Combination of atezolizumab and pirfenidone in second-line and beyond NSCLC: A phase I/II study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2678-TPS2678
Author(s):  
Takefumi Komiya ◽  
Jun Zhang ◽  
Prakash C. Neupane ◽  
Kathan Mehta ◽  
Chao Hui Huang
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Tgf Beta ◽  
Small Cell Lung

TPS2678 Background: Checkpoint inhibitors (CPI) targeting the PD1/PD-L1 axis significantly improved patient outcomes in stage IV non-small cell lung cancer (NSCLC). However, these patients will eventually develop resistance and progression. There is a need to identify novel treatment options. Poor response to PD-L1 antibody was correlated with increase in cancer-associated fibroblasts (CAF), which is known to interact with cytotoxic T cells (CTLs) by suppressing their function in a manner similar to regulatory T cells (Tregs). Production of cytokines by CAFs leads to impaired antitumor immunity by impairing CTL function (TGF beta) and prevent recruitment/mobilization of CTLs into tumors. These effects suggesting that CAF can be a therapeutic target in lung cancer resistant to checkpoint inhibitors. Pirfenidone (P) is approved to treat pulmonary fibrosis with anti-fibrotic effect by blocking the differentiation of fibroblasts into CAFs and suppress the production of TGF beta and TGF beta-induced signaling pathways/collagens. Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD-L1 and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (CD80), both of which function as inhibitory receptors expressed on T cells. We proposed a phase I/II trial to test the combination of atezolizumab (A) with P in patients with recurrent non-small cell lung cancer (NSCLC) after progression with CPI. The primary objective of phase I is to determine the maximum tolerated (MTD) dose of P in combination with A and assess the safety and tolerability of this combination. The secondary objective is to determine the efficacy of AP in all NSCLC participants treated in this study. Exploratory objectives include the measurement of circulating levels of TGF beta and research in expression of CAF related proteins. Methods: The initial phase I will enroll 3 patients using P at 801 mg po TID. A will be at 1200mg iv every 3 weeks. If there is ≤ 1 DLT, the study will proceed to phase II If there are 2- 3 DLT, P will be reduced to 534 mg TID. If there is ≤ 1 DLT, then this dose will proceed to phase II. If there is 2-3 DLT, then the study will be terminated. The phase II will enroll 16 patients to assess efficacy. Main inclusion criteria are patients with recurrent NSCLC after progression with first-line therapy CPI with or without chemotherapy, measurable disease, ECOG 0-2, and adequate organ function. Clinical trial information: NCT04467723.

Phase I-II Study of Gemcitabine and Carboplatin in Stage IIIB-IV Non–Small-Cell Lung Cancer

1999 ◽  
Vol 17 (3) ◽  
pp. 921-921 ◽  
Author(s):  
Rosario Vincenzo Iaffaioli ◽  
Anna Tortoriello ◽  
Gaetano Facchini ◽  
Francesco Caponigro ◽  
Maria Gentile ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Stage Iiib ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy ◽  
Duration Of Response

PURPOSE: Platinum-based chemotherapy currently represents standard treatment for advanced non–small-cell lung cancer. Gemcitabine is one of the most interesting agents currently in use in advanced non–small-cell lung cancer, and high response rates have been reported when it is administered in combination with cisplatin. The aim of the present study was to evaluate the combination of gemcitabine and carboplatin in a phase I-II study. PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB-IV non–small-cell lung cancer received carboplatin at area under the concentration-time curve (AUC) 5 mg/mL/min and gemcitabine at an initial dose of 800 mg/m2, subsequently escalated by 100 mg/m2 per step. Gemcitabine was administered on days 1 and 8 and carboplatin on day 8 of the 28-day cycle. Dose escalation proceeded up to dose-limiting toxicity (DLT), which was defined as grade 4 neutropenia or thrombocytopenia or grade 3 nonhematologic toxicity. RESULTS: Neutropenia was DLT, inasmuch as it occurred in three of five patients receiving gemcitabine 1,200 mg/m2. Nonhematologic toxicities were mild. Gemcitabine 1,100 mg/m2 plus carboplatin AUC 5 was recommended for phase II studies. An objective response was observed in 13 (50%) of 26 patients, including four complete responses (15%) and nine partial responses (35%). Median duration of response was 13 months (range, 3 to 23 months). Median overall survival was 16 months (range, 3 to 26 months). CONCLUSION: The combination of gemcitabine and carboplatin is well tolerated and active. Neutropenia was DLT. The observed activity matches that observable in cisplatin-gemcitabine studies, whereas duration of response and survival are even higher. A phase II trial is under way.

