Adjuvant Breast Cancer Study of the Netherlands Working Party for Autotransplantation in Solid Tumors
NCT ID: NCT00851110
Last Updated: 2009-02-25
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
TERMINATED
Clinical Phase
PHASE2
Total Enrollment
50 participants
Study Classification
INTERVENTIONAL
Study Start Date
2004-10-31
Brief Summary
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Objectives of the study:
This randomized multicenter phase II study compares the tolerability, toxicity and quality of life between two high-dose chemotherapy regimens based on cyclophosphamide, thiotepa and carboplatin.
Regimen A: full dose CTC. Regimen B: two courses of CTC (tCTC) with 33% dose reduction.
Primary endpoints are:
* Maximum degree of non-hematological toxicity.
Secondary endpoint:
* Total number of hospital days.
* Quality of life evaluations during and following high-dose chemotherapy (up to 1 year).
* Effect of therapeutic dose monitoring of CTC or tCTC.
Trial design:
This investigation is a multicenter prospective randomized phase II study. Patients eligible for the study will be identified after mastectomy or wide tumor excision with axillary clearance. Following randomization, all patients will receive four courses of cyclophosphamide, epirubicin and fluorouracil (FEC). Patients with early progressive disease at any time will be taken off study. The first chemotherapy course must be given as soon as possible after the surgical procedure, preferably within 3 weeks, but not later than 6 weeks since primary surgery. After the third or fourth FEC course G-CSF is administered and peripheral stem cells will be harvested. All radiation therapy (including radiation therapy administered as part of a breast conserving strategy) must be postponed until all chemotherapy has been concluded.
Questionnaires, comprising the Rotterdam Symptom Checklist (RSCL) and the Short-Form General Health Survey (SF-36) will be sent by mail before randomization, after chemotherapy, 3 months thereafter, further on every l/2 yr till at least 1 year follow-up as performed earlier. \[6, 28, 29\].
All patients will be randomized before the initiation of chemotherapy.
* The 'standard' treatment arm will include 4 courses of FEC followed by high-dose chemotherapy with a single course of full dose CTC followed by peripheral stem cell reinfusion. Subsequently, conventional external beam radiotherapy to the breast or chest wall and to the regional lymph node areas including the axilla and the parasternal area will be administered following guidelines of the individual center. Patients with hormone receptor positive disease will go on to receive 5 years of tamoxifen. Patients with receptor positive disease who have not entered menopause will be advised to undergo ovarian ablation as well.
* The 'experimental' treatment arm will be identical to the 'standard' one, except that the single course of CTC will be replaced by 2 courses of tCTC each followed by peripheral stem cell reinfusion.
This randomized multicenter phase II study compares the tolerability, toxicity and quality of life between two high-dose chemotherapy regimens based on cyclophosphamide, thiotepa and carboplatin.
Regimen A: full dose CTC. Regimen B: two courses of CTC (tCTC) with 33% dose reduction.
Primary endpoints are:
* Maximum degree of non-hematological toxicity.
Secondary endpoint:
* Total number of hospital days.
* Quality of life evaluations during and following high-dose chemotherapy (up to 1 year).
* Effect of therapeutic dose monitoring of CTC or tCTC.
Trial design:
This investigation is a multicenter prospective randomized phase II study. Patients eligible for the study will be identified after mastectomy or wide tumor excision with axillary clearance. Following randomization, all patients will receive four courses of cyclophosphamide, epirubicin and fluorouracil (FEC). Patients with early progressive disease at any time will be taken off study. The first chemotherapy course must be given as soon as possible after the surgical procedure, preferably within 3 weeks, but not later than 6 weeks since primary surgery. After the third or fourth FEC course G-CSF is administered and peripheral stem cells will be harvested. All radiation therapy (including radiation therapy administered as part of a breast conserving strategy) must be postponed until all chemotherapy has been concluded.
Questionnaires, comprising the Rotterdam Symptom Checklist (RSCL) and the Short-Form General Health Survey (SF-36) will be sent by mail before randomization, after chemotherapy, 3 months thereafter, further on every l/2 yr till at least 1 year follow-up as performed earlier. \[6, 28, 29\].
