scholarly journals Geothermal and geopressure blowout control. Phase I. Study of existing technology. Phase II. Program plan for geothermal and geopressure blowout control

1978 ◽  
Author(s):  
W A Rehm ◽  
W C Goins, Jr
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Control Phase ◽  
Program Plan

Use of Antifungal Therapy in Hospitalized Patients II. Results after the Marketing of Fluconazole

1994 ◽  
Vol 28 (2) ◽  
pp. 261-270 ◽  
Author(s):  
Thaddeus H. Grasela ◽  
Mary T. Pasko ◽  
S. Diane Goodwin ◽  
Cynthia A. Walawander ◽  
Nicole Blackwelder ◽  
...  
Keyword(s):  
Phase I ◽  
Amphotericin B ◽  
Phase Ii ◽  
Antifungal Therapy ◽  
Antifungal Agent ◽  
Phase I Study ◽  
Antifungal Agents ◽  
Hospitalized Patients ◽  
Prescribing Patterns ◽  
Systemic Antifungal Therapy

OBJECTIVE: To evaluatethe prescribing patternsof antifungal agents in the hospital setting after the introduction of fluconazole, a new broad-spectrum bis-triazole antifungal agent. Also comparedare the prescribing patterns of antifungal agents prior to (phase I) and following (phase II) fluconazole marketing. DESIGN: A prospective cohort of hospitalized patients prescribed topical or systemic antifungal agents. Data were collected from December 1990 to April 1991. SETTING: Fifty-seven hospitals ranging in size from 100 to more than 500 beds. Sixty-three percentare affiliated with medical schools. PATIENTS: Participating pharmacists consecutively identified 15 patients receiving systemic antifungal therapy and 5 patients receiving topical antifungal therapy. INTERVENTIONS: Observational data on patient antifungal therapy, risk factors for fungal infections, comorbidities, concurrent medications, and culture data were collected. MEASURES: Differences in prescribing patterns before and after the marketing of fluconazole were assessed using t-tests and chi-square tests. RESULTS: Of 818 patients studied, 615 (75.2 percent) received systemic antifungal therapy. Five hundred forty-six patients received a single antifungal agent; 348 (63.7 percent) received fluconazole, 105 (19.2 percent) received ketoconazole, 92 (16.8 percent) received amphotericin B, and 1 (0.2 percent) received flucytosine. Sixty-nine patients received two or more systemic agents either concurrently or consecutively. The use of parenteral amphotericin B, alone or in combination with flucytosine and/or an azole, declined from 56.8 percent in the phase I study to 24.2 percent in the current study. The use of parenteral therapy also declined from 56.8 to 40.2 percent. Ketoconazole was used in more than 90 percent of the oral and esophageal infections in the phase I study, but its use declined to only 33 percent in this study. Fluconazole was used most frequently across all sites of presumed or documented infections, with the exception of fungemia. Of the presumed or proven systemic or blood infections, amphotericin B was used alone or in combination in 48.4 percent of the patients and fluconazole was used exclusively in 39.0 percent of the patients. Fluconazole was used more often than amphotericin B (22 vs. 3 patients, respectively) for prophylaxis of systemic infections. The overall use of antifungal prophylaxis also increased from the phase I (9.5 percent) to phase II (13.7 percent). CONCLUSIONS: The introduction of fluconazole had a major impact on the prescribing patterns of antifungal therapy. Although amphotericin B remained the preferred agent for treatment of suspected or proven systemic, central nervous system, or blood infections, use of fluconazole for these indications approached nearly 40 percent. Further studies are needed to address the role of fluconazole in the prophylaxis and treatment of systemic mycoses.

Bleeding Diathesis in Patients (pts) with Chronic Myelogenous Leukemia Receiving Dasatinib Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2958-2958 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Farhad Ravandi ◽  
Jan Burger ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Phase I ◽  
Median Time ◽  
Phase Ii ◽  
Phase I Study ◽  
Vaginal Bleeding ◽  
Myelogenous Leukemia ◽  
Bleeding Diathesis ◽  
Gingival Bleeding ◽  
Phase Ii Studies ◽  
Bleeding Episodes

