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A PHASE IB STUDY OF ERLOTINIB PLUS CAPECITABINE AND DOCETAXEL IN METASTATIC BREAST CANCER (MBC)
R Jones,1 J Trigo,2 F DeRosa,3 U Brennscheidt,3 A Rakhit,4 T Wright,1 X Carbonell Castellon,2 C Twelves,1 J Baselga2
Beatson Oncology Centre, Glasgow, UK; 2Medical Oncology Service, Vall d’Hebron University Hospital, Barcelona, Spain; 3F. Hoffmann-La Roche, Basel, Switzerland; 4F. Hoffmann-La Roche, Nutley, New Jersey, USA
1
Determination of MTD
Abstract
● When one or more of three patients, or two or more of six patients, in a cohort
experienced a dose-limiting toxicity (DLT), the cohort below was increased to
12 patients. The expanded cohort was used to determine the toxicity profile at the
MTD.
Erlotinib (TarcevaTM) is an orally active, potent, selective inhibitor of the HER1/EGFR tyrosine kinase
with clinical activity in development for the treatment of various solid tumours. Capecitabine has
been approved for the treatment of patients with metastatic breast cancer (MBC) and the
combination of capecitabine and docetaxel has shown significant advantages in progression free
survival and overall survival. Preclinical data suggest that the combination of capecitabine and
erlotinib results in additive efficacy. Erlotinib has a favourable toxicity profile and therefore we
conducted a trial to evaluate treatment with erlotinib plus capecitabine and docetaxel in patients
with locally advanced or MBC. Patients with histologically confirmed, incurable disease, who had
received adjuvant chemotherapy and no more than one chemotherapy for their disease and who had
acceptable cardiac, renal and hepatic function were eligible for the study. The objectives of the study
are the assessments of the dose-limiting toxicity (DLT) and the maximal tolerated dose (MTD).
Patients received study medication, sequentially, as shown in Figure 1. In Cohort C, two DLTs were
observed (Gr. 4 febrile neutropenia, Gr. 3 diarrhoea) out of six patients (one patient in Cohort C
received incorrect dose), Cohort B was then expanded to 12 patients to confirm MTD. To date,
patients have received up to 10 cycles of treatment; apart from the DLTs described above, the most
frequent adverse events observed were neutropenia, rash, hyperbilirubinemia and diarrhoea. So far,
12 partial responses (PR: seven confirmed) have been observed in the 18 evaluable patients treated.
Accrual of patients into the expanded Cohort B has been completed. Updated results and
pharmacokinetic data will be reported at the meeting. Supported by F. Hoffmann-La Roche.
●
many human tumours.1 Studies have shown that it is expressed in breast tumours,
where it is thought to play a role in tumour growth and progression, although reports
differ regarding the level of receptor expression (14–91%).2–5
● Erlotinib is a highly potent and orally available HER1/EGFR-tyrosine kinase inhibitor.
Phase I studies show that erlotinib is well tolerated and active in patients with various
solid tumours.6
● Results of phase II monotherapy studies of erlotinib 150mg/day in patients with
advanced non-small cell lung, ovarian and head and neck cancer suggest a survival
benefit compared with current treatment options.7–9
● In a recent study of patients with advanced breast cancer, the average survival of
patients who received a combination of capecitabine and docetaxel was longer than
those treated with docetaxel alone.10 Therefore, combining erlotinib with capecitabine
and docetaxel may improve survival in patients with metastatic breast cancer (MBC).
● New therapies are urgently required to prolong progression-free disease and overall
survival and improve quality of life in patients with MBC.
● The primary objective was to determine the maximum tolerated dose (MTD) of erlotinib
in combination with capecitabine and docetaxel in patients with locally advanced or
MBC.
● Secondary objectives included evaluating the safety and pharmacokinetic (PK) profile of
the combination regimen and evaluating its effect on response in patients with locally
advanced or MBC.
Study design
● Open-label, two-centre phase Ib study of erlotinib in combination with capecitabine and
docetaxel.
● Each cohort consisted of between three and six patients, and six additional patients
were treated at the MTD. The study design and planned accrual are presented in
Figure 1.
any toxicity necessitating the interruption of erlotinib administration during Cycle 1
●
any other laboratory abnormality occurring during Cycle 1 necessitating a dose
reduction.
Results
Twenty-five patients were enrolled (one of whom was assigned an incorrect dose). The
baseline characteristics of the 24 eligible patients are shown in Table 1. All patients in
Cohorts A, B and C received at least one dose of study medication.
Table 1. Patient characteristics at baseline.
Figure 1. Study design and planned accrual.
● Histologically documented, incurable and locally advanced and/or MBC.