All patients will be randomized before the initiation of chemotherapy.
* The 'standard' treatment arm will include 4 courses of FEC followed by high-dose chemotherapy with a single course of full dose CTC followed by peripheral stem cell reinfusion. Subsequently, conventional external beam radiotherapy to the breast or chest wall and to the regional lymph node areas including the axilla and the parasternal area will be administered following guidelines of the individual center. Patients with hormone receptor positive disease will go on to receive 5 years of tamoxifen. Patients with receptor positive disease who have not entered menopause will be advised to undergo ovarian ablation as well.
* The 'experimental' treatment arm will be identical to the 'standard' one, except that the single course of CTC will be replaced by 2 courses of tCTC each followed by peripheral stem cell reinfusion.
Detailed Description
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High-dose chemotherapy with the alkylating agent combination CTC appears to add significantly to the efficacy of conventional dose chemotherapy in patients with high-risk breast cancer, provided that the HER-2/neu gene is not amplified in the tumor. As a high-dose chemotherapy regimen, CTC is associated with significant toxicity \[31,32\]. Although high-dose alkylating therapy seems to be effective, there is virtually nothing known about the dose-response curve for this combination (for a detailed discussion see the classical paper by E. Frei III \[32\]. If one assumes that the efficacy increase levels off with increasing dose, the efficacy of tCTC might be almost as great as that of CTC, but with considerably less toxicity. In addition, two closely spaced courses of tCTC might further increase the efficacy of the regimen. There are some suggestions that a double transplant may be more effective than a single one, in multiple myeloma and in Ewing sarcoma. A similar suggestion has also been made for breast cancer (study of Nitz et al ref 4, table 1).
Conditions
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High-Risk Breast Cancer
Keywords
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high dose
breast cancer
adjuvant
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Interventions
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stem cell reinfusion
hematopoietic stem cell reinfusion
Intervention Type
PROCEDURE
Chemotherapy
High-dose chemotherapy consisting of cyclophosphamide, thiotepa and carboplatin
Intervention Type
DRUG
Eligibility Criteria
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Inclusion Criteria
1. Modified radical mastectomy (or breast conserving surgery) and axillary clearance, histologically confirmed stage IIA, IIB or IIIA adenocarcinoma (excluding supraclavicular lymph nodes) of the breast, with 4 or more involved axillary lymph nodes. Presence of tumor cells near or in the resection margins at microscopic examination is acceptable
2. The primary tumor must be immunohistochemically negative for HER-2/neu expression. An immunohistochemistry score of 1+ is also acceptable. A score of 3+ is not acceptable. A score of 2+ is only acceptable if a FISH analysis (or equivalent) has clearly shown that there is no HER-2/neu gene-amplification
3. No prior chemotherapy or radiotherapy
4. No evidence of distant metastases
5. Age \< 50 years
6. Performance status (ECOG-ZUBROD) 0 or 1;
7. Normal bone marrow function, WBC \> 4.0 x 109/l, platelets \> 100 x 109/l;
8. Adequate renal function (creatinine clearance \> 60 ml/min.);
9. Adequate hepatic function (serum bilirubin \< 25 umol/l);
10. Study treatment must begin within 6 weeks of surgery;
11. No other malignancy except adequately treated in situ carcinoma of the cervix or basal cell carcinoma of the skin;
12. No significant prior or concomitant disorder that might interfere with adherence to the intensive treatment regimen, including but not limited to a history of angina, myocardial infarction or heart failure, severe lung function impairment, peptic ulcer disease, etc.;
13. Availability for follow-up.
2. The primary tumor must be immunohistochemically negative for HER-2/neu expression. An immunohistochemistry score of 1+ is also acceptable. A score of 3+ is not acceptable. A score of 2+ is only acceptable if a FISH analysis (or equivalent) has clearly shown that there is no HER-2/neu gene-amplification
3. No prior chemotherapy or radiotherapy
4. No evidence of distant metastases
5. Age \< 50 years
6. Performance status (ECOG-ZUBROD) 0 or 1;
7. Normal bone marrow function, WBC \> 4.0 x 109/l, platelets \> 100 x 109/l;
8. Adequate renal function (creatinine clearance \> 60 ml/min.);
9. Adequate hepatic function (serum bilirubin \< 25 umol/l);
10. Study treatment must begin within 6 weeks of surgery;
11. No other malignancy except adequately treated in situ carcinoma of the cervix or basal cell carcinoma of the skin;
12. No significant prior or concomitant disorder that might interfere with adherence to the intensive treatment regimen, including but not limited to a history of angina, myocardial infarction or heart failure, severe lung function impairment, peptic ulcer disease, etc.;
