Breast NeoplasmsPhase 2NCT00001493
Antimetabolite Induction, High-Dose Alkylating Agent Consolidation and Retroviral Transduction of the MDR1 Gene Into Peripheral Blood Progenitor Cells Followed by Intensification Therapy With Sequential Paclitaxel and Doxorubicin for Stage 4 Breast Cancer
A Phase 2 study testing peripheral blood progenitor cells carrying MDR1 in people with Breast Neoplasms and Neoplasm Metastasis, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
This study examines the feasibility of using gene therapy to prevent some of the toxicities of an intensive chemotherapy regimen in patients with metastatic breast cancer. Patients who do not wish to participate in the gene therapy procedures will be offered identical chemotherapy on a different protocol. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Breast Neoplasms, Neoplasm Metastasis
- What is being tested?
- peripheral blood progenitor cells carrying MDR1
- How many people
- 42 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 1995to Jun 2000
- 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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Patients with stage IV breast cancer are eligible provided they have not received chemotherapy for metastatic disease. Patients with stage IV breast cancer who have received prior adjuvant chemotherapy are eligible.
Patients who have received prior doxorubicin therapy will be eligible. Patients who have received a lifetime doxorubicin dose greater than 550 mg/m(2) or who have an initial MUGA ejection fraction of between 40% and less than 50% will receive vinblastine instead of doxorubicin.
Age greater than or equal to 18.
ECOG performance status of 0-2.
Adequate cardiac function as defined by an LVEF greater than or equal to 40% on MUGA scan or an echocardiogram which demonstrates normal LV function.
Adequate hematologic function with neutrophils greater than 1,200/mm(3) and platelets less than 100,000/mm(3) unless due to metastatic bone marrow involvement.
Adequate renal and hepatic function with creatinine less than 2.0 mg/dl, bilirubin less than 1.8 mg/dl, and hepatic transaminases less than 2 times the upper limit of normal unless due to metastatic cancer.
A 12-24 hour creatinine clearance greater than 50 ml/min.
No prior chemotherapy or radiation therapy within 3 weeks before starting protocol therapy and patients must have recovered from any toxicity from any prior therapy.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Cancer Institute (NCI)
Bethesda, Maryland, 20892
About this study
Official title: Antimetabolite Induction, High-Dose Alkylating Agent Consolidation and Retroviral Transduction of the MDR1 Gene Into Peripheral Blood Progenitor Cells Followed by Intensification Therapy With Sequential Paclitaxel and Doxorubicin for Stage 4 Breast Cance
This study examines the feasibility of using gene therapy to prevent some of the toxicities of an intensive chemotherapy regimen in patients with metastatic breast cancer. Patients who do not wish to participate in the gene therapy procedures will be offered identical chemotherapy on a different protocol. Patients will be treated initially with chemotherapy which is active against breast cancer, but which has a low potential to hurt blood-forming cells. Then, the patient will receive high dose chemotherapy, during which time blood cells which are capable of rebuilding patients' bone marrows will be removed from the patients' bloodstream. We will use these blood cell collections to isolate peripheral blood progenitor cells (PBPCs), those cells which are thought to be the forbears of all other blood cells.
A portion of the PBPCs will be exposed to a disabled virus which either carries genetic material referred to as the multidrug resistance gene (MDR1). The virus will transfer the MDR1 gene into a portion of the patient's PBPCs. The purpose of putting the MDR1 gene into the patients' PBPCs is to try to make these blood cells and their offspring resistant to the toxic effects of certain types of breast cancer chemotherapy. The MDR1 protein (Pgp) that is made from the MDR1 gene makes cells resistant to chemotherapy in laboratory systems by pumping the drug out of cells before the drug is able to kill the cell. Another portion of the patients PBPCs will be exposed to a similar disabled virus carrying a different gene called the NeoR gene. The NeoR gene should not change the effects of chemotherapy on blood forming cells. The purpose of using the NeoR gene is that it will serve as a point of comparison, to see if the presence of the MDR1 drug resistance gene really helps blood forming cells withstand subsequent chemotherapy.