Abstract Dasatinib (Sprycel®, Bristol-Myers Squibb) is an oral potent ATP-competitive multikinase inhibitor active against BCR-ABL and SRC family kinases (SFKs). Dasatinib is approximately 300-fold more potent than imatinib against BCR-ABL and is active against a wide array of imatinib-resistant BCR-ABL kinase mutants at clinically achievable concentrations. Dasatinib has demonstrated high efficacy and safety in patients (pts) with chronic myelogenous leukemia (CML). The most frequent non-hematologic side effects associated with dasatinib therapy are gastrointestinal, rash, and fluid retention syndromes. In addition, dasatinib therapy may be associated with increased risk of bleeding in some pts. We evaluated the incidence of bleeding episodes associated with dasatinib therapy among 138 consecutive pts (69 female) with CML treated at our institution between November 2003 and January 2006 after failure or resistance to imatinib. The median age for the entire cohort was 57 years (range, 15 to 81 years). Among 50 pts treated in the phase I study, 23 (46%) were in chronic (CP), 7 (14%) in accelerated (AP), and 20 (40%) in blastic phase (BP) at the time of dasatinib start, whereas 88 pts, 43 (49%) in CP, 25 (28%) in AP, and 20 (23%) in BP, received dasatinib in phase II studies. Fifteen (11%) pts started dasatinib at a dose <100 mg, 22 (16%) at 100 mg, 92 (67%) at 140 mg, and 9 (6%) at >140 mg daily. The median time on dasatinib therapy for the study group was 42 weeks (range, 4–120): 69 weeks (range, 18–120) for pts in the phase I study and 34 weeks (range, 4–61) for those in phase II studies. Thirty-seven bleeding episodes occurred in 32 (23%) pts, 11 (22%) treated in the phase I study and 21 (24%) in the phase II studies. Seven (5%) pts had grade 1, 16 (12%) grade 2, and 9 (7%) grade 3 bleeding. No grade 4–5 bleeding episodes were observed. The median time to development of bleeding was 6 weeks (range, 0.5–38), occurring within the first 3 months of therapy in 22 (69%) pts. Most bleeding episodes occurred in the gastrointestinal tract (81%) (lower gastrointestinal bleed [LGIB; n=22]; upper gastrointestinal bleeding [UGIB; n=8]. Other bleeding types included: gingival (n=4), vaginal (n=2), and epistaxis (n=1). Six (19%) pts experienced >1 concomitant bleeding type: 4 with LGIB and UGIB, 1 with LGIB, gingival bleeding, and scalp hematoma, and 1 with gingival and vaginal bleeding. In addition, 12 (37%) pts (5 CP, 2 AP, and 5 BP) had recurrent bleeding episodes: 8 LGIB (in 2 separate occasions in 3 of them), 1 UGIB, 2 gingival bleeding, and 1 vaginal bleed. Bleeding led to transient dasatinib interruptions in 15 (47%) pts, 8 with LGIB (2 of them also with UGIB), 6 with UGIB (2 of them also with LGIB), 2 with gingival bleeding, and 1 with vaginal bleeding. Bleeding episodes were observed in 12% of pts treated in CP, 31% in AP, and 35% in BP (p=0.02) and were more frequent among pts treated at daily doses ≥140 mg compared to those treated at ≤100 mg (84% vs 16%; p=0.001). Fifty-one percent of bleeding episodes were observed in pts with platelet counts ≥30×109/L, including 37% in pts with platelet counts >100×109/L. Basic coagulation studies (PT, aPTT, fibrinogen, D-Dimer) were normal in all but 1 BP patient. In conclusion, bleeding diathesis is a relatively frequent complication of dasatinib therapy, particularly among pts with advanced CML receiving dasatinib ≥140 mg. Early identification, transient dasatinib interruption, and dasatinib dose reduction are required to adequately manage pts with this complication.

Phase I/II study of irinotecan, UFT, and leucovorin with hepatic arterial infusion in colorectal cancer patients with unresectable liver metastases: Preliminary results

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14549-14549
Author(s):  
T. Yamaguchi ◽  
H. Matsumoto ◽  
K. Takahashi ◽  
M. Yasutome ◽  
T. Mori
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Liver Metastases ◽  
Phase Ii ◽  
Phase I Study ◽  
Phase Ii Study ◽  
Hepatic Arterial Infusion ◽  
Arterial Infusion ◽  
Unresectable Liver Metastases ◽  
Colorectal Cancer Patients

14549 Background: To determine the maximum-tolerated dose (MTD) and to evaluate the efficacy and tolerability of combination chemotherapy of irinotecan (CPT-11), UFT and leucovorin (LV) with hepatic arterial infusion (HAI) in colorectal cancer patients with unresectable liver metastases. Methods: Patients who had unresectable liver metastases from colorectal cancer were treated concurrently with intravenous CPT-11 on day1 of each 14-day treatment cycle with dose escalation, with orally UFT and LV on day 1–7 of each cycle, and with HAI of 5-FU on day 8–14 of each cycle. The primary objective of this phase I study was to determine the MTD of biweekly intravenous CPT-11 and UFT/LV with HAI of 5-FU. In the phase II study, the primary endpoint was to determine the response rate. Results: In the phase I study, the recommended dose of CPT-11 for phase II study was 140 mg/m2 combined with UFT 300 mg/m2/day, LV 75 mg/body/day and 5-FU 2,000 mg/body/week. Sixteen patients were enrolled onto the phase II study. The six patients treated at the recommended dose during the phase I study also included in the phase II analysis (n = 22). Median number of liver metastases was 12 (range, 3 to 35). Median size of maximum diameter was 6.3 cm (range, 2.0 to 12.0 cm). The most common adverse event was neutropenia. The complete and partial response rate totaled 81.8%. Median survival time has not been reached yet. Eleven patients (50.0%) were ultimately able to undergo liver resection. Conclusions: The combination chemotherapy of CPT-11 and UFT/LV with HAI was safe, well tolerate and effective in current population of the patients with unresectable liver metastases from colorectal cancer. Updated toxicity and response data will be available in the spring of 2007. No significant financial relationships to disclose.