13. Availability for follow-up.
Minimum Eligible Age
18 Years
Maximum Eligible Age
50 Years
Eligible Sex
FEMALE
Accepts Healthy Volunteers
No
Sponsors
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University Medical Center Groningen
OTHER
Sponsor Role
lead
Principal Investigators
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Elisabeth G.E. de Vries, MD, PhD
Role: STUDY_DIRECTOR
University Medical Center Groningen
Sjoerd Rodenhuis, MD, PhD
Role: STUDY_DIRECTOR
The Netherlands Cancer Institute
Locations
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Free University Hospital
Amsterdam, , Netherlands
Site Status
The Netherlands Cancer Institute
Amsterdam, , Netherlands
Site Status
Academic Medical Center
Amsterdam, , Netherlands
Site Status
Medisch Spectrum Twente
Enschede, , Netherlands
Site Status
University Medical Centre Groningen
Groningen, , Netherlands
Site Status
Leiden University Medical Centre
Leiden, , Netherlands
Site Status
University Hospital Maastricht
Maastricht, , Netherlands
Site Status
University Medical Centre Nijmegen St. Radboud
Nijmegen, , Netherlands
Site Status
Erasmus MC, Daniel den Hoed Cancer Center
Rotterdam, , Netherlands
Site Status
University Medical Centre Utrecht
Utrecht, , Netherlands
Site Status
Countries
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Netherlands
References
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Weiss RB, Rifkin RM, Stewart FM, Theriault RL, Williams LA, Herman AA, Beveridge RA. High-dose chemotherapy for high-risk primary breast cancer: an on-site review of the Bezwoda study. Lancet. 2000 Mar 18;355(9208):999-1003. doi: 10.1016/S0140-6736(00)90024-2.
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Nitz UA, Frick M, Mohrmann S. Lindemann H, Jackisch C, Werner C, Souchon R, Metzner B, Rufert U, Bender HG. Tandem high dose chemotherapy versus dose-dense conventional chemotherapy for patients with high risk breast cancer: Interim results from a multicenter phase III trial. Proc Am Soc Clin Oncol 22: 2003 (abstract 3344).
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Rodenhuis S, Bontenbal M, Beex LV, Wagstaff J, Richel DJ, Nooij MA, Voest EE, Hupperets P, van Tinteren H, Peterse HL, TenVergert EM, de Vries EG; Netherlands Working Party on Autologous Transplantation in Solid Tumors. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med. 2003 Jul 3;349(1):7-16. doi: 10.1056/NEJMoa022794.
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Rodenhuis S, Westermann A, Holtkamp MJ, Nooijen WJ, Baars JW, van der Wall E, Slaper-Cortenbach IC, Schornagel JH. Feasibility of multiple courses of high-dose cyclophosphamide, thiotepa, and carboplatin for breast cancer or germ cell cancer. J Clin Oncol. 1996 May;14(5):1473-83. doi: 10.1200/JCO.1996.14.5.1473.
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Rodenhuis S, de Wit R, de Mulder PH, Keizer HJ, Sleijfer DT, Lalisang RI, Bakker PJ, Mandjes I, Kooi M, de Vries EG. A multi-center prospective phase II study of high-dose chemotherapy in germ-cell cancer patients relapsing from complete remission. Ann Oncol. 1999 Dec;10(12):1467-73. doi: 10.1023/a:1008328012040.
