Description:
The current standard of care for stage I-III HER2-positive breast cancer is adjuvant
chemotherapy combined with 1 year of adjuvant trastuzumab. Neoadjuvant chemotherapy in early
stage breast cancer has the advantages of i) tumour downsizing, ii) higher breast
conservation rates, and iii) enabling the evaluation of tumour biology. Pathologic complete
response following neoadjuvant chemotherapy has been shown to be an independent, strong
predictor of outcome in operable HER2-positive breast cancer. The addition of neoadjuvant
anti-HER2 therapy to chemotherapy results in a 2-3 fold increase in pCR rates in operable
HER2-positive breast cancer. However, the optimal neoadjuvant regimen has not been defined in
HER2-positive breast cancer. The investigators recently completed a phase II study of
neoadjuvant lapatinib combined with weekly paclitaxel/ carboplatin in stage I-III
HER2-positive breast cancer. Preliminary analysis suggested that the utility of the regimen
might have been limited by its unfavourable efficacy/ toxicity ratio. ASLAN001 is a small
molecule tyrosine kinase inhibitor against HER1, HER2, and HER4. Preclinical data have shown
ASLAN001 to be more potent than lapatinib and neratinib in inhibiting HER1 and HER2, and
early phase clinical studies have demonstrated superior pharmacokinetics and pharmacodynamic
target inhibition compared to lapatinib. Furthermore, ASLAN001 has demonstrated a better
safety profile than lapatinib in early phase studies.
• The investigators hypothesize that ASLAN001 combined with paclitaxel/carboplatin will
induce favorable pathological complete response (of at least 30%) in stage I-III HER2
positive breast cancer, with a more favourable safety profile than lapatinib combined with
paclitaxel/carboplatin.
Title
- Brief Title: Dose-confirmation Study of ASLAN001 Combined With Weekly Paclitaxel and Carboplatin in Advanced Solid Tumours, Followed by a Study in Patients With Stage I-III HER2 Positive Breast Cancer
- Official Title: Phase Ib Dose-confirmation Study of ASLAN001 Combined With Weekly Paclitaxel and Carboplatin in Advanced Solid Tumours, Followed by an Open-label Phase II Study in Patients With Stage I-III HER2 Positive Breast Cancer
Clinical Trial IDs
- ORG STUDY ID:
2014/01282
- NCT ID:
NCT02396108
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Paclitaxel + Carboplatin + ASLAN001 | | Paclitaxel + Carboplatin + ASLAN001 |
Purpose
The current standard of care for stage I-III HER2-positive breast cancer is adjuvant
chemotherapy combined with 1 year of adjuvant trastuzumab. Neoadjuvant chemotherapy in early
stage breast cancer has the advantages of i) tumour downsizing, ii) higher breast
conservation rates, and iii) enabling the evaluation of tumour biology. Pathologic complete
response following neoadjuvant chemotherapy has been shown to be an independent, strong
predictor of outcome in operable HER2-positive breast cancer. The addition of neoadjuvant
anti-HER2 therapy to chemotherapy results in a 2-3 fold increase in pCR rates in operable
HER2-positive breast cancer. However, the optimal neoadjuvant regimen has not been defined in
HER2-positive breast cancer. The investigators recently completed a phase II study of
neoadjuvant lapatinib combined with weekly paclitaxel/ carboplatin in stage I-III
HER2-positive breast cancer. Preliminary analysis suggested that the utility of the regimen
might have been limited by its unfavourable efficacy/ toxicity ratio. ASLAN001 is a small
molecule tyrosine kinase inhibitor against HER1, HER2, and HER4. Preclinical data have shown
ASLAN001 to be more potent than lapatinib and neratinib in inhibiting HER1 and HER2, and
early phase clinical studies have demonstrated superior pharmacokinetics and pharmacodynamic
target inhibition compared to lapatinib. Furthermore, ASLAN001 has demonstrated a better
safety profile than lapatinib in early phase studies.
• The investigators hypothesize that ASLAN001 combined with paclitaxel/carboplatin will
induce favorable pathological complete response (of at least 30%) in stage I-III HER2
positive breast cancer, with a more favourable safety profile than lapatinib combined with
paclitaxel/carboplatin.
Detailed Description
Breast cancer is the leading cause of cancer death among women worldwide, with approximately
800, 000 breast cancer deaths annually projected to occur in 2030 globally[1]. Activation and
over-expression of oncogenes encoding trans-membrane receptor tyrosine kinases of the
epidermal growth factor receptor (EGFR) family, including ErbB1 (also known as HER1/EGFR) and
ErbB2 (also known as human epidermal growth factor receptor 2 or HER2), play an important
role in the development of breast cancer. Overexpression of HER2 has been shown to be a poor
prognostic indicator associated with increased relapse rates and poorer overall survival in
breast cancer. Several therapeutic strategies have been developed to block HER2 signaling
pathways in order to improve the treatment of breast cancer.