A phase I trial of S-1 plus vinorelbine in patients with unresectable advanced or metastatic non-small cell lung cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19098-e19098
Author(s):  
H. Suyama ◽  
Y. Shigeoka ◽  
T. Igishi ◽  
S. Matsumoto ◽  
M. Kodani ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Dose Level ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Phase I Trial ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung

e19098 Background: We reported the efficacy of the combination treatment of tegafur-uracil (UFT) and vinorelbine (VNR) for the elderly patients (pts) (>70) with advanced non-small cell lung cancer (NSCLC) in ASCO 2007 (Abstract - No. 18075). Although the cisplatin-based doublets are still milestone for the pts with advanced NSCLC, non-platinum based doublet regimens remain as a matter of development judging from recent meta-analysis. Tegafur-5-chloro-2,4-dihydroxypyridine-potassium oxonate (S-1), a new oral fluoropyrimidine, has been studied extensively, and appears promising for various kinds of cancers including NSCLC. Thus, we conducted this phase I trial using VNR and new oral fluoropyrimidine, S-1. Methods: Pts with advanced NSCLC, who had received at least one prior platinum-containing regimen, were eligible. In this phase I study, VNR was infused on days 1 and 8, and S-1 was administered from day 2 to day 6 and from day 9 to day 13 of a 3-week cycle. The starting dose of S-1 was 80 mg/m2/day and, if necessary, the dose was decreased to 65 mg/m2/day; VNR was increased from 20 to 25 mg/m2 in this trial. Results: From August 14, 2007 to April 1, 2008, 8 pts enrolled in this study. Median age was 61 (range 49–75). Dose limiting toxicity (DLT) was evaluated during the first 6 weeks of the treatment. No DLT was observed at dose level I (80 mg/m2/day S-1, 20 mg/m2 VNR). At dose level II (80 mg/m2/day S-1, 25 mg/m2 VNR), DLT in the form of neutropenia, hyperglycemia and hyponatremia was observed in 3 of 5 pts. The maximum tolerated dose (MTD) for the present treatment was 80 mg/m2/day S-1 and 25 mg/m2 VNR; the recommended tolerable dose for future phase II trials is therefore 80 mg/m2/day S-1 and 20 mg/m2 VNR. Conclusions: Three-week cycle of VNR (20 mg/m2), infused on days 1 and 8; S-1 (80 mg/m2/day), administered from day 2 to day 6 and from day 9 to day 13, is being examined in our phase II trial for first-or second-line treatment of NSCLC. No significant financial relationships to disclose.

scholarly journals Primary Analysis of the Phase II Component of a Phase I/II Dose Intensification Study Using Three-Dimensional Conformal Radiation Therapy and Concurrent Chemotherapy for Patients With Inoperable Non–Small-Cell Lung Cancer: RTOG 0117

2010 ◽  
Vol 28 (14) ◽  
pp. 2475-2480 ◽  
Author(s):  
Jeffrey D. Bradley ◽  
Kyounghwa Bae ◽  
Mary V. Graham ◽  
Roger Byhardt ◽  
Ramaswamy Govindan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Radiation Therapy ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Median Survival ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Lung Toxicity ◽  
Small Cell Lung

