Osimertinib in Elderly Patients with Epidermal Growth Factor Receptor T790M-Positive Non-Small-Cell Lung Cancer Who Progressed During Prior Treatment: A Phase II Trial [CLINICAL TRIAL RESULTS]

3 weeks 2 days ago
Lessons Learned. O_LINon-small-cell lung cancer (NSCLC) represents 85% of lung cancer in elderly patients. C_LIO_LIIn the present study performed in the 36 elderly subjects with epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, osimertinib 80 mg demonstrated statistically significant improvement in the objective response rate, which was comparable to those in the nonelderly population. C_LIO_LIOsimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation; further research in larger scale is warranted. C_LI Background.Previous findings suggest the possibility of relatively safe use of osimertinib for patients with T790M-positive non-small-cell lung cancer (NSCLC), with few serious adverse events for the elderly in comparison with conventional endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and with an antitumor effect. Methods.This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients aged [≥]75 years with ineffective prior EGFR TKI treatment or with recurrence in T790M EGFR TKI resistance mutation-positive NSCLC. Results.A total of 36 patients were included in the analyses. Among the 36 subjects, 63.9% were female, with mean age of 79.9 years. The objective response rate (ORR) was 58.3% (95% confidence interval [CI], 42.2%-72.9%), demonstrating statistically significant efficacy of osimertinib (p = .0017). The median duration of response (DOR) was 27.9 weeks (95% CI, 21.1-82.0). Complete response (CR) and partial response (PR) were 2.8% and 55.6%, respectively. Disease control rate (DCR) was 97.2%. A waterfall plot revealed that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had stable disease (SD). All adverse events were not reason for discontinuation of the study drug. Conclusion.Osimertinib may be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation.
Nakao, A.

S-1 plus Raltitrexed for Refractory Metastatic Colorectal Cancer: A Phase II Trial [CLINICAL TRIAL RESULTS]

3 weeks 2 days ago
Lessons Learned.O_LIThe upregulation of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important mechanisms of resistance to 5-fluorouracil (5-FU) in metastatic colorectal cancer (mCRC) after long exposure to 5-FU. C_LIO_LIS-1 (containing a DPD inhibitor) combined with raltitrexed (a TS inhibitor) showed a moderate effect, which needs further study as a third- or later-line therapy in mCRC. C_LI Background.5-fluorouracil (5-FU) is a fundamental drug in the treatment of metastatic colorectal cancer (mCRC). Patients with mCRC are often exposed to 5-FU and/or its analogues for a long time because of its central role in treatment regimens. The upregulation of dihydropyrimidine dehydrogenase (DPD) and/or thymidylate synthase (TS) are important mechanisms of resistance of 5-FU. To evaluate the efficacy and safety of S-1 (containing a DPD inhibitor) and raltitrexed (a TS inhibitor) for refractory mCRC, a one-center, single-arm, prospective phase II trial was conducted. Methods.Patients who had mCRC that had progressed after treatment with fluoropyrimidine, irinotecan, and oxaliplatin and who had at least one measurable lesion were eligible for this trial. Patients received oral S-1 (80-120 mg for 14 days every 3 weeks) plus an intravenous infusion of raltitrexed (3 mg/m2 on day 1 every 3 weeks). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Results.In total, 46 patients were enrolled. Three patients did not complete the first assessment because of adverse events and unwillingness, leaving tumor response evaluation available in 43 patients. Of 43 evaluable patients, the ORR was 13.9% and disease control rate was 58.1%. In the intention-to-treat population (n = 46), the ORR was 13.0% and disease control rate was 54.3%. Median PFS and median OS were 107 days (95% confidence interval [CI], 96.3-117.7) and 373 days (95% CI, 226.2-519.8), respectively. Most of the adverse effects were mild to moderate. Conclusion.S-1 combined with raltitrexed for refractory mCRC showed moderate effect, and it is worthy of further study as third- or later-line therapy in mCRC.
Chen, Y.

A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma: North Central Cancer Treatment Group Trial N064B (Alliance) [CLINICAL TRIAL RESULTS]

3 weeks 2 days ago
Lessons Learned. O_LIDual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy. C_LIO_LIA significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy. C_LIO_LIThe dual EGFR-directed therapy resulted in increased toxicity. C_LI Background.Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. Methods.Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than .20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. Results.A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530-1.260; p = .1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555-1.280; p = .4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p = .9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p = .0018). Conclusion.Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.
Halfdanarson, T. R.

