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K. Roszkowski-Sliz
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ORAL 01 - Chemotherapy Developments for Lung Cancer (ID 88)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G. Blumenschein, S. Lee
- Coordinates: 9/07/2015, 10:45 - 12:15, 401-404
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ORAL01.05 - Phase I/II Dose Escalation Study of Immunoconjugate L-DOS47 as a Monotherapy in Non-Squamous Non-Small Cell Lung Cancer Patients (ID 3272)
11:28 - 11:39 | Author(s): K. Roszkowski-Sliz
- Abstract
- Presentation
Background:
L‑DOS47, a cancer therapeutic designed to exploit the acidic tumour extracellular environment, is a protein conjugate consisting of a urease conjugated to a camelid monoclonal antibody (AFAIKL2) that is targeted to the CEACAM6 antigenic tumour marker. The AFAIKL2 antibody serves as a targeting agent to deliver the enzyme to the tumor sites while the urease enzyme converts urea, an abundant natural metabolite, into ammonia and generates a local pH increase. The combined effect of ammonia toxicity and pH increase is cytotoxic to cancer cells in culture and in xenograft models. This first in human study of L‑DOS47 was designed to define the maximum tolerated dose of multiple doses of L-DOS47 administered intravenously to patients with non-squamous NSCLC when given as a monotherapy.
Methods:
Stage IIIb or IV histologically confirmed non-squamous NSCLC patients (aged ≥18 yrs, ECOG PS ≤2) receive multiple cycles of L-DOS47 during the study treatment period. L-DOS47 is administered once weekly over 14 days followed by 7 days rest in each treatment cycle. Patients are recruited into cohorts and received the same dose of L-DOS47 on Days 1 and 8 of each treatment cycle. Dose levels of L-DOS47 are escalated in further cohorts following a review of safety data by the Trial Steering Committee.
Results:
Thirty-three (33) pts (median age 61, 58% male) were enrolled in the first ten cohorts (dose levels: 0.12, 0.21, 0.33, 0.46, 0.59, 0.78, 1.04, 1.38, 1.84, 2.45 µg/kg) in four Polish centers. L-DOS47 was well tolerated at the dose levels reviewed. No DLTs were reported. Adverse events reported to date were expected for the population under study. None of the patients treated to date have had a partial or complete response as defined by RECIST v1.1. Sixteen (16) patients had an overall response of stable disease after completing two cycles of L-DOS47. One patient in cohort 9 was dosed for 9 cycles without disease progression.
Conclusion:
L-DOS47 monotherapy is well tolerated at dose levels up to 2.45 µg/kg. ClinicalTrials.gov identifier: NCT02340208
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-075 - The Biological and Clinical Significance of Alpha-1 Antitrypsin in Non-Small Cell Lung Cancer (ID 2132)
09:30 - 09:30 | Author(s): K. Roszkowski-Sliz
- Abstract
Background:
Lung cancer progression is generally associated with extensive tissue remodeling to provide a suitable environment for tumor growth, invasion and metastasis, and it is known that proteinases expressed by cancer cells and/or host cells play a key role in this process. However, the biological role of alpha-1 antitrypsin (AAT) in lung carcinogenesis is not clear.
Methods:
Serum and FFPE tissue samples from 206 NSCLC patients (stages I-IV) were analyzed for AAT and CRP blood concentration, AAT phenotype and AAT protein expression in tumor cells. Reference groups consisted of 183 PiMM COPD patients and 23 PiMM patients with benign lung nodules (positive chest radiograph).
Results:
Only 10/206 (5%) NSCLC patients carried deficient AAT allele (mean AAT blood concentration 150 mg/dl). In the PiMM NSCLC patients mean AAT serum concentration (195.5 mg/dl) was significantly higher than in the PiMM COPD group (171 mg/dl) and the patients with benign lung nodules (154 mg/dl; p<0.0001). AAT concentration was significantly higher in SQC type (202 mg/dl) than ADC (175 mg/dl; p<0.029) patients, and in advanced (IIIb-IV, 247 mg/dl) versus early stage disease (I-IIIa, 190 mg/dl, p<0.0001). The AAT levels significantly correlated with CRP (R=0.6; p<0.0001), however CRP level did not differentiate NSCLC from COPD. Importantly, the strong AAT expression observed in tumor tissue was positively associated with the higher AAT blood levels, while weak or no AAT expression directly correlated with the lower AAT blood levels.
Conclusion:
Our results evidenced that local production of AAT by tumor cells significantly contribute to high levels of AAT in blood of NSCLC patients reflecting an active role of this anti-protease in lung carcinogenesis. The study is on-going.