Patients are then treated with a very high dose of another anti-breast cancer drug, one that is very toxic to bone marrow cells, and patients will then receive the frozen PBPCs, which contain the new genes, to help them recover from the chemotherapy. After recovery, patients will then be treated with high doses of paclitaxel (Taxol) and doxorubicin (Adriamycin) chemotherapy. Both of these drugs are very active against breast cancer, and the MDR1 gene may potentially protect bone marrow cells against these drugs. Samples of peripheral blood cells will be obtained before each of these doses of chemotherapy to determine whether the number of blood cells that contain the MDR1 gene in comparison to the number that contain the NeoR gene has increased in response to the chemotherapy.
Read the detailed description
This pilot trial will determine whether retroviral-transduced peripheral blood progenitor cells (PBPCs) can be selected and expanded in vivo after non-ablative chemotherapy in patients with metastatic breast cancer. It will also examine the feasibility of administering induction high-dose therapy with antimetabolites, followed with consolidation using high-dose single alkylating agent therapy and finally intensification therapy with sequential cycles of very high doses of the natural product breast cancer chemotherapeutic agents (paclitaxel followed by doxorubicin).
Patients will receive induction therapy with antimetabolite agents (methotrexate, leucovorin and 5-fluorouracil) for two to four cycles. Patients will then receive consolidation therapy with two cycles of high-dose alkylating agents. First, patients will receive one cycle of high-dose cyclophosphamide administered with growth factor support. PBPCs will be harvested during the recovery phase of the cyclophosphamide cycle.
One-half of the cells to be reinfused will be transduced with a retroviral vector containing the gene for the multidrug resistance protein (MDRI in vector G1MD) and the other half will be transduced with a vector containing the neomycin resistance gene (NeoR in vector G1Na.40). Both of these vectors have previously been approved by the Recombinant DNA Advisory Committee for PBPC transduction in Medicine Branch protocols.
The next cycle will consist of high-dose single agent thiotepa. Hematopoietic stem cells mobilized and collected during the previous cyclophosphamide cycle and transduced with the retroviral vectors will be reinfused following treatment with thiotepa to augment recovery of bone marrow function. After recovery, intensification with natural product chemotherapy will be administered, consisting of four cycles of paclitaxel given as a 24-hour infusion followed by four cycles of single agent doxorubicin. Peripheral blood mononuclear cells will be monitored following each cycle of paclitaxel and doxorubicin for the presence of the MDRI and NeoR transgenes. The ration of the levels of MDRI to NeoR transgenes in peripheral blood will determine whether in vivo expansion of the PBPCs containing the selectable MDRI marker has been achieved.
This protocol combines several highly active chemotherapeutic agents in an attempt to improve upon response rates achieved with current combinations. Patients who do not wish to participate in the gene therapy procedures will be offered identical chemotherapy in a different protocol.
- Conditions
- Breast Neoplasms, Neoplasm Metastasis
- Being tested
- peripheral blood progenitor cells carrying MDR1
- Keywords
- Dose Intensity, Gene Therapy, Multidrug Resistance
- Medical subject headings
- Breast Neoplasms, Neoplasm Metastasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
peripheral blood progenitor cells carrying MDR1Genetic
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Dec 2002 (estimated)
- Study startOct 1995
- Study completionJun 2000
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Breast NeoplasmsStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The 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
- Enrolment
- 42 participants
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00001493
- Sponsor's protocol ID
- 960007
- Other IDs
- 96-C-0007
- Status last verified
- Aug 1999
- First submitted
- 3 Nov 1999
- Last updated
- 4 Mar 2008
- Results posted
- No
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Antimetabolite Induction, High-Dose Alkylating Agent Consolidation and Retroviral Transduction of the MDR1 Gene Into Peripheral Blood Progenitor Cells Followed by Intensification Therapy With Sequential Paclitaxel and Doxorubicin for Stage 4 Breast Cance
- ClinicalTrials.gov ID
- NCT00001493
- Acronym / sponsor ID
- 960007
- Conditions
- Breast Neoplasms, Neoplasm Metastasis
- Keywords
- Dose Intensity, Gene Therapy, Multidrug Resistance
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Oct 1995
- Study completion
- Jun 2000
- First posted
- 10 Dec 2002 (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.
This study examines the feasibility of using gene therapy to prevent some of the toxicities of an intensive chemotherapy regimen in patients with metastatic breast cancer. Patients who do not wish to participate in the gene therapy procedures will be offered identical chemotherapy on a different protocol. Patients will be treated initially with chemotherapy which is active against breast cancer, but which has a low potential to hurt blood-forming cells. Then, the patient will receive high dose chemotherapy, during which time blood cells which are capable of rebuilding patients' bone marrows will be removed from the patients' bloodstream. We will use these blood cell collections to isolate peripheral blood progenitor cells (PBPCs), those cells which are thought to be the forbears of all other blood cells.
