Gefitinib (ZD-1839) with concurrent docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel/gefitinib for patients with stage III NSCLC: A phase I study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18165-18165
Author(s):  
A. Blackstock ◽  
J. Petty ◽  
T. Oaks ◽  
M. Porosnicu ◽  
H. Clark ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Three Dimensional ◽  
Maximum Tolerated Dose ◽  
Stage Iii ◽  
3 Dimensional ◽  
Thoracic Radiation ◽  
Stage Iii Nsclc ◽  
Experienced Grade ◽  
Grade Iii

18165 Background: The safety of 3-dimensional (3D) conformal thoracic radiation delivered with concurrent gefitinib/docetaxel chemotherapy in patients with inoperable stage III NSCLC has not been evaluated. Methods: Patients with inoperable stage III NSCLC received weekly intravenous (i.v.) docetaxel starting at a dose of 15 mg/m2 escalating to 30 mg/m2 in 5 mg/m2 increments and daily gefitinib (250 mg given orally). Patients recieved concurrent thoracic radiation to a dose of 70 Gy utilizing 3-D techniques. The chemoradiation therapy was followed by 2 cycles of consolidative docetaxel (75 mg/m2) given q 21 days and gefitinib 250 mg p.o. for 1 year or until disease progression. Results: Beginning December 2003, 15 patients have been entered to date to this IRB approved phase I trial to determine the maximum tolerated dose of weekly docetaxel when given concurrent with gefitinib and thoracic radiation. The dose-limiting toxicities (DLT) observed were primarily non-hematologic and occured at dose level 3 (25 mg/m2). One patient experienced grade III esophagitis that resulted in a grade III dehydration, a second patient experienced grade III diarrhea while a third patient suffered a grade V interstitial pneumonitis, believed to be related to the gefinitib. While 14 of 15 patients completed the chemoradiation portion of the study and 2 patients completed all planned therapy, 4 patients progressed during therapy, 3 patients discontinued treatment due to toxicity, and 2 patients refused to continue treatment. The median and 1-year survival thus far is 21 months and 56%, respectively. Conclusions: 70 Gy conformal thoracic radiation and concurrent gefitinib/docetaxel thus far appears feasible but with modest toxicity. The study is currently enrolling patients at the weekly 20 mg/m2 docetaxel dose level concurrent with 250 mg of daily gefitinib. This study was supported in-part by Sanofi-Aventis and Astra Zeneca. No significant financial relationships to disclose.

A phase I/II trial of perioperative paclitaxel (P), carboplatin (C), and erlotinib (E) with concurrent accelerated hyperfractionated radiation (HFRT) followed by maintenance E for stage III non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7557-7557
Author(s):  
N. A. Pennell ◽  
G. M. Videtic ◽  
S. Murthy ◽  
D. Mason ◽  
T. W. Rice ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Pathologic Complete Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Stage Iii ◽  
Stage Iiia ◽  
Open Label ◽  
Thoracic Radiation ◽  
Stage Iii Nsclc

7557 Background: Concurrent chemoradiotherapy (CRT) is standard treatment for stage III NSCLC, although the management of resectable patients (pts) remains controversial. We report an open-label phase I/II trial of the epidermal growth factor receptor inhibitor E added to perioperative CRT for resectable stage III NSCLC pts, followed by maintenance (m) E. Methods: Eligible pts had stage IIIA/B NSCLC, PS 0–1, and were resectable as determined by a thoracic surgeon. Pts received weekly P (50 mg/m2), and C (AUC 2) with daily oral E for 28 days concurrent with twice daily thoracic radiation (1.5 Gy/fraction) to 30 Gy, followed by restaging. Non-progressors underwent resection followed by the same CRT regimen and 2 years of mE (150mg). The primary endpoint of the phase I portion was the maximum tolerated dose (MTD) of E given with CRT; and for the phase II was safety and tolerability. Secondary endpoints were pathologic complete response (pCR) rate, pathologic downstaging of mediastinal nodes, progression free survival (PFS), and overall survival (OS). Results: 9 pts were enrolled in the phase I trial. The MTD of E was150mg, which was the phase II dose used. 25 pts were treated in the phase II component: median age 60, 92% stage IIIA, 64% female, 72% PS 0, 64% adenocarcinoma, and 16% never smokers. The median duration of mE was 5.5 months, with the most common reason for discontinuation being pt preference. There was no grade 4 toxicity. Grade 3 toxicity seen in >5% of pts: rash (12%), diarrhea (9%), nausea (9%), and encephalopathy (6%). The most common toxicities during mE: grade 1/2 diarrhea (72%), rash (61%), fatigue (56%), nausea (22%), and dry eyes (17%).1 pt (4%) had a pCR after neoadjuvant CRT, and 46% were downstaged to pN0–1 at surgery. At a median follow-up of 36.5 mos the median PFS is 41.8 mos (95% CI 9.3-not yet reached). The median OS has not been reached. 3 year survival is 69%. Pts downstaged to pN0–1 vs those with persistent pN2–3 had a median PFS of 41.8 vs 18.1 mos (p=0.11). Conclusions: Perioperative P, C, and E given concurrently with HFRT was well tolerated and showed promising efficacy, while compliance was poor with maintenance E. [Table: see text]

