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

High-Risk Breast Cancer Clinical Trial

Official title:

A Prospective Randomized Feasibility and Phase II Adjuvant Breast Cancer Study of the Netherlands Working Party for Autotransplantation in Solid Tumors.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00851110
• Other study ID #: METc 2004/110
• Secondary ID: CKTO 2005-15
• Status: Terminated
• Phase: Phase 2
• First received: February 23, 2009
• Last updated: February 24, 2009
• Start date: October 2004

Study information

• Verified date: February 2009
• Source: University Medical Center Groningen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

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.

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 50
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• High-Risk Breast Cancer

Intervention

Procedure:
• stem cell reinfusion
hematopoietic stem cell reinfusion

Drug:
• Chemotherapy
High-dose chemotherapy consisting of cyclophosphamide, thiotepa and carboplatin

Locations

Country	Name	City	State
Netherlands	Academic Medical Center	Amsterdam
Netherlands	Free University Hospital	Amsterdam
Netherlands	The Netherlands Cancer Institute	Amsterdam
Netherlands	Medisch Spectrum Twente	Enschede
Netherlands	University Medical Centre Groningen	Groningen
Netherlands	Leiden University Medical Centre	Leiden
Netherlands	University Hospital Maastricht	Maastricht
Netherlands	University Medical Centre Nijmegen St. Radboud	Nijmegen
Netherlands	Erasmus MC, Daniel den Hoed Cancer Center	Rotterdam
Netherlands	University Medical Centre Utrecht	Utrecht

Sponsors (1)

Lead Sponsor	Collaborator
University Medical Center Groningen

Country where clinical trial is conducted

Netherlands, 

References & Publications (34)

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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. — View Citation

Huitema ADR, Mathôt RAA, Tibben MM, Reinders C, Rodenhuis S, Beijnen JH: Pharmacokinetics of cyclophosphamide and its metabolite 2-dechloroethylcyclophosphamide in a high-dose combination with thioTEPA and carboplatin. Submitted

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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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. — View Citation

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* Note: There are 34 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum degree of non-hematological toxicity.
Secondary	Total number of hospital days
Secondary	Quality of life evaluations during and following high-dose chemotherapy (up to 1 year)