We estimate that the anthracycline and cyclophosphamide dose could be significantly (>=15%) increased in at least 15% of ACC-treated patients. Therefore, in order to diminish the risk of under-dosing ACC, we aim to develop a neutrophil-guided…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Rather arbitrarily, neutrophil-guided dose escalation will be considered
potentially useful if a >=15% dose escalation is feasible in at least three out
of thirty patients.
Secondary outcome
Assessment of interindividual variability (IIV) in neutrophil counts after a
first cycle of anthracyclin/cyclophosphamide chemotherapy (ACC).
Background summary
Cytotoxic anticancer treatments have narrow therapeutic margins and huge
inter-individual variability (IIV) in treatment effects (anticancer efficacy,
toxicity) that is not sufficiently reduced by standard body surface area
(BSA)-based dosing. Neutropenia is a major side-effect, and often the
dose-limiting factor which also applies for
anthracycline/cyclophosphamide-based chemotherapy (ACC). Furthermore, there is
evidence of an association between chemotherapy-induced neutropenia and
treatment efficacy. In clinical practice, treatment overdose (e.g. manifested
by febrile neutropenia) is managed by dose reduction and/or addition of
granulocyte colony-stimulating factor (G-CSF) and/or prophylactic antibiotic
treatment whereas an inappropriate low dose of chemotherapy is not routinely
detected and therefore will not be corrected for during subsequent treatment
cycles. This could result in sub-therapeutic dosing in a substantial number of
cancer patients.
Study objective
We estimate that the anthracycline and cyclophosphamide dose could be
significantly (>=15%) increased in at least 15% of ACC-treated patients.
Therefore, in order to diminish the risk of under-dosing ACC, we aim to develop
a neutrophil-guided dosing algorithm. Furthermore, IIV for chemotherapy-related
neutropenia will be assessed.
Study design
Non-blinded, intra-patient stepwise chemotherapy dose escalation pilot study
guided by absolute neutrophil counts (ANC) during the first two cycles of ACC.
Intervention
Patients with clinically non-significant (grade 0-2) neutropenia and no other
dose-limiting toxicity after the first cycle of chemotherapy will undergo a
10-25% (depending on the course of ANC) dose escalation during the second
cycle. If possible, in the same manner, a further 10-25% dose escalation will
be undertaken for the third treatment cycle. Patients that continue treatment
for a total of >3 cycles will receive subsequent cycles according to standard
BSA-based dosing. Patients with nadir grade 3-4 neutropenia will not undergo
dose escalation during subsequent treatment cycles, and patients with febrile
neutropenia will be treated according to the usual standard of care.
Study burden and risks
The main risk of participation in this study consists of excessive toxicity
after dose escalation of chemotherapy. Therefore, the amount of dose escalation
has been chosen rather cautious when compared to the large IIV in drug
exposure. Furthermore, subjects will be thoroughly assessed for toxicity,
especially after dose escalation. During the first cycle of treatment, and
during the second and third treatment cycle in patients undergoing dose
escalation, extra blood counts will be obtained on days 8, 11 and 15 along with
scoring of non-hematologic toxicity using the Common Cytotoxicity Criteria
(CTC) version 3.0. Finally, for safety reasons, a maximum of three patients
will be allowed on study treatment simultaneously.
Montessoriweg 1
3083 AN Rotterdam
NL
Montessoriweg 1
3083 AN Rotterdam
NL
Listed location countries
Age
Inclusion criteria
(1) breast cancer patients aged >=18 years planned for treatment with at least three cycles of one of the above-mentioned ACC-regimens (AC, FAC, or FEC) at the Department of Medical Oncology, Ikazia Hospital, Rotterdam, The Netherlands
(2) WHO performance status 0-1
(3) Life expectancy >3 months
(4) Adequate peripheral blood counts: leukocytes >=4.0x109/L and ANC >=2.0x109/L and platelet count >=150x109/L
(5) Adequate renal function defined as normal serum creatinine concentration and/or estimated creatinine clearance >=60 mL/min (by Cockroft-Gault formula: [140 - age (years)] x 1.05 x body weight (kg)] : serum creatinine concentration (µmol/L))
(6) Adequate liver function defined as normal serum bilirubin concentration (<=17 µmol/L) and serum ASAT and ALAT <=3 times the upper limit of normal (<=5 times the upper limit of normal in case of hepatic metastases)
(7) Normal serum albumin concentration (35-50 g/L)
(8) Written informed consent
Exclusion criteria
(1) Previous treatment with chemotherapy
(2) Unable to consent with weekly follow-up for blood counts and toxicity assessment
(3) Symptomatic brain metastasis
(4) History of cardiac dysfunction
(5) Uncontrolled arterial hypertension (blood pressure systolic >=180 mmHg and/or diastolic >=110 mmHg) and/or unstable angina pectoris
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-020309-33-NL |
| CCMO | NL32077.101.10 |