Phase I pilot study of oxaliplatin, infusional 5-FU, and cetuximab in recurrent or metastatic head and neck cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e16027-e16027
Author(s):  
Jay S. Dalal ◽  
Joshua B. Greene ◽  
Craig C. Hofmeister ◽  
Ann Lau Clark ◽  
Joseph Clark
Keyword(s):  
Pilot Study ◽  
Phase I ◽  
Head And Neck ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Platinum Based Chemotherapy ◽  
Acneiform Rash ◽  
Level 1 ◽  
Level 2 ◽  
Experienced Grade

e16027 Background: Platinum-based chemotherapy including cisplatin, 5-fluorouracil (5-FU), and the EGFR-directed monoclonal antibody cetuximab, are active in the treatment of head and neck squamous cell carcinoma (HNSCC). Patients with inoperable recurrent or metastatic HNSCC have a poor prognosis and many have difficulty tolerating cisplatin-based regimens. Oxalipatin, a third-generation platinum derivative, has demonstrated antitumor activity and lacks many of the limiting side effects of cisplatin. We conducted a phase I pilot study to investigate the dose-limitation of oxaliplatin in addition to infusional 5-FU and cetuximab in patients with untreated recurrent or metastatic HNSCC. Methods: The planned dose escalation schedule included: dose level 1: oxaliplatin 100mg/m2 day 1, 5-FU CIV 750mg/m2 over 96 hours beginning day 1, and cetuximab 400mg/m2 cycle 1, day 1 (and 250mg/m2 weekly thereafter) on a 21-day cycle. Dose level 2: oxaliplatin 130mg/m2 day 1, 5-FU CIV 1000mg/m2 over 96 hours beginning day 1 and the same dose and schedule of cetuximab. Results: A total of 10 patients were accrued, consisting of 4 females and 6 males. The first seven were enrolled onto dose level 1 and the following three onto dose level 2. Dose level 1 was tolerated well with acceptable toxicity, including grade 1-2 oral mucositis, grade 1-2 fatigue, grade 1-2 acneiform rash, grade 1 nausea, grade 1-2 anemia and grade 1 transaminitis. All responses observed, (1 MR, 1 PR, 1 CR), were short-lived. Dose level 2 was more toxic than anticipated; 2 of 3 patients experienced grade 4 toxicities (mucositis, diarrhea, acute renal failure) requiring hospitalization with a treatment-related death in one of these patients. The phase I portion of the trial was therefore closed and dose level 1 is considered the maximum tolerated dose. Conclusions: The regimen of oxaliplatin 100mg/m2 day 1, infusional 5-FU 750mg/m2 over 96 hours beginning day 1, and cetuximab 400mg/m2 cycle 1, day 1 (with 250mg/m2 weekly thereafter), given on a 21-day cycle, has manageable toxicity; these doses are recommended for phase II evaluation in the treatment of unresectable or metastatic HNSCC.