● Patients may have received adjuvant chemotherapy and not more than one prior
chemotherapy regimen for metastatic and/or locally advanced disease.
● Patients should not have received prior docetaxel.
● Measurable disease (≥2cm on conventional CT or ≥1cm on spiral CT scan, palpation or
calliper measurement).
● ECOG performance status of 0–1.
● Life expectancy ≥12 weeks.
● Adequate haematological, hepatic and renal function.
Treatment
were selected (Figure 1).
● Patients received up to 6 cycles of therapy (1 cycle = 21 days). Patients with an objective
response or stable disease after 6 cycles could receive further treatment until disease
progression or unacceptable toxicity.
● Dose modification or interruption of erlotinib, capecitabine or docetaxel was permitted
for adverse events (AEs).
Assessments
● Tumour response was assessed after every 2 cycles (6 weeks) using the standard
Methods
grade 4 neutropenia for >5 days’ duration or febrile neutropenia
●
treatment, as well as any toxicities observed after Cycle 1.
Selection criteria
response evaluation criteria in solid tumours (RECIST).
Cohort A
Cohort B
Cohort C*
No. of patients
6
12
6
Age (years)
Mean (range)
53.5 (38–61)
49.3 (40–63)
53.5 (50–58)
ECOG performance status
0
4
7
3
1
2
5
3
Duration of primary disease (months)
Median (range)
38.65 (0.1–117.7) 59.6 (10.0–86.3) 56.2 (21.1–111.7)
Primary cancer of ductal subtype
5
12
6
Prior treatment (no. of patients)
5
12
6
Chemotherapy✝
Radiotherapy
3
11
5
Hormonal therapy
4
6
3
Histological grade of primary tumour
Well differentiated
0
0
2
Moderately differentiated
1
6
1
Poorly differentiated
3
6
3
Anaplastic
0
0
0
Unknown
2
0
0
Oestrogen receptor status of primary tumour (status of metastatic tumour)
Positive
2 (2)
6 (0)
3 (2)
Negative
3 (1)
5 (0)
2 (1)
Unknown
1 (3)
1 (12)
1 (3)
Progesterone receptor status of primary tumour (status of metastatic tumour)
Positive
2 (1)
4 (0)
2 (3)
Negative
2 (1)
4 (0)
2 (0)
Unknown
2 (4)
4 (12)
2 (3)
*seven patients entered this cohort; however, one patient was assigned the wrong dose and is not
included in the analysis
✝
in the majority of patients chemotherapy was given in the adjuvant or neoadjuvant setting
● Pharmacokinetic parameters included maximum plasma concentration (Cmax), time to
reach maximum plasma concentration (Tmax), area under the plasma concentration-time
curve (AUC) and apparent half life (t1/2), were evaluated for capecitabine and docetaxel
alone (Day 1), and erlotinib alone (Days 21 and 36) or in combination with capecitabine
and docetaxel (Day 22).
Grades
3/4 only
Cohort B
All
grades
Grades
3/4 only
Gastrointestinal disorders
Diarrhoea
5
0
12
0
Nausea
2
0
8
0
Vomiting
1
0
5
0
Abdominal pain (upper)
2
0
4
0
Stomatitis
0
0
5
0
Dyspepsia
3
0
1
0
Dry mouth
1
0
3
0
Abdominal pain (nos)
0
0
4
1
Mouth ulceration
1
0
1
0
Dysphagia
0
0
3
0
Skin and subcutaneous tissue disorders
Alopecia
2
0
9
0
Rash (nos)
1
1
10
0
Palmar-plantar
erythrodysaesthesia synd. 2
0
8
0
Onycholysis
0
0
2
0
Pruritus
0
0
2
0
Rash pustular
3
0
0
0
General disorders and conditions related to site of administration
Asthenia
4
0
7
0
Mucosal inflammation (nos) 2
0
8
0
Lethargy
0
0
5
0
Rigors
0
0
3
0
Eye disorders
Conjunctivitis
2
0
3
0
Dry eye (nos)
0
0
2
0
Other
Anorexia
4
0
4
0
Epistaxis
0
0
4
0
Arthralgia
1
0
4
0
Paraesthesia
0
0
3
0
Rhinorrhoea
1
0
2
0
Ageusia
0
0
2
0
Cohort A
Cohort C
All
grades
Grades
3/4 only
6
3
5
1
2
2
1
0
2
0
0
0
0
0
0
0
0
0
1
0
5
5
0
0
3
3
1
0
0
0
0
0
3
2
2
0
0
0
0
0
3
0
0
0
3
3
1
2
0
2
0
0
0
0
0
0
nos = not otherwise specified
Tolerability
● The most commonly reported treatment-related AEs (>15% incidence, or of specific
relevance to study medication) are shown in Table 2.