PurposePhase I of Radiation Therapy Oncology Group (RTOG) 0117 determined that 74 Gy was the maximum-tolerated dose with concurrent weekly carboplatin/paclitaxel chemotherapy for inoperable non–small-cell lung cancer (NSCLC). Phase II results are reported here.Patients and MethodsPatients with unresectable stages I-III NSCLC were eligible. Chemotherapy consisted of weekly paclitaxel at 50 mg/m2and carboplatin at area under the curve 2 mg/m2. The radiation dose was 74 Gy given in 37 fractions. Radiation therapy volumes included those of the gross tumor and involved nodes. The volume of lung at or exceeding 20 Gy (V20) was mandated to be ≤ 30%.ResultsOf the combined phase I/II enrollment, a total of 55 patients received 74 Gy, of whom 53 were evaluable. The median follow-up was 19.3 months (range, 0.9 to 57.9 months) for all patients and 25.4 months (range, 13.1 to 57.9 months) for those still alive. The median survival for all patients was 25.9 months. The percentage surviving at least 12 months was 75.5% (95% CI, 65.7% to 85.2%). The median overall survival (OS) and progression-free survival (PFS) times for stage III patients (n = 44) were 21.6 months and 10.8 months, respectively. OS and PFS rates at 12 months were 72.7% and 50.0%, respectively. Twelve patients experienced grade ≥ 3 lung toxicity (two patients had grade 5 lung toxicity).ConclusionThe median survival time and OS rate at 12 months for this regimen are encouraging. These results serve as projection expectations for the high-dose radiation arms of the current RTOG 0617 phase III intergroup trial.

scholarly journals A Phase I/II Study of GTI-2040 Plus Docetaxel as Second-Line Treatment in Advanced Non-small Cell Lung Cancer: A Study of the PMH Phase II Consortium

2009 ◽  
Vol 4 (9) ◽  
pp. 1163-1169 ◽  
Author(s):  
Natasha B. Leighl ◽  
Scott A. Laurie ◽  
Xueyu E. Chen ◽  
Peter Ellis ◽  
Frances A. Shepherd ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Line Treatment ◽  
Second Line ◽  
Small Cell Lung

scholarly journals Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial

2020 ◽  
Vol 8 (2) ◽  
pp. e001001
Author(s):  
James Welsh ◽  
Hari Menon ◽  
Dawei Chen ◽  
Vivek Verma ◽  
Chad Tang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Progression Free Survival ◽  
Small Cell ◽  
Liver Lesions ◽  
Small Cell Lung ◽  
End Point

BackgroundIn this phase I/II trial, we evaluated the safety and effectiveness of pembrolizumab, with or without concurrent radiotherapy (RT), for lung and liver lesions from metastatic non-small cell lung cancer (mNSCLC).MethodsPatients with lung or liver lesions amenable to RT plus at least one additional non-contiguous lesion were included regardless of programmed death-ligand 1 (PD-L1) status. Pembrolizumab was given at 200 mg every 3 weeks for up to 32 cycles with or without concurrent RT. Metastatic lesions were treated with stereotactic body RT (SBRT; 50 Gy in 4 fractions) if clinically feasible or with traditionally fractionated RT (45 Gy in 15 fractions) if not. The primary end point was the best out-of-field lesion response, and a key secondary end point was progression-free survival (PFS).ResultsThe median follow-up time was 20.4 months. One hundred patients (20 phase I, 80 phase II) were evaluable for toxicity, and 72 phase II patients were evaluable for treatment response. No patients in the phase I group experienced grade 4–5 events; in the phase II group, two had grade 4 events and nine had grade 3 events. The ORR in the combined-modality cohort (irrespective of RT schema) was 22%, vs 25% in the pembrolizumab group (irrespective of receipt of salvage RT) (p=0.99). In the concurrent pembrolizumab+RT groups, the out-of-field ORRs were 38% in the pembrolizumab+SBRT group and 10% in the pembrolizumab+traditional RT group. When examining the pembrolizumab-alone patients, the out-of-field ORRs were 33% in those designated to receive salvage SBRT (if required) and 17% for salvage traditional RT. In all patients, the median PFS for pembrolizumab alone was 5.1 months (95% CI 3.4 to 12.7 months), and pembrolizumab/RT (regardless of schema) was 9.1 months (95% CI 3.6 to 18.4 months) (p=0.52). An exploratory analysis revealed that for patients with low PD-L1 expression, the median PFS was 4.6 vs 20.8 months for pembrolizumab with and without RT, respectively (p=0.004).ConclusionsConcurrent immunoradiotherapy for mNSCLC is safe, although larger trials are required to address which patients benefit most from RT.Trial registration numberNCT02444741.