Endostatin and Oxaliplatin-Based Chemoradiotherapy for Inoperable Esophageal Squamous Cell Carcinoma: Results of a Phase II Study [CLINICAL TRIAL RESULTS]

1 month 3 weeks ago
Lessons Learned. O_LIDefinitive concurrent chemoradiotherapy based on oxaliplatin and endostatin was effective with the objective response rate exceeding 80%, and the treatment-related toxicities were acceptable. C_LIO_LIThe treatment compliance of the current combination was much higher, without significant reduction in survival outcomes, than historical reports. C_LI Background.This phase II trial aimed at assessing the efficiency and safety of definitive concurrent chemoradiotherapy (dCRT) using oxaliplatin (OHP) and endostatin in patients with inoperable esophageal squamous cell carcinoma (ESCC). Methods.Radiotherapy was delivered with a daily fraction of 2.0 Gy to a total dose of 60.0 Gy over 6 weeks. Endostatin and OHP were both intravenously administered at doses of 7.5 mg/m2 daily for 2 weeks and 135 mg/m2 on day 1, respectively, every 3 weeks. The primary endpoint was the objective response rate (ORR). Results.The analysis included 37 patients. The median age was 63 years (range: 49-71 years), and all patients were stage III-IVA. Of these patients, 97.3% (36/37) completed the dCRT course with an ORR of 83.8%, including 10 (27.0%) patients with complete response and 21 (56.8%) patients with partial response. The median overall survival (OS) time was 18.5 months (95% confidence interval [CI]: 10.6-26.4) with a 2-year OS rate of 39.6% (95% CI: 0.202-0.590). The median progression-free survival (PFS) time was 11.5 months (95% CI: 7.6-15.4) with a 2-year PFS rate of 20.2% (95% CI: 0.049-0.355). Grade 3 toxicities included esophagitis (five patients) and leukocytopenia (three patients). Grade 4 leukopenia was observed in one patient. Late toxicity was infrequent, and no treatment-related death occurred. Posttreatment dysphagia scores were significantly improved when compared with baseline (p < .001). Conclusion.dCRT based on OHP and endostatin resulted in high treatment compliance with manageable toxicities. This combination resulted in encouraging ORR without compromising survival outcomes. It should be validated in future clinical studies.
Li, W.

A Phase II Study of S-1 and Paclitaxel Combination Therapy as a First-Line Treatment in Elderly Patients with Advanced Non-Small Cell Lung Cancer [CLINICAL TRIAL RESULTS]

1 month 3 weeks ago
Lessons Learned. O_LICoadministration of S-1 and paclitaxel in elderly patients with advanced non-small cell lung cancer showed favorable efficacy. C_LIO_LICoadministration of S-1 and paclitaxel in elderly patients with advanced non-small lung cancer showed tolerable toxicity. C_LI Background.Although monotherapy with cytotoxic agents including docetaxel or vinorelbine are recommended for elderly patients with advanced non-small cell lung cancer (NSCLC), the outcome is not satisfactory. We evaluated the efficacy and safety of S-1 and paclitaxel (PTX) as a first-line cotreatment in elderly patients with advanced NSCLC. Methods.Oral S-1 was administered on days 1-14 every 3 weeks at 80, 100, and 120 mg per day for patients with body surface area < 1.25 m2, 1.25-1.5 m2, and > 1.5 m2, respectively. PTX was administered at 80 mg/m2 on days 1 and 8. The primary endpoint was response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results.Seventeen patients were enrolled with response and disease control rates of 47.1% and 88.2%, respectively. Median PFS and OS were 5.6 and 35.0 months, respectively. Hematological grade 3 or 4 toxicities included leukopenia (55.8%), neutropenia (52.9%), febrile neutropenia (11.8%), and anemia (11.8%). Nonhematological grade 3 toxicities included stomatitis (23.5%), diarrhea (5.9%), and interstitial lung disease (5.9%), and grade 5 toxicities included interstitial lung disease (5.9%). Conclusion.This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC.
Yoshimura, A.