A portion of the PBPCs will be exposed to a disabled virus which either carries genetic material referred to as the multidrug resistance gene (MDR1). The virus will transfer the MDR1 gene into a portion of the patient's PBPCs. The purpose of putting the MDR1 gene into the patients' PBPCs is to try to make these blood cells and their offspring resistant to the toxic effects of certain types of breast cancer chemotherapy. The MDR1 protein (Pgp) that is made from the MDR1 gene makes cells resistant to chemotherapy in laboratory systems by pumping the drug out of cells before the drug is able to kill the cell. Another portion of the patients PBPCs will be exposed to a similar disabled virus carrying a different gene called the NeoR gene. The NeoR gene should not change the effects of chemotherapy on blood forming cells. The purpose of using the NeoR gene is that it will serve as a point of comparison, to see if the presence of the MDR1 drug resistance gene really helps blood forming cells withstand subsequent chemotherapy.
Patients are then treated with a very high dose of another anti-breast cancer drug, one that is very toxic to bone marrow cells, and patients will then receive the frozen PBPCs, which contain the new genes, to help them recover from the chemotherapy. After recovery, patients will then be treated with high doses of paclitaxel (Taxol) and doxorubicin (Adriamycin) chemotherapy. Both of these drugs are very active against breast cancer, and the MDR1 gene may potentially protect bone marrow cells against these drugs. Samples of peripheral blood cells will be obtained before each of these doses of chemotherapy to determine whether the number of blood cells that contain the MDR1 gene in comparison to the number that contain the NeoR gene has increased in response to the chemotherapy.
Detailed description
This pilot trial will determine whether retroviral-transduced peripheral blood progenitor cells (PBPCs) can be selected and expanded in vivo after non-ablative chemotherapy in patients with metastatic breast cancer. It will also examine the feasibility of administering induction high-dose therapy with antimetabolites, followed with consolidation using high-dose single alkylating agent therapy and finally intensification therapy with sequential cycles of very high doses of the natural product breast cancer chemotherapeutic agents (paclitaxel followed by doxorubicin).
Patients will receive induction therapy with antimetabolite agents (methotrexate, leucovorin and 5-fluorouracil) for two to four cycles. Patients will then receive consolidation therapy with two cycles of high-dose alkylating agents. First, patients will receive one cycle of high-dose cyclophosphamide administered with growth factor support. PBPCs will be harvested during the recovery phase of the cyclophosphamide cycle.
One-half of the cells to be reinfused will be transduced with a retroviral vector containing the gene for the multidrug resistance protein (MDRI in vector G1MD) and the other half will be transduced with a vector containing the neomycin resistance gene (NeoR in vector G1Na.40). Both of these vectors have previously been approved by the Recombinant DNA Advisory Committee for PBPC transduction in Medicine Branch protocols.
The next cycle will consist of high-dose single agent thiotepa. Hematopoietic stem cells mobilized and collected during the previous cyclophosphamide cycle and transduced with the retroviral vectors will be reinfused following treatment with thiotepa to augment recovery of bone marrow function. After recovery, intensification with natural product chemotherapy will be administered, consisting of four cycles of paclitaxel given as a 24-hour infusion followed by four cycles of single agent doxorubicin. Peripheral blood mononuclear cells will be monitored following each cycle of paclitaxel and doxorubicin for the presence of the MDRI and NeoR transgenes. The ration of the levels of MDRI to NeoR transgenes in peripheral blood will determine whether in vivo expansion of the PBPCs containing the selectable MDRI marker has been achieved.
This protocol combines several highly active chemotherapeutic agents in an attempt to improve upon response rates achieved with current combinations. Patients who do not wish to participate in the gene therapy procedures will be offered identical chemotherapy in a different protocol.
Study design
- Primary purpose
- Treatment
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
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 |
|---|---|---|
| peripheral blood progenitor cells carrying MDR1 | Genetic | – |
Primary outcome
Not reported in the source record.
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 4 Mar 2008.
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing peripheral blood progenitor cells carrying MDR1 in people with Breast Neoplasms and Neoplasm Metastasis, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Mar 2008. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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.
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 4 Mar 2008.