- Investigators
- Maysa Abu-Khalaf, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00411788
- Sponsor's protocol ID
- 0605001396
- Status last verified
- Aug 2016
- First submitted
- 14 Dec 2006
- Last updated
- 21 Sep 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Study of Rapamycin (Rapamune, Sirolimus) and Trastuzumab (Herceptin) for Patients With HER-2 Receptor Positive Metastatic Breast Cancer
- ClinicalTrials.gov ID
- NCT00411788
- Acronym / sponsor ID
- 0605001396
- Conditions
- Breast Cancer
- Keywords
- HER-2 positive, breast cancer, HER-2 positive breast cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 11 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- Genentech, Inc.
- Study start
- Dec 2006
- Primary completion
- May 2010 (actual)
- Study completion
- May 2010 (actual)
- First posted
- 15 Dec 2006 (estimated)
- Results
- Posted 21 Sep 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| sirolimus and trastuzumab | Experimental | Drug: Rapamycin, Drug: TrastuzumabPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- 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
Key exclusion criteria (17 listed)
- 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).
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 |
|---|---|---|
| RapamycinAlso: Rapamune, Sirolimusoral rapamycin 6 mg daily | Drug | sirolimus and trastuzumab |
| TrastuzumabAlso: HerceptinTrastuzumab 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. | Drug | sirolimus and trastuzumab |
Primary outcome
Proportion of Patients Who Are Progression-free (CR, PR and Stable Disease)
Time frame: 16 weeks
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.
5 secondary outcomes
Objective Response Rate (ORR)
Time frame: study completion up to 58 weeks
Incidence of Cardiac Dysfunction
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Upon completion of study
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
Maysa Abu-Khalaf, MD principal investigator
Yale University
2 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 Rapamycin and Trastuzumab in people with Breast Cancer, run by Yale University 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 17 inclusion and 17 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 21 Sep 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 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?
Yes. Results are posted in the registry (first posted 21 Sep 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?
Proportion of Patients Who Are Progression-free (CR, PR and Stable Disease) (time frame: 16 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 21 Sep 2016.