An Open-Label Phase II Trial of Bevacizumab plus Docetaxel and Gemcitabine in Advanced, Previously Untreated Nonsquamous Non-Small Cell Lung Cancer [CLINICAL TRIAL RESULTS]

1 month 3 weeks ago
Lessons Learned. O_LIThe combination of bevacizumab with docetaxel-gemcitabine resulted in unacceptable toxicity, particularly a high rate of pulmonary toxicity (30%). C_LIO_LIDespite promising efficacy, excessive toxicity of this regimen does not support its use in patients with advanced nonsquamous non-small cell lung cancer. C_LI Background.Prior to immunotherapy, standard treatment for advanced non-small cell lung cancer (NSCLC) was platinum doublet chemotherapy. In a previous phase II study, docetaxel-gemcitabine demonstrated comparable efficacy and tolerability to platinum doublets. In this phase II trial, we evaluated the efficacy and tolerability of adding bevacizumab to docetaxel- gemcitabine in patients with advanced nonsquamous NSCLC. Methods.Patients with untreated advanced nonsquamous NSCLC were treated with up to six cycles of docetaxel-gemcitabine-bevacizumab, followed by bevacizumab until progression. The primary endpoint for this study was 1-year progression-free survival (PFS); secondary endpoints were safety, overall response rate (ORR) and overall survival (OS). The planned sample size was 46 patients. Results.A total of 13 patients were enrolled and received a median of six cycles of chemotherapy and four cycles of bevacizumab. The treatment was poorly tolerated, with five patients requiring dose reduction and four discontinuing treatment for toxicity. Grade 3-5 nonhematologic toxicity was seen in 10 patients, and 4 (30%) were hospitalized with pulmonary toxicity possibly related to study drugs. At this point, enrollment was halted for safety concerns. The 12-month PFS was 8%. In 11 evaluable patients, ORR was 72%, median PFS 6 months, and median OS was 11 months. Conclusion.Docetaxel, gemcitabine, and bevacizumab at this dose and schedule resulted in excessive toxicity. Despite promising efficacy, in light of efficacious and safe alternative therapies, this regimen should not be used to treat advanced NSCLC.
Patil, P. D.

Phase I, First-in-Human, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Vorolanib in Patients with Advanced Solid Tumors [CLINICAL TRIAL RESULTS]

1 month 3 weeks ago
Lessons Learned. O_LIPharmacokinetic results underscore that the vorolanib (X-82) study design was successful without the need for further dose escalation beyond 400 mg once daily (q.d.). C_LIO_LITherefore, the recommended dose of X-82 as a single agent in patients with advanced cancer is 400 mg q.d. C_LI Background.Vorolanib (X-82) is a novel, oral, multikinase vascular endothelial growth factor (VEGF) receptor/platelet-derived growth factor (PDGF) receptor inhibitor that was developed on the same chemical scaffold as sunitinib, but designed to improve upon the safety profile while maintaining the efficacy of sunitinib. By targeting the VEGF and PDGF receptors, X-82 was expected to disrupt tumor angiogenesis and be active in a broad spectrum of solid tumors. Therefore, we determined the maximum tolerated dose (MTD) and characterized the preliminary pharmacokinetics and clinical tumor response of X-82 as a single agent in patients with advanced solid tumors. Methods.Adult patients with advanced solid tumors received X-82 as tablets or capsules (once daily [q.d.] or b.i.d.) every 4 weeks. Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. Results.Fifty-two patients received study treatment in 17 cohorts. X-82 capsule dosing was as follows: cohorts 1-6 (20-400 mg q.d.) and cohorts 7-8 (140-200 mg b.i.d.). Patients in cohorts 9-17 received 50-800 mg q.d. tablet dosing. The median time on treatment was 58 days. X-82 blood pharmacokinetics appeared dose-independent with a t1/2 of 5.13 hours and 6.48 hours for capsule and tablet formulations, respectively. No apparent accumulation was observed after 21 days of daily dosing. Conclusion.X-82 had a safety profile consistent with its mechanism of action. It has a short half-life and was well tolerated by most patients. Study enrollment ended prior to the determination of the MTD because of the apparent saturation of absorption at 400-800 mg. The recommended dose of X-82 as a single agent in patients with advanced cancer is 400 mg q.d.
Bendell, J. C.