Cohort B
Cohort C*
Total
Evaluable patients†
6
12
Complete response (confirmed)
0
2 (0)
0
2 (0)
Partial response (confirmed)
4 (3)
5 (4)
4 (2)
13 (9)
5‡
23
*excludes patient assigned to wrong dose
patients are still continuing on study medication
†
follow-up response data were not available from one patient
‡
● There is no apparent causative relationship between erlotinib exposure (Cmax or AUC at
Cycle 2) and the most commonly reported AEs i.e. rash and diarrhoea, occurring within
the first 3 cycles.
● There is no evidence of a causative relationship between exposure to capecitabine (and
its metabolites) and diarrhoea.
Figure 2. Mean plasma erlotinib concentration versus time (Cohort B).
Conclusions
● The combination of erlotinib, docetaxel and capecitabine is generally well
● Two patients, both in Cohort A, reported hepatotoxicity and facial rash (pustular),
respectively, and discontinued treatment.
● There were no drug-related deaths.
Antitumour activity
● In Cohort A, four patients had partial responses (PRs), of which three were confirmed.
The confirmed PRs lasted for 124–>128 days (Table 3).
● In Cohort B, two patients had an unconfirmed complete response (CR) and five patients
had a PR, one of which was unconfirmed. The confirmed PRs lasted for 81–>145 days.
● In Cohort C, four patients had PRs, of which two were confirmed.
tolerated. The most commonly reported treatment-related AEs were skin and
subcutaneous tissue disorders (100%) and diarrhoea (96%).
● The recommended phase II dose of erlotinib is 100mg/day p.o. in combination
with capecitabine 825mg/m2 b.i.d. and docetaxel 75mg/m2 i.v. in this patient
population.
● Based on preliminary analyses of available data, there is no evidence of any
appreciable pharmacokinetic interaction between erlotinib, capecitabine and
docetaxel or metabolites thereof.
● Overall, the results of this study are encouraging and further trials should be
considered to evaluate this combination therapy in MBC.
Pharmacokinetic analysis
● The mean plasma concentration–time curves for erlotinib in Cohort B patients are
● Safety was assessed by monitoring AEs using the National Cancer Institute Common
Toxicity Criteria (NCI-CTC version 2.0) and changes in laboratory variables, including
opthamalogical examination.
All
grades
≥ CTC grade 3 non-haematological toxicity except for fever, chills and flu-like
symptoms
● Dose escalation was based on the number, if any, of DLTs observed during Cycle 1 of
● Based on previously published safety and efficacy data for each agent, six dose levels
Objectives
No. of patients
Cohort A
●
Table 3. Response to treatment.
No. of patients
● A DLT was defined as one or more of the following:
Introduction
● The epidermal growth factor receptor (HER1/EGFR) is expressed or dysregulated in
Table 2. Summary of AEs classified as at least remotely related to treatment
occurring in >15% of patients in each cohort or grades 3/4 in severity.
shown in Figure 2. These data indicate that there is no pharmacokinetic interaction
between capecitabine or docetaxel and erlotinib and its metabolite.
● There is no evidence for any appreciable pharmacokinetic interaction between erlotinib
and capecitabine or docetaxel or any metabolites thereof.
● In Cohort C, three DLTs were reported (grade 4 febrile neutropenia and two events of
● There is no evidence of a causative relationship between erlotinib exposure (Cmax or AUC
grade 3 diarrhoea [during the first 21 days of treatment]). Therefore, Cohort B was
expanded to 12 patients.
at Cycle 2) and any laboratory abnormality i.e. bilirubin and transaminase elevations,
occurring within the first 3 cycles.
References
1. Salomon DS et al. Crit Rev Oncol Hematol 1995;19:183–232.
2. Walker RA et al. Breast Cancer Res Treat 1999;53:167–76.
3. Esteva FJ et al. Pathol Oncol Res 2001;7:171–7.
4. Klijn JG et al. Endocr Rev 1992;13:3–17.
5. Suo Z et al. Int J Surg Pathol 2002;10:91–9.
6. Hidalgo M et al. J Clin Oncol 2001;19:3267–79.
7. Perez-Soler R et al. Am Soc Clin Oncol Mol Ther Symp 2002.
8. Finkler N et al. Proc Am Soc Clin Oncol 2001;20:208a (abstract 831).
9. Hidalgo M. Consort Novel Targeted Therapies Head and Neck Cancer 2003.
10. O'Shaughnessy J et al. J Clin Oncol 2002;20:2812–23.
Erlotinib HCl is a tripartite collaboration between Genentech, Inc., OSI Pharmaceuticals, Inc., and F. Hoffmann-La Roche, Inc.
ASCO, Chicago, USA, May–June 2003.