A phase I trial of E7974 administered on days 1 and 15 of a 28-day cycle in patients with solid malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2550-2550 ◽  
Author(s):  
S. Madajewicz ◽  
N. J. Zojwalla ◽  
A. G. Lucarelli ◽  
P. Hentschel ◽  
J. Giardelli ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Efflux Pump ◽  
Human Tumor ◽  
Maximum Tolerated Dose ◽  
Common Mechanism ◽  
Post Dose ◽  
Grade 3 ◽  
Experienced Grade

2550 Background: E7974 is a synthetic hemiasterlin analogue exhibiting binding to a and β tubulin. It induces disruption of spindle formation and mitotic arrest characteristic of anti-tubulin cancer drugs. Unlike taxanes and vincas, E7974 is a poor substrate for the PgP drug efflux pump, potentially overcoming this common mechanism of drug resistance. E7974 demonstrates broad anti-tumor activity against a variety of human tumor xenografts. Methods: An accelerated phase I dose escalation design was used to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of E7974 administered IV over 2–5 minutes on Days 1 and 15 of a 28-day cycle. Results: Seventeen patients (14 male, 3 female) with a median age of 59 yrs. (range: 42–77 yrs.) were treated at doses of 0.18 mg/m2, 0.25 mg/m2, 0.31 mg/m2, and 0.39 mg/m2. Patients with colorectal (6), esophageal (3), prostate (2), urothelial (2), NSCLC (2), and other (2) cancers were enrolled. At the 0.39 mg/m2 dose level, one patient experienced grade 3 neutropenia and 2 patients experienced grade 4 neutropenia. The 0.31 mg/m2 dose was declared the MTD. Additional drug related toxicities (grade 1–2) included fatigue (8 pts.), constipation (4 pts), neuropathy (3 pts.), diarrhea (2 pts.), flushing (2 pts.) and myalgia (1 pt.). One patient with esophageal cancer had a partial response at the 0.39 mg/m2 dose level and one patient with prostate cancer had >50% decline in PSA and significant clinical benefit for >4 months at the 0.31 mg/m2 dose level. Stable disease was seen in two patients, one with esophageal cancer (8 cycles) and one with colorectal cancer (4 cycles). The PK profile of E7974 was characterized by moderate to large distribution (Vss = 55 - 187 L), slow clearance (CL = 1.99 - 8.77 L/hr) and moderate to slow elimination (t1/2 = 11.9 - 31.6 hr). Approximately 26 - 85% of the administered dose of E7974 was recovered unchanged in the urine 48 hours post-dose. Conclusions: The recommended phase 2 dose of E7974 on days 1 and 15 of a 28-day schedule is 0.31mg/m2. Observed toxicities were manageable and reversible. No significant financial relationships to disclose.

scholarly journals Continuous Infusion of Cilengitide with Radio-Chemotherapy in Stage III Nsclc: a Phase I Study

2014 ◽  
Vol 25 ◽  
pp. iv421
Author(s):  
E.L. Cohen-Jonathan Moyal ◽  
C. Massabeau ◽  
T. Filleron ◽  
A. Modesto ◽  
J. Bachaud ◽  
...  
Keyword(s):  
Phase I ◽  
Continuous Infusion ◽  
Phase I Study ◽  
Stage Iii ◽  
Stage Iii Nsclc ◽  
Radio Chemotherapy

Phase I trial of the somatostatin analog octreotide acetate in the treatment of fluoropyrimidine-induced diarrhea.

1995 ◽  
Vol 13 (1) ◽  
pp. 222-226 ◽  
Author(s):  
S Wadler ◽  
H Haynes ◽  
P H Wiernik
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Response To Therapy ◽  
Somatostatin Analog ◽  
Watery Diarrhea ◽  
Gastrointestinal Malignancies ◽  
Octreotide Acetate

