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

NCT02396108 | Unknown Phase 1

• 1 other identifier: 2014/01282
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (1)

• Pathologic complete response rate

  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.

  Post neoadjuvant chemotherapy (within 2-3 weeks after last dose of neoadjuvant chemotherapy)

Secondary Outcomes (5)

• Treatment related toxicities, using descriptive statistics

  Until death or disease progression, whichever occurs first (up to 5 years)

• Breast conservation rates, using descriptive statistics

  Post neoadjuvant chemotherapy (within 2-3 weeks after last dose of neoadjuvant chemotherapy)

• Clinical response rate, using descriptive statistics

  Post neoadjuvant chemotherapy (within 2-3 weeks after last dose of neoadjuvant chemotherapy)

• Relapse free survival (RFS), using Kaplan Meier/ log-rank test

  2 and 5 year post neoadjuvant chemotherapy/time of surgery

• Identification of tumor biomarkers, using chi-square

  Post neoadjuvant chemotherapy (within 2-3 weeks after last dose of neoadjuvant chemotherapy)

Study Arms (1)

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.

Drug: Paclitaxel + Carboplatin + ASLAN001

Interventions

Paclitaxel + Carboplatin + ASLAN001 DRUG

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

Paclitaxel + Carboplatin + ASLAN001

Eligibility Criteria

• Age: 21 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National University Hospital, Singapore: lead

Study Sites (1)

National University Hospital

Singapore, Singapore, 119228, Singapore

RECRUITING

Related Publications (4)

• Wong A, Tan SH, Soh T, Tan CS. Phase II study of neoadjuvant weekly paclitaxel and carboplatin with lapatinib in HER2+ breast cancer. J Clin Oncol 32:5s, (suppl; abstr 619), 2014.

  BACKGROUND

• Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. doi: 10.1056/NEJMoa052122.

  PMID: 16236738 BACKGROUND

• Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA, Wolmark N. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366-73. doi: 10.1200/JCO.2011.35.0868. Epub 2011 Jul 18.

  PMID: 21768458 BACKGROUND

• Lee MX, Wong ALA, Ow S, Sundar R, Tan DSP, Soo RA, Chee CE, Lim JSJ, Yong WP, Lim SE, Goh BC, Wang L, Lee SC. Phase Ib Dose-Finding Study of Varlitinib Combined with Weekly Paclitaxel With or Without Carboplatin +/- Trastuzumab in Advanced Solid Tumors. Target Oncol. 2022 Mar;17(2):141-151. doi: 10.1007/s11523-022-00867-0. Epub 2022 Feb 23.

  PMID: 35195837 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Paclitaxel; Carboplatin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes

Study Officials

• Soo Chin Lee

  National University Hospital, Singapore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Soo Chin Lee

CONTACT

(65) 6779 5555

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 15, 2015
• First Posted: March 24, 2015
• Study Start: March 1, 2015
• Primary Completion: March 1, 2018
• Study Completion: March 1, 2019
• Last Updated: February 3, 2017

Record last verified: 2017-02

Locations

SG (1)