A phase I study of XL228, a potent IGF1R/AURORA/SRC inhibitor, in patients with solid tumors or hematologic malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3512-3512
Author(s):  
D. C. Smith ◽  
C. Britten ◽  
D. O. Clary ◽  
L. T. Nguyen ◽  
P. Woodard ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Solid Tumors ◽  
Cell Lung Cancer ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Small Cell ◽  
Clinical Activity ◽  
Small Cell Lung

3512 Background: XL228 is a protein kinase inhibitor targeting IGF1R, the AURORA kinases, FGFR1–3, ABL and SRC family kinases. It is being evaluated in a phase 1 trial in patients (pts) with advanced malignancies. Methods: XL228 is administered as weekly 1-hour IV infusions. Cohorts of pts with refractory solid tumors or lymphoma are evaluated for determination of the maximum tolerated dose, pharmacokinetics, and pharmacodynamic effects using FDG-PET, signal pathway analysis in tumor and normal tissue biopsies, and plasma marker analysis. MTD expansion cohorts will include pts with multiple myeloma and colorectal cancer. Results: Thirty-six pts have been treated at doses ranging from 0.45 to 8.0mg/kg. The maximum administered dose was defined as 8.0mg/kg as a result of the dose limiting toxicities of Grade (Gr) 4 neutropenia, and Gr 3 neutropenia requiring dose skipping. XL228 is generally well tolerated; one serious adverse event of drug-related Gr 3 vomiting has been observed. Common drug-related adverse events include Gr 1 nausea, fatigue, decreased appetite, and flushing, and Grade 1–2 hyperglycemia (fasting) lasting up to 4 hours post- infusion. XL228 exposure was approximately dose-proportional; the mean terminal half-life (t1/2, z) ranged from 27 to 54 hours. Low accumulation was observed after weekly administration. Protein phosphorylation measurements in skin, hair, and blood samples demonstrate inhibition of IGF1R, SRC and FGFR1 signaling by XL228, including reductions in hair follicle phospho-IGF1R and phospho-FAK1 of 39% and 42%, respectively, in a pt dosed at 5.4mg/kg. Evidence of clinical activity includes one non-small cell lung cancer pt with an unconfirmed partial response (confirmation pending) and 9 additional pts (of 30 evaluable) with stable disease (SD) lasting >3 months, including a small cell lung cancer pt on study for 13.3+ months after failing carboplatin/etoposide. For pts with SD, the median time on study is currently 5.9 months (range 3.3+ to 13.3+). Conclusions: XL228 is generally well tolerated and has shown encouraging preliminary clinical and pharmacodynamic activity. [Table: see text]

scholarly journals Phase 1/2 study of the safety and clinical activity of durvalumab in patients with non-small cell lung cancer (NSCLC)

2016 ◽  
Vol 27 ◽  
pp. vi421 ◽  
Author(s):  
S.J. Antonia ◽  
J.R. Brahmer ◽  
S. Khleif ◽  
A.S. Balmanoukian ◽  
S.-H.I. Ou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Phase 1 ◽  
Small Cell ◽  
Clinical Activity ◽  
Small Cell Lung

scholarly journals Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

2018 ◽  
Vol 24 (5) ◽  
pp. 638-646 ◽  
Author(s):  
Jacqulyne P. Robichaux ◽  
Yasir Y. Elamin ◽  
Zhi Tan ◽  
Brett W. Carter ◽  
Shuxing Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitor ◽  
Small Cell ◽  
Clinical Activity ◽  
Small Cell Lung ◽  
Exon 20 ◽  
Selective Kinase Inhibitor

Phase 1 dose-expansion study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1 (ASS1)–deficient non-squamous non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9097-9097
Author(s):  
Akhila Ganeshi Wimalasingham ◽  
Melissa Mary Phillips ◽  
Louise Lim ◽  
Sukaina Rashid ◽  
Peter Edward Hall ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Small Cell ◽  
Arginine Deiminase ◽  
Small Cell Lung ◽  
Plasma Arginine

9097 Background: Pegylated arginine deiminase (ADI-PEG20) targets ASS1-ve tumors, including non–small-cell lung cancer (NSCLC), by potentiating pemetrexed cytotoxicity via arginine depletion. In Beddowes et al (JCO 2017) we showed a 100% disease control rate in thoracic cancers treated with ADI-PEG20, cisplatin and pemetrexed (ADIPemCis). Thus, we tested ADIPemCis in a phase I dose-expansion cohort study of patients (pts) with non-squamous NSCLC. Methods: Good performance (ECOG 0-1) advanced non-squamous NSCLC pts were enrolled at the maximum tolerated dose (MTD) of ADIPemCis, using tumoral ASS1 loss as a selection biomarker. Pem (500mg/m2) and Cis (75mg/m2) were given every 3 weeks with weekly IM ADI-PEG20 (36mg/m2) for up to 4 cycles with maintenance ADI-PEG20 or Pem in responding pts. Primary endpoint was tumor response rate (RR by RECIST 1.1), with secondary endpoints including progression-free survival (PFS), overall survival (OS), and toxicity. We also measured plasma [arginine] and [citrulline], anti-ADI-PEG20 antibodies, and PD-L1 expression. Results: 21 of 70 screened pts (median age 60.1) were enrolled between April 15 and August 17. A confirmed partial response (PR) was observed in 55.6 % (n = 10/18 evaluable pts). Median PFS and OS were 4 months (95% CI 2.9-4.8) and 7.2 months (95% CI 5.1-18.4), respectively. 9% (n = 2/21) remain alive on subsequent therapies. 43% (n = 9/21) experienced grade 3/4 treatment-related toxicities, commonly non-febrile neutropenia. Plasma [arginine] declined rapidly and [citrulline] increased; both changes persisted at 16 weeks. 55% of pts’ tumors (n = 6/11 ) were PD-L1 < 1% by immunohistochemistry. Conclusions: The ADIPemCis regimen is active and safe in ASS1-ve NSCLC pts almost doubling the expected RR. However, the short survival compared with ASS1-agnostic historical controls indicates that ASS1 (and frequent PD-L1) loss selects for a biologically more aggressive and immunorefractory NSCLC phenotype. The iTRAP study opening Q2 of 2019 will assess the safety and tolerability of ADIPemPlatinum(Carbo) with atezolizumab in pts with ASS1-deficient non-squamous NSCLC. Clinical trial information: NCT02029690.

