Adjuvant Breast Cancer Study of the Netherlands Working Party for Autotransplantation in Solid Tumors

This study has been terminated.
Sponsor:
Information provided by:
University Medical Centre Groningen
ClinicalTrials.gov Identifier:
NCT00851110
First received: February 23, 2009
Last updated: February 24, 2009
Last verified: February 2009
  Purpose

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.

Condition Intervention Phase
High-Risk Breast Cancer
Procedure: stem cell reinfusion
Drug: Chemotherapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Prospective Randomized Feasibility and Phase II Adjuvant Breast Cancer Study of the Netherlands Working Party for Autotransplantation in Solid Tumors.

Resource links provided by NLM:


Further study details as provided by University Medical Centre Groningen:

Primary Outcome Measures:
  • Maximum degree of non-hematological toxicity.

Secondary Outcome Measures:
  • Total number of hospital days
  • Quality of life evaluations during and following high-dose chemotherapy (up to 1 year)

Estimated Enrollment: 50
Study Start Date: October 2004
Intervention Details:
    Procedure: stem cell reinfusion
    hematopoietic stem cell reinfusion
    Drug: Chemotherapy
    High-dose chemotherapy consisting of cyclophosphamide, thiotepa and carboplatin
Detailed Description:

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).

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00851110

Locations
Netherlands
The Netherlands Cancer Institute
Amsterdam, Netherlands, 1066 CX
Free University Hospital
Amsterdam, Netherlands, 1007 MB
Academic Medical Center
Amsterdam, Netherlands, 1105 AZ
Medisch Spectrum Twente
Enschede, Netherlands, 7511 JX
University Medical Centre Groningen
Groningen, Netherlands, 9713 GZ
Leiden University Medical Centre
Leiden, Netherlands, 2333 JS
University Hospital Maastricht
Maastricht, Netherlands, 6202 AZ
University Medical Centre Nijmegen St. Radboud
Nijmegen, Netherlands, 6525 GA
Erasmus MC, Daniel den Hoed Cancer Center
Rotterdam, Netherlands, 3075 EA
University Medical Centre Utrecht
Utrecht, Netherlands, 3584 CX
Sponsors and Collaborators
University Medical Centre Groningen
Investigators
Study Director: Elisabeth G.E. de Vries, MD, PhD University Medical Centre Groningen
Study Director: Sjoerd Rodenhuis, MD, PhD The Netherlands Cancer Institute
  More Information

Publications:
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).
Servent V, Bonneterre J, Roche H, Kerbrat P, Bremond A, Fumoleau P, Namer M, Goudier MJ, Fargeot P, Chapelle-Marcillac I. 10-year follow-up update of French adjuvant study gropu 05 trial: FEC 100 regimen remains superior to FEC 50 in adjuvant chemotherapy of poor prognosis, node-positive, early breast cancer patients. Breast 12 Suppl 1: S35, 2003.
Peters WP, Rosner G, Vredenburgh J, Shpall EJ, Crump M, Marks L, Cirrincione C, Hurd D, Norton L, Ann B. Updated results of a prospective, randomized comparison of two doses of combination alkyating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): CALGB 9082/SWOG 9114/NCIC Ma-13. Proc ASCO 20:81, 2001
Gianni A, Bonadonna G. Five-Year Results of the randomized clinical trial comparing standard versus high-dose myeloablative chemotherapy in the adjuvant treatment of breast cancer with > 3 positive nodes (LN+). Proc ASCO 20: 80, 2001
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
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
ten Vergert EM, S Rodenhuis, M Bontenbal, DJ Richel, JH Schornagel, NH Mulder, J Wagstaff, CJ Rodenburg, GH Blijham, de Wit R, MA Nooy, LV Beex, PS Hupperets, de Vries EG. Quality of life in a randomized adjuvant breast carcinoma study with standard vs high dose chemotherapy Proc Am Soc Clin Oncol. Abstract No: 77 1996
Buijs C, Nieboer P, Rodenhuis S, Bontenbal M, Van der Wall E, Nooij MA, Voest EE, Ten Vergert EM, Mulder NH, Van der Graaf WTA. Fatigue after adjuvant chemotherapy for breast cancer.Proc Am Soc Clin Oncol 22: Abstract No: 127, 2003
Neglia J, Shapiro R, Haake R, Ramsay N, McGlave P, Kersey J. Bone marrow transplantation-II. Allogeneic transplantation-clinical studies. Second neoplasms (SNs) following bone marrow transplantation (BMT) [Abstract 667]. Blood 80, 1992

ClinicalTrials.gov Identifier: NCT00851110     History of Changes
Other Study ID Numbers: METc 2004/110, CKTO 2005-15
Study First Received: February 23, 2009
Last Updated: February 24, 2009
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by University Medical Centre Groningen:
high dose
breast cancer
adjuvant

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases

ClinicalTrials.gov processed this record on April 16, 2014