scholarly journals Phase I/II Study of Docetaxel and S-1 in Previously-Treated Patients with Advanced Non-Small Cell Lung Cancer: LOGIK0408

2019 ◽  
Vol 8 (12) ◽  
pp. 2196
Author(s):  
Koichi Takayama ◽  
Junji Uchino ◽  
Masaki Fujita ◽  
Shoji Tokunaga ◽  
Tomotoshi Imanaga ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Response Rate ◽  
Small Cell ◽  
Small Cell Lung ◽  
Previously Treated Patients ◽  
Previously Treated

Background: As docetaxel plus S-1 may be feasible for cancer treatment, we conducted a phase I/II trial to determine the recommended docetaxel dose and the fixed S-1 dose (phase I), as well as confirm the regimen’s efficacy and safety (phase II) for previously-treated patients with advanced non-small cell lung cancer. Methods: Patients ≤75 years with performance status ≤1 and adequate organ function were treated at three-week intervals with docetaxel on day 1 and 80 mg/m2 oral S-1 from days 1–14. The starting docetaxel dose was 45 mg/m2 and this was escalated to a maximum of 70 mg/m2. In phase II, response rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. Results: The recommended doses were 50 mg/m2 docetaxel (day 1) and 80 mg/m2 S-1 (days 1–14). Grades 3 and 4 leukocytopenia and neutropenia occurred in 44% and 67% of patients, respectively. Nonhematologic toxicities were generally mild. Overall response to chemotherapy was 7.7% (95% confidence interval (CI), 1.6–20.9%), and median PFS and OS were 18.0 weeks (95% CI; 11.3–22.9 weeks) and 53.0 weeks, respectively. Conclusion: Fifty mg/m2 docetaxel plus 80 mg/m2 oral S-1 had a lower response rate than anticipated; however, the survival data were encouraging. A further investigation is warranted to select the optimal patient population.

A phase II study of vorolanib in combination with toripalimab in patients with non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21053-e21053
Author(s):  
Jun Zhao ◽  
Jianjie Li ◽  
Hanxiao Chen ◽  
Xue Yang ◽  
Jia Zhong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Phase Ii Study ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