Phase I study of cisplatin/carboplatin/irinotecan (CPI) regimen in patients with ED small-cell lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18202-18202
Author(s):  
M. Ichiki ◽  
Y. Yoshida ◽  
A. Ishimatsu ◽  
S. Minami ◽  
K. Taguchi ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Phase Ii Study ◽  
Active Form ◽  
Dose Intensity ◽  
Maximum Tolerated Dose ◽  
Hematological Toxicity ◽  
Standard Regimen ◽  
Level 1

18202 Cisplatin/irinotecan(IP) is standard regimen for ED-SCLC in Japan. Cisplatin (CDDP)-based treatment requires copious hydration, which can lead to a deterioration of outpatients’ quality of life. CDDP and carboplatin (CBDCA) have a common active form, but are associated with different adverse reactions. We considered that the combined use of these two agents could increase the dose intensity of active form platinum complexes without enhancing their toxicities. The IP was modified to nearly half the dose of CDDP/CBDCA to facilitate outpatient administration. We conducted a phase I study to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of this modified regimen for patients with ED-SCLC and stage IV NSCLC. Eligibility criteria included: PS 0–1, age <75 yrs, no prior therapy, measurable disease, adequate organ functions. DLT was defined as follows: 1) grade 4 neutropenia lasting 4 days or febrile neutropenia, 2) grade 4 thrombocytopenia, 3) prolongation of treatment due to toxicity, 4) grade 3 or worse non-hematological toxicity. Three patients were enrolled at level 1(CDDP/CBDCA: 25 mg/m2/AUC2), 3 patients at level 2 (25 mg/m2/AUC 2.5) and 3 patients at level 3 (30 mg/m2/ AUC 2.5), respectively. DLT was not observed at level 1, 2, 3. At dose level 4 (30 mg/m2/AUC3), two of three patients experienced DLT, suggesting this level to be the MTD. The recommended dose for phase II study is CDDP 30 mg/m2 on day 1, CBDCA AUC 2.5 on day 1 and irinotecan 60 mg/m2 on days 1, 8, 15. A phase II study of this regimen in ED-SCLC is ongoing. No significant financial relationships to disclose.

A phase I study of EP-100, a luteinizing hormone releasing hormone (LHRH) ligand conjugated to a synthetic cytolytic peptide in patients with advanced refractory LHRH- receptor (R)-expressing tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3060-3060
Author(s):  
Ramesh K. Ramanathan ◽  
Manpreet Chadha ◽  
John Sarantopoulos ◽  
Donald W. Northfelt ◽  
Glen J. Weiss ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Antibody Production ◽  
Phase I Study ◽  
Standard Dose ◽  
Pharmacokinetic Profile ◽  
Best Response ◽  
Expression Rate ◽  
Tumor Expression

3060 Background: EP-100 is a synthetic 28 amino acid LHRH peptide conjugated to an 18 aa cytolytic peptide. Selective targeting in LHRH-R expressing cells occurs via direct binding to the extracellular membrane receptor followed by disruption of the membrane by the cytolytic peptide portion. A first in human, phase I study was performed. Methods: Eligible pts had adequate organ function and LHRH-R tumor expression, as determined by IHC. EP-100 was given IV (30-60 min) weekly x 3 for cohorts 1- 6 (n=20 at 0.6 - 5.2 mg/m2) and then twice weekly x 3 for cohorts 7- 11 (n=18 at 7.8 - 40 mg/m2) with a week break. The pharmacokinetic profile of EP-100 and antibody production against EP-100 was determined by a validated HPLC/MS and ELISA respectively. Potential activity of EP-100 on the pituitary gonadotropes was determined by plasma LH and FSH. Results: We screened 97 pts, archival tumor tissue obtained from 81 pts; 53 (65%) were positive for LHRH-R, of which 37 were enrolled (female 76%) and treated. The LHRH-R expression rate in breast was 81% (N=21) and in ovarian cancer 56% (n=18). Most pts had breast (n= 16, 42%) ovary (n=7,18%), colon (n=4, 11%) or uterine (n=3, 8%) cancer. Pts were treated in a 3 + 3 standard dose escalation scheme. Doses were escalated 100% in the absence of a grade 2 drug related toxicity. MTD was not reached at the highest