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Rodenhuis S, Demol J, Westermann A, Holtkamp MJ, Nooijen WJ, Slaper-Cortenbach ICM, Schornagel JH, Baars JW: The feasibility of three courses of 'tiny CTC' (tCTC) in patients with advanced breast cancer. in: KA Dicke and A Keating (Eds.) Autologous Marrow and Blood Transplantation. Proceedings of the Eighth International Symposium Arlington, Texas. Carden Jennings Publishing Company, Charlottesville, Virginia 1997. p 277-285
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Schrama JG, Baars JW, Holtkamp MJ, Schornagel JH, Beijnen JH, Rodenhuis S. Phase II study of a multi-course high-dose chemotherapy regimen incorporating cyclophosphamide, thiotepa, and carboplatin in stage IV breast cancer. Bone Marrow Transplant. 2001 Jul;28(2):173-80. doi: 10.1038/sj.bmt.1703105.
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Westermann AM, Holtkamp MM, Linthorst GA, van Leeuwen L, Willemse EJ, van Dijk WC, Nooijen WJ, Baars JW, Schornagel JH, Rodenhuis S. At home management of aplastic phase following high-dose chemotherapy with stem-cell rescue for hematological and non-hematological malignancies. Ann Oncol. 1999 May;10(5):511-7. doi: 10.1023/a:1026427724108.
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van Warmerdam LJ, Rodenhuis S, van Tellingen O, Maes RA, Beijnen JH. Validation of a limited sampling model for carboplatin in a high-dose chemotherapy combination. Cancer Chemother Pharmacol. 1994;35(2):179-81. doi: 10.1007/BF00686644.
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van Warmerdam LJ, Rodenhuis S, van der Wall E, Maes RA, Beijnen JH. Pharmacokinetics and pharmacodynamics of carboplatin administered in a high-dose combination regimen with thiotepa, cyclophosphamide and peripheral stem cell support. Br J Cancer. 1996 Apr;73(8):979-84. doi: 10.1038/bjc.1996.191.
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BACKGROUND
van Maanen RJ, van Ooijen RD, Zwikker JW, Huitema AD, Rodenhuis S, Beijnen JH. Determination of N,N',N"-triethylenethiophosphoramide and its active metabolite N,N',N"-triethylenephosphoramide in plasma and urine using capillary gas chromatography. J Chromatogr B Biomed Sci Appl. 1998 Nov 20;719(1-2):103-12. doi: 10.1016/s0378-4347(98)00381-8.
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van Maanen MJ, Tijhof IM, Damen JM, Versluis C, van den Bosch JJ, Heck AJ, Rodenhuis S, Beijnen JH. A search for new metabolites of N,N',N''-triethylenethiophosphoramide. Cancer Res. 1999 Sep 15;59(18):4720-4.
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van Maanen MJ, Huitema AD, Rodenhuis S, Beijnen JH. Urinary excretion of thioTEPA and its metabolites in patients treated with high-dose cyclophosphamide, thioTEPA and carboplatin. Anticancer Drugs. 2001 Jul;12(6):519-24. doi: 10.1097/00001813-200107000-00005.
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Huitema AD, Tibben MM, Kerbusch T, Kettenes-van den Bosch JJ, Rodenhuis S, Beijnen JH. Simple and selective determination of the cyclophosphamide metabolite phosphoramide mustard in human plasma using high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl. 2000 Aug 18;745(2):345-55. doi: 10.1016/s0378-4347(00)00295-4.
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Huitema ADR, Tibben MM, Kerbusch T, Kettenes-van den Bosch JJ, Rodenhuis S, Beijnen JH: High performance liquid chromatographic determination of the stabilized cyclophosphamide metabolite 4-hydroxycyclophosphamide in plasma and red blood cells. J Liq Chrom Rel Technol 2000, 23: 1725-1744
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Huitema AD, Reinders C, Tibben MM, Rodenhuis S, Beijnen JH. Sensitive gas chromatographic determination of the cyclophosphamide metabolite 2-dechloroethylcyclophosphamide in human plasma. J Chromatogr B Biomed Sci Appl. 2001 Jun 15;757(2):349-57. doi: 10.1016/s0378-4347(01)00178-5.
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Other Identifiers
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CKTO 2005-15
Identifier Type: -
Identifier Source: secondary_id
METc 2004/110
Identifier Type: -
Identifier Source: org_study_id