PURPOSE Diarrhea is one of the dose-limiting toxicities for administration of fluorouracil (5FU) in patients with gastrointestinal malignancies and can result in severe morbidities or mortality. The somatostatin analog octreotide acetate has been used in the treatment of 5FU-induced diarrhea with promising results. A phase I trial was initiated to determine the maximum-tolerated dose of octreotide acetate that could be administered in this setting. PATIENTS AND METHODS Patients were required to have National Cancer Institute Common Toxicity Criteria > or = grade 2 diarrhea or watery diarrhea secondary to treatment with 5FU or a modulated 5FU regimen. At least three patients were treated at each dose level; after satisfactory completion of this dose level (zero of three or one of six patients with < or = grade 2 toxicity), additional patients were added at the next dose level. Doses of octreotide acetate studied were 50 to 2,500 micrograms subcutaneously three times daily for 5 days. RESULTS A total of 35 patients received 49 courses of therapy. The only significant toxicities occurred at 2,500 micrograms. At this dose level, one patient developed an allergic reaction with flushing, nausea, and dizziness after each of the first two injections. A second patient developed asymptomatic hypoglycemia with a serum glucose level of 26 mg/dL. The maximum-tolerated dose was 2,000 micrograms. The efficacy of the treatment correlated significantly (P = .01) with the dose of octreotide administered, and more patients completed the course of therapy at the higher doses. CONCLUSION Octreotide acetate can be safely administered for the treatment of fluoropyrimidine-induced diarrhea in patients with gastrointestinal malignancies. The dose-limiting toxicities were allergic (nausea, rash, and light-headedness) and endocrine (hypoglycemia). There was a significant correlation between complete response to therapy and octreotide dose.

Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies.

1993 ◽  
Vol 11 (3) ◽  
pp. 499-506 ◽  
Author(s):  
J Weber ◽  
J C Yang ◽  
S L Topalian ◽  
D R Parkinson ◽  
D S Schwartzentruber ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Interleukin 6 ◽  
Phase Ii Trials ◽  
Organ Toxicity ◽  
Advanced Malignancies ◽  
Major Organ ◽  
Dose Levels ◽  
Grade Iii

PURPOSE Based on preclinical evidence in murine models that interleukin-6 (IL-6) mediates regression of metastatic tumors, we performed a phase I study of recombinant human IL-6 in patients with refractory advanced malignancies to determine its pharmacokinetics, toxicities, and possible immunologic and antitumor effects. PATIENTS AND METHODS Recombinant IL-6 was administered as a single subcutaneous dose daily for 7 days, with 7 days off therapy followed by another 7 days of IL-6. Doses were escalated in cohorts of three patients starting at 3 micrograms/kg/d, provided that toxicity at the preceding dose level was not dose-limiting. Dose-limiting toxicity was defined as grade III or IV major organ toxicity that did not resolve to grade II or less in 24 hours after stopping IL-6, using the National Cancer Institute Common Toxicity Criteria. Patients were treated with 3, 10, and 30 micrograms/kg/d IL-6 subcutaneously. RESULTS Three patients each were treated at the 3- and 10-micrograms dose levels. Two of five patients treated with 30 micrograms/kg/d IL-6 subcutaneously had grade III major organ toxicity that required IL-6 therapy to be discontinued. All patients experienced fever, chills, and minor fatigue. Significant increases in C-reactive protein (CRP), fibrinogen, platelet counts, and lymphocyte IL-2 receptor levels were seen in patients at the 10- and 30-micrograms/kg dose levels. Decreases in albumin and hemoglobin were observed, particularly at the 30-micrograms/kg dose level. The half-life (T1/2 beta) was 4.2 hours, with a peak IL-6 level at 5 hours. No antitumor responses were seen. CONCLUSION A safely tolerated dose of daily subcutaneous IL-6 is 10 micrograms/kg, with hepatotoxicity and cardiac arrhythmia being the dose-limiting toxicities at 30 micrograms/kg. Phase II trials of IL-6 administered subcutaneously daily for at least 7 days for two cycles with an intervening week of rest are recommended for phase II trials. However, patients with extensive replacement of liver by tumor and abnormal liver functions should receive IL-6 therapy with caution.

Phase I study of docetaxel with concomitant thoracic radiation therapy.

1998 ◽  
Vol 16 (1) ◽  
pp. 159-164 ◽  
Author(s):  
A M Mauer ◽  
G A Masters ◽  
D J Haraf ◽  
P C Hoffman ◽  
S M Watson ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Optimal Schedule ◽  
Late Toxicity ◽  
Maximum Tolerated Dose ◽  
Small Cell Lung ◽  
Weekly Administration ◽  
Thoracic Radiation ◽  
Radiation Sensitizers ◽  
Administration Schedules