Trastuzumab is a recombinant, humanized, monoclonal antibody that binds to the extracellular
domain of the HER2 protein. Treatment with trastuzumab improves the outcomes of women with
HER2 over-expressing early stage and metastatic breast cancer (MBC) [3, 4]. The current
standard of care for stage I-III HER2-positive breast cancer patients is the addition of 1
year of adjuvant trastuzumab to chemotherapy [5]. This results in a 40-50% improvement in 5-
year disease-free survival (DFS), and 30% improvement in 5-year overall survival (OS) over
chemotherapy alone.
Preoperative (primary or neoadjuvant) chemotherapy which is the standard therapy for patients
with locally advanced breast cancer, is increasingly used in patients with operable breast
cancer [15]. Randomised trials comparing preoperative and adjuvant chemotherapy for early
operable breast cancer demonstrated that preoperative chemotherapy has several potential
advantages over the adjuvant approach. It significantly increased the rate of breast
conserving surgery over mastectomy. Pathological complete response following preoperative
chemotherapy in the breast and lymph nodes significantly predicted better patient survival.
Furthermore, preoperative chemotherapy was associated with fewer adverse events (AEs) [16,
17].
These data have prompted the increasing use of preoperative chemotherapy in patients with
operable breast cancer. Given the increasingly important role of anti-HER2 therapy in both
early and advanced stage HER2-positive breast cancer, our aim is to expand current
therapeutic options by developing an efficacious and tolerable combination of chemotherapy
and targeted therapy. In the neoadjuvant setting, the addition of trastuzumab to chemotherapy
has been reported to result in a 2-3 fold increase in pCR rates in operable HER2-positive
breast cancer [18].
However, the optimal neoadjuvant regimen for early stage HER2-positive breast cancer has yet
to be defined. We recently completed a phase II study of neoadjuvant weekly paclitaxel and
carboplatin in combination with lapatinib in patients with stage I-III HER2-positive breast
cancer. Pathologic complete response rates were lower than expected (11.1%) due to a high
proportion of locally advanced tumours. In addition, dose interruptions and reductions were
common, and dose intensity was difficult to maintain. Grade 3 and above non-hematologic
toxicities occurred in 19.4% and common toxicities (¬>20%) included diarrhea (80%),
peripheral neuropathy (65.7%), rash (57.1%), nausea (40%), fatigue (40%), vomiting (34.3%),
non-neutropenic infections (25%) and transaminitis (22.8%) [19]. ASLAN001 is a small molecule
tyrosine kinase inhibitor against HER1, HER2, and HER4.
Preclinical data have shown ASLAN001 to be more potent than lapatinib and neratinib in
inhibiting HER1 and HER2, and early phase clinical studies have demonstrated superior
pharmacokinetics and pharmacodynamic target inhibition compared to lapatinib. Furthermore,
ASLAN001 has demonstrated a better safety profile than lapatinib in early phase studies. We
hypothesize that the novel combination of ASLAN001 with weekly paclitaxel/carboplatin will
induce favorable pathological complete response (of at least 30%) in stage I-III HER2
positive breast cancer, with a more favourable safety profile than lapatinib combined with
paclitaxel/carboplatin. All patients will receive 1 year of adjuvant trastuzumab following
completion of anthracycline-containing chemotherapy post-operatively, in accordance with
standard practice.
Trial Arms
Name | Type | Description | Interventions |
---|
Paclitaxel + Carboplatin + ASLAN001 | Experimental | Phase I:
A modified 3+3 study de-escalating dose design will be employed for dose determination. Subjects will receive treatment in 21-day cycles until disease progression, intolerable toxicities or withdraws consent. In the presence of intolerable toxicities to one or more of the drugs in the regimen (but not all 3), the drug in question may be discontinued and the other drugs continued with the patient remaining in the study, if the patient is deemed to be benefiting, after discussion with the Principal Investigator.
Phase II:
Patients with stage I-III HER2-positive breast cancer with a primary breast tumour of 2cm or greater will receive up to 4 cycles of pre-operative ASLAN001 and weekly paclitaxel/ carboplatin delivered in 21-day cycles. Prior to administration of chemotherapy, there will be lead-in dosing of single-agent ASLAN001 administered daily for 2 weeks at the recommended phase II dose. | - Paclitaxel + Carboplatin + ASLAN001
|
Eligibility Criteria
Inclusion Criteria:
- Age ≥ 21 years
- Karnofsky performance status of 70 or higher
- Estimated life expectancy of at least 12 weeks
- Adequate organ function including the following:
Bone marrow:
oAbsolute neutrophil (segmented and bands) count (ANC) ≥ 1.5 x 109/L oPlatelets ≥ 100 x
109/L
Hepatic:
oBilirubin ≤ 1.5 x upper limit of normal (ULN), oALT and AST ≤ 2.5x ULN
Renal:
oCalculated creatinine clearance >30ml/minute
- Left ventricular ejection fraction ≥50% measured by 2D echo or MUGA
- Signed informed consent from patient or legal representative
- Patient with reproductive potential must use an approved contraceptive method if
appropriate (e.g. intrauterine device, birth control pills, or barrier device) during
and for three months after the study. Females with childbearing potential must have a
negative serum pregnancy test within 7 days prior to study enrollment
Specific to phase I:
•Any patient with advanced cancer where treatment with weekly paclitaxel/ carboplatin is
indicated, as determined by his/her physician
Specific to phase II:
- Histologic or cytologic diagnosis of breast carcinoma
- T1-4 breast cancer with measurable primary breast tumor, defined as palpable tumor
with the largest diameter measuring 2.0cm or greater by calipers. For T1 breast
cancer, the primary tumor must measure at least 2.0cm
- Tumor is HER2 positive either by IHC (3+) or FISH amplification (amplification ratio
>2.0)
Exclusion Criteria:
- Concurrent administration of any other tumor therapy, including cytotoxic
chemotherapy, endocrine therapy, and immunotherapy
- Major surgery within 28 days of study drug administration
- Active infection that in the opinion of the investigator would compromise the
patient's ability to tolerate therapy
- Breast feeding
- Serious cardiac illness or medical conditions including but not confined to:
oHistory of documented congestive cardiac failure or systolic dysfunction (LVEF <50%)
oHigh-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade AV block,
supraventricular arrhythmias which are not adequately rate-controlled) oHistory of
significant ischaemic heart disease oClinically significant valvular heart disease oPoorly
controlled hypertension (e.g. systolic BP > 180mmHg or diastolic >100mmHg)
- Poorly controlled diabetes mellitus.
- Second primary malignancy that is clinically detectable at the time of consideration
for study enrollment.
- History of significant neurological or mental disorder, including seizures or
dementia.
- Subjects who have current active hepatic or biliary disease (with exception of
patients with Gilbert's syndrome, asymptomatic gallstones or stable chronic liver
disease per investigator assessment)
Specific to phase I:
•Treatment with anti-tumour therapy, defined as chemotherapy, immunotherapy or
investigational product within 21 days prior to first dose of study drug
Specific to phase II:
- Stage IV breast cancer
- Stage I breast cancer with primary breast tumor measuring <2.0cm
- Treatment within the last 28 days with any investigational drug
Maximum Eligible Age: | 99 Years |
Minimum Eligible Age: | 21 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Pathologic complete response rate |
Time Frame: | Post neoadjuvant chemotherapy (within 2-3 weeks after last dose of neoadjuvant chemotherapy) |
Safety Issue: | |
Description: | Defined as the absence of invasive cancer in both the primary tumor as well as the axillary lymph nodes at the time of surgical resection. |
Secondary Outcome Measures
Measure: | Treatment related toxicities, using descriptive statistics |
Time Frame: | Until death or disease progression, whichever occurs first (up to 5 years) |
Safety Issue: | |
Description: | Adverse events of special interest include febrile neutropenia, diarrhea, hepatotoxicity, and left ventricular dysfunction. |
Measure: | Breast conservation rates, using descriptive statistics |
Time Frame: | Post neoadjuvant chemotherapy (within 2-3 weeks after last dose of neoadjuvant chemotherapy) |
Safety Issue: | |
Description: | Odds ratio with approximate 95% confidence intervals for mastectomy (vs breast conservation) will be calculated for clinico-pathological factors known to influence breast surgery outcome following neoadjuvant chemotherapy, including clinical T and N stage at diagnosis, hormone receptor status, age (>40 vs ≤40) , and clinical response to chemotherapy. |
Measure: | Clinical response rate, using descriptive statistics |
Time Frame: | Post neoadjuvant chemotherapy (within 2-3 weeks after last dose of neoadjuvant chemotherapy) |
Safety Issue: | |
Description: | Will be calculated as the ratio of the number of complete and partial responders to the total number of evaluable patients, on completion of neoadjuvant chemotherapy. The response will be determined according to the RECIST criteria. A 80% confidential interval for the response rate will be computed based on the binomial distribution function. Waterfall plots will be constructed to visualize the extent of tumor regression after completing neoadjuvant chemotherapy and prior to surgery. |
Measure: | Relapse free survival (RFS), using Kaplan Meier/ log-rank test |
Time Frame: | 2 and 5 year post neoadjuvant chemotherapy/time of surgery |
Safety Issue: | |
Description: | Kaplan Meier curves of RFS at 2 and 5 years, of the entire cohort, the cohort that achieves pathological complete response and the cohort that does not achieve pathological complete response, will be plotted. Log-rank testing will be performed to identify clinical and pathological factors that influence RFS. |
Measure: | Identification of tumor biomarkers, using chi-square |
Time Frame: | Post neoadjuvant chemotherapy (within 2-3 weeks after last dose of neoadjuvant chemotherapy) |
Safety Issue: | |
Description: | Correlative testing of potential tumour biomarkers with presence or absence of pCR. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Unknown status |
Lead Sponsor: | National University Hospital, Singapore |
Last Updated
February 3, 2017