First-in-Human Phase I Study of MBC-11, a Novel Bone-Targeted Cytarabine-Etidronate Conjugate in Patients with Cancer-Induced Bone Disease [CLINICAL TRIAL RESULTS]

2 months 3 weeks ago
Lessons Learned. O_LIResults are consistent with MBC-11 targeting and treating cancer-induced bone lesions by concentrating cytarabine and etidronate at the site of disease. C_LIO_LIMBC-11 was well tolerated, with an maximum tolerated dose of 5 mg/kg per day and myelosuppression as the principal toxicity. C_LIO_LITreatment significantly reduced cancer cell activity in over half of bone lesions detected at baseline. C_LIO_LIMBC-11 pharmacokinetic and pharmacodynamic parameters are consistent with the novel drug design goals, and encouraging results warrant further clinical development. C_LI Background.MBC-11 is a first-in-class conjugate of the bone-targeting bisphosphonate etidronate covalently linked to the antimetabolite cytarabine (araC). This first-in-human phase I dose escalation study assessed safety, tolerability, maximum tolerated dose (MTD), plasma pharmacokinetics, bone turnover, tumor biomarkers, and bone lesion activity by fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging. Methods.Fifteen patients with advanced solid cancers and cancer-induced bone disease (CIBD) were treated with 0.5-10 mg/kg per day of MBC-11 administered daily for 5 days of every 4 weeks for up to four cycles. Results.Grade 1-2 myelosuppression, involving all lineages, was the principal toxicity. Two of three patients treated with 10 mg/kg experienced dose-limiting grade 4 neutropenia and thrombocytopenia (adverse event [AE] duration [≤]5 days); the MTD was 5 mg/kg. Four of five patients with pretreatment elevations of the bone resorption marker TRAP5b (tartrate resistant acid phosphatase-5b) had persistent decrements. Six of 13 patients who reported baseline pain noted a reduction after MBC-11. 18F-FDG-PET/CT imaging demonstrated partial metabolic responses in three patients and stable metabolic responses in three other patients. SUVmax (standard unit of emission normalized to total uptake) was reduced by at least 25% in 110 (52%) of 211 bone lesions. Significant activity was noted across all doses, and myelosuppression increased with dose. Conclusion.At MBC-11 doses that were well tolerated, substantial reductions in metabolic activity of bone-associated cancer cells provide a foundation for further disease-directed efficacy studies.
Zinnen, S. P.

Association of Modified-FOLFIRINOX-Regimen-Based Neoadjuvant Therapy with Outcomes of Locally Advanced Pancreatic Cancer in Chinese Population [CLINICAL TRIAL RESULTS]

2 months 3 weeks ago
Lessons Learned. O_LIModification of FOLFIRINOX significantly improves safety and tolerability in Chinese patients with locally advanced pancreatic cancer. C_LIO_LIPatients with locally advanced pancreatic cancer benefit from neoadjuvant therapy and experience a much better survival than patients with upfront surgery. C_LI Background.The objective of this study was to evaluate the efficacy of modified-FOLFIRINOX (mFOLFIRINOX) regimens in Chinese patients with locally advanced pancreatic cancer (LAPC) and to compare outcomes between patients with LAPC treated with mFOLFIRINOX-based neoadjuvant therapy (LAPC-N) and patients with LAPC who underwent upfront surgery (LAPC-S). Methods.Forty-one patients with LAPC-N were enrolled prospectively. Imaging features, chemotherapy response, adverse events, perioperative complications, histology, and survival were analyzed. Seventy-four patients with resectable pancreatic cancer (RPC) (from April 2012 to November 2017) and 19 patients with LAPC-S (from April 2012 to March 2014) were set as observational cohorts, and data were collected retrospectively. LAPC-N patients with adequate response underwent surgical treatment, whereas continuous chemotherapy was given to LAPC-N patients who were not deemed resectable after treatment, and the response was re-evaluated every 2 months. Results.Forty-one patients with LAPC received mFOLFIRINOX with a response rate of 37.1%. The most common severe adverse events were neutropenia and anemia. mFOLFIRINOX-based neoadjuvant therapy contributed to a remarkable decrease in CA19-9 level and tumor diameter. Fourteen LAPC-N patients underwent surgery (LAPC-N-S) after downstaging. Compared with LAPC-N-S cases, LAPC-S patients had longer operative time, more blood loss, and a higher risk of grade 5 complications. The median overall survival (OS) and progression-free survival (PFS) of LAPC-N-S patients were 27.7 months and 19.3 months, respectively, which were similar to those of patients with RPC (30.0 months and 23.0 months) and much longer than those of patients with LAPC-S (8.9 months and 7.6 months), respectively. Conclusion.Neoadjuvant chemotherapy such as the mFOLFIRINOX regimen can be recommended for Chinese patients with LAPC after dose modification. Patients with LAPC-N who underwent surgery obtained significantly improved survival compared with patients in the observational LAPC-S cohort, who did not undergo neoadjuvant therapy.
Li, X.
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