scholarly journals Clinical Activity and Safety of Atezolizumab in a Phase 1 Study of Patients With Relapsed/Refractory Small-Cell Lung Cancer

2020 ◽  
Vol 21 (5) ◽  
pp. 455-463.e4 ◽  
Author(s):  
Anne C. Chiang ◽  
Lecia Van Dam Sequist ◽  
Jill Gilbert ◽  
Paul Conkling ◽  
Dana Thompson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Phase 1 ◽  
Small Cell ◽  
Clinical Activity ◽  
Small Cell Lung ◽  
Phase 1 Study

Gefitinib Therapy for Advanced Non–Small-Cell Lung Cancer

2003 ◽  
Vol 37 (11) ◽  
pp. 1644-1653 ◽  
Author(s):  
Chin Y Liu ◽  
Susan Seen
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Optimal Dose ◽  
Small Cell ◽  
Clinical Activity ◽  
Small Cell Lung

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and toxicity of gefitinib in non–small-cell lung cancer (NSCLC). DATA SOURCES: Primary literature search through MEDLINE and CANCERLIT, and abstract presentations (1966–May 2003). STUDY SELECTION AND DATA EXTRACTION: All published trials and abstracts citing gefitinib were evaluated, and all information deemed relevant was included in this article. DATA SYNTHESIS: NSCLC is known to overexpress epidermal growth factor receptor (EGFR). Gefitinib is a selective EGFR tyrosine kinase inhibitor. Based on the Phase I/II trial results, the optimal dose is 250 mg/d orally. It is well tolerated, with minimal and reversible toxicity. Skin rash and diarrhea are the most common adverse effects. Recent trials have shown that gefitinib provided a 10% tumor response rate and improved disease-related symptoms in patients with refractory, advanced NSCLC. CONCLUSIONS: Gefitinib, with a unique mechanism of action and favorable toxicity profile, has demonstrated clinical activity in NSCLC patients with chemotherapy-refractory disease. It provides a valuable addition to the treatment options as monotherapy in patients with advanced NSCLC after failure of both platinum-based and docetaxel chemotherapies. Further research is required to evaluate the use of gefitinib in different clinical settings.

A phase II, multicenter, placebo-controlled trial of apatinib in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after two previous treatment regimens.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7548-7548 ◽  
Author(s):  
Li Zhang ◽  
Meiqi SHI ◽  
Cheng Huang ◽  
Xiaoqing Liu ◽  
Jian ping Xiong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Kinase Inhibitor ◽  
Group Versus ◽  
Small Cell ◽  
Clinical Activity ◽  
Small Cell Lung ◽  
Primary Object

7548 Background: Apatinib is an oral, small molecular tyrosine-kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR). Phase II study has showed that apatinib significantly improved the outcome of patients with advanced or metastatic gastric cancer (Li J, et al. ASCO 2011). The primary object of this study is to determine whether apatinib can improve progression free survival (PFS) compared with placebo in patients with advanced non-squamous NSCLC who failed two lines of treatment. Methods: This study recruited histologically diagnosed advanced non-squamous NSCLC patients who failed more than two lines of treatment including EGFR TKIs. Other eligible criteria included ECOG ≤1, adequate organ function and no prior exposure to VEGFR-TKI. The patients were randomized to receive apatinib at a dose of 750 mg or placebo (at allocation ratio of 2:1) orally once daily until the disease progression or unacceptable toxicity. Results: 135 patients (90 in apatinib arm, 45 in placebo arm) were included at 20 centers in China until Aug 2011. Median PFS was 4.7 months for apatinib group versus 1.9 months for placebo group, hazard ratio (HR) was 0.278 (95% CI 0.170, 0.455) (p<0.0001). The response rate (RR) and disease control rate (DCR) were also significantly better in study arm (12.2% and 68.9%) than in placebo arm (0% and 24.4%)(P=0.0158 and P<0.0001). The most frequently observed AEs were hypertension, proteinuria, and hand-foot syndrome (HFS). These AEs were generally mild or moderate in severity and were manageable. Conclusions: This randomized phase II trial shows that apatinib has substantial clinical activity without significant additional toxicity in patients with advanced non-squamous and non-small cell lung cancer. Continued investigation of apatinib is warranted in future clinical studies.

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