PURPOSE The taxanes have demonstrated activity as radiation sensitizers in preclinical studies. This study was designed to determine the maximum-tolerated dose (MTD), optimal schedule, and toxicities of docetaxel in combination with concomitant standard chest radiotherapy. PATIENTS AND METHODS Twenty-nine patients with advanced non-small-cell lung or esophageal cancer enrolled in this phase I study to evaluate escalating docetaxel doses at three schedules. Docetaxel was administered as two 21-day cycles at doses of 40, 60, and 75 mg/m2 per cycle. Docetaxel administration schedules were as follows: schedule A, once every 3 weeks; schedule B, 2 of 3 weeks; or schedule C, weekly. Six weeks of concomitant standard chest radiotherapy in 1.8- to 2.0-Gy daily fractions was delivered to 60 Gy total. RESULTS Dose-limiting esophagitis and neutropenia were encountered with schedules A and B at docetaxel doses of 60 mg/m2 per cycle. The docetaxel MTD for schedules A and B was 40 mg/m2 per cycle. Dose-limiting esophagitis was also observed with schedule C; however, there was no neutropenia. For schedule C, we identified the MTD as 60 mg/m2 per cycle (20 mg/m2/wk). Other toxicities encountered included thrombocytopenia, hypersensitivity reaction, and pulmonary infiltrates (fatal in two patients). Late toxicity of esophageal stricture occurred in five patients. CONCLUSION Esophagitis and neutropenia are the dose-limiting toxicities of docetaxel administered with concomitant chest radiotherapy. Weekly administration of docetaxel allows for the highest total docetaxel dose during chest radiotherapy. We identified the recommended phase II docetaxel dose as 20 mg/m2 administered weekly with concomitant chest radiotherapy for 6 weeks.

Phase I Trial of Intravenous Thymidine and Carboplatin in Patients With Advanced Cancer

1999 ◽  
Vol 17 (9) ◽  
pp. 2922-2922 ◽  
Author(s):  
H. Ian Robins ◽  
Kendra Tutsch ◽  
Doerthe M. Katschinski ◽  
Elaine Jacobson ◽  
Minesh Mehta ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Combined Therapy ◽  
High Grade Glioma ◽  
Maximum Tolerated Dose ◽  
Metastatic Colon Cancer ◽  
Minor Response ◽  
The North ◽  
A Minor

PURPOSE: To evaluate the biologic interactions and toxicities of carboplatin combined with a 24-hour infusion of thymidine 75 mg/m2 in a phase I trial. PATIENTS AND METHODS: Thirty-two patients with cancer refractory to conventional therapy were treated. The first set of patients (n = 7) received thymidine alone 4 weeks before subsequent planned courses of thymidine combined with carboplatin followed (4 weeks) by carboplatin alone. Carboplatin was administered over 20 minutes at hour 20 of the 24-hour thymidine infusion. The carboplatin dose was escalated in patient groups: 200 mg/m2 (n = 3); 300 mg/m2 (n = 7); 350 mg/m2 (n = 4); 400 mg/m2 (n = 3); 480 mg/m2 (n = 10); and 576 mg/m2 (n = 5). At the maximum-tolerated dose (480 mg/m2), five patients received combined therapy first and carboplatin alone second, and five patients received carboplatin first and combined therapy second. Maintenance therapy for stable or responding patients was combined therapy. RESULTS: Evaluation demonstrated a trend toward thymidine protection of carboplatin-induced treatment-limiting thrombocytopenia. Neutropenia with carboplatin alone or in combination was negligible. Thymidine alone had no myelosuppressive effects and produced reversible grade 1 or 2 nausea and vomiting (57%), headache (25%), and grade 1 neurotoxicity (22%). Thymidine did not enhance expected carboplatin toxicities. There was no therapy-related infection or bleeding. Analysis of platinum in plasma ultrafiltrate and urine showed no effect by thymidine. Similarly, thymidine pharmacokinetics was not affected by carboplatin. As predicted, nicotinamide adenine dinucleotide levels in peripheral lymphocytes were increased during exposure to carboplatin and/or thymidine but were decreased by carboplatin alone. In three patients with high-grade glioma, responses included one complete remission (21 months) and one partial remission (14 months) at the 480-mg/m2-dose level, and disease stabilization (7 months) at the 400-mg/m2-dose level. A minor response was observed in a patient with metastatic colon cancer (5 months) at the 480-mg/m2-dose level. CONCLUSION: The combination of carboplatin and thymidine as described is well tolerated. The data presented have resulted in a phase II study by the North American Brain Tumor Consortium.

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