e21053 Background: VEGF promotes an immunosuppressive microenvironment and contributes to resistance of immune checkpoint inhibitors in cancer treatment. VEGF inhibitors have been shown to enhance efficacy of checkpoint inhibitors in clinical studies. Vorolanib (CM082) is a multi-target tyrosine kinase inhibitor including VEGF, PDGF, c-kit, and Flt-3. Toripalimab (JS001) is a humanized IgG4 mAb against programmed death-1 (PD-1). This phase II study aims to evaluate efficacy and safety of the combination of vorolanib and JS001 in non-small cell lung cancer (NSCLC) patients who progressed with prior first-line standard therapy. Methods: This single-arm, single-center, phase II study (NCT03848611) enrolls NSCLC patients with measurable disease (RECIST 1.1) and Eastern Cooperative Oncology Group performance status ≤ 1, regardless of PD-L1 status. 15 patients received 150 mg oral CM082 daily plus 240 mg intravenous JS001 every 3 weeks while 3 patients received 100 mg oral CM082 daily plus 240 mg intravenous JS001 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR). Results: Between April 2019 and July 2020, 18 patients were enrolled. Median age was 64 years. 9 of 18 patients (50%) were adenocarcinoma and 9 of 18 patients (50%) were squamous. Males account for 83% (15/18) with 4 non-smokers among the male patients. At the data cutoff (January 11, 2021), we observed 2 (11%) confirmed and 1 (6%) unconfirmed partial response (PR), 6 (33%) stable disease (SD) and 9 (50%, including 2 PR of the target lesions) progression disease (PD). Tumor shrinkage was seen in 6 (33%) of the 18 patients. Two (11%) patients were still on the study drugs. Interestingly, all the patients with confirmed PR or PR of the target lesions were squamous histology. The most common treatment-related adverse events were proteinuria (67%), elevated ALT (60%), elevated AST (53%), hypertension (40%), and increased bilirubin (40%). Grade 3 adverse events include elevated ALT (20%), elevated AST (20%), liver function damage (13%), elevated GGT (7%), fatigue (7%), bellyache (7%), ruptured and infected tumor (7%), and dysphagia (7%). One Grade 4 adverse event was pulmonary embolism. Conclusions: Vorolanib with toripalimab showed a promising antitumor activity with acceptable safety profiles for patients with NSCLC. We hypothesized that the potential benefits of combination therapy for patients with squamous cell carcinoma may be better than those for patients with adenocarcinoma, and the study is ongoing. Clinical trial information: NCT03848611.

Cisplatin Plus Gemcitabine or Vinorelbine for Elderly Patients With Advanced Non–Small-Cell Lung Cancer: The MILES-2P Studies

2007 ◽  
Vol 25 (29) ◽  
pp. 4663-4669 ◽  
Author(s):  
Cesare Gridelli ◽  
Paolo Maione ◽  
Alfonso Illiano ◽  
Franco Vito Piantedosi ◽  
Adolfo Favaretto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Elderly Patients ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung ◽  
Unacceptable Toxicity

PurposeTwo phase I/II trials were done to evaluate the feasibility of cisplatin combined with gemcitabine or vinorelbine in elderly patients with advanced non–small-cell lung cancer (NSCLC).Patients and MethodsPatients with advanced NSCLC who were older than 70 years of age and who had a performance status of 0 to 1 were eligible. Cisplatin was given on day 1 (a starting dose of 50 mg/m2with increasing increments of 10 mg/m2at each level) and gemcitabine (1,000 mg/m2) or vinorelbine (25 mg/m2) on days 1 and 8. Cycles were repeated every 21 days. A two-stage flexible optimal design was applied in the phase II study, and unacceptable toxicity was the primary end point.ResultsOverall, 159 patients were enrolled: 38 in phase I and 121 in phase II studies. Cisplatin was feasible at 60 mg/m2with gemcitabine and at 40 mg/m2with vinorelbine. With the former combination, 50 of 60 (83.3%) patients were treated without unacceptable toxicity; objective responses were reported in 26 of 60 patients (43.5%; 95% CI, 30.6 to 56.8); median progression-free and overall survivals were 25.3 and 43.6 weeks, respectively. With the latter combination, 50 (82.0%) of 61 patients were treated without unacceptable toxicity; objective responses were reported in 22 of 61 patients (36.1%; 95% CI, 24.2 to 49.4); median progression-free and overall survivals were 21.1 and 33.1 weeks, respectively.ConclusionBoth cisplatin (60 mg/m2) plus gemcitabine and cisplatin (40 mg/m2) plus vinorelbine are feasible and active in the treatment of elderly patients with advanced NSCLC. The former combination, which provides a higher dose of cisplatin, deserves comparison versus single-agent chemotherapy in this setting of patients.

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