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

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

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

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.

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.

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.

Phase I IV Paclitaxel 80mg/m2, day 1, 8, 15 of a 21-day cycle IV Carboplatin AUC of 1.5, day 1, 8, 15 of a 21-day cycle PO ASLAN001 daily continuously (starting dose 500mg BID) Phase II •PO ASLAN 001 daily continuously at the recommended phase II dose x 2 weeks Followed by: IV Paclitaxel 80mg/m2, day 1, 8, 15 of a 21-day cycle x 4 cycles IV Carboplatin AUC of 1.5, day 1, 8, 15 of a 21-day cycle x 4 cycles PO ASLAN001 daily continuously at the recommended phase II dose x 12 weeks

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.

Adverse events of special interest include febrile neutropenia, diarrhea, hepatotoxicity, and left ventricular dysfunction.

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.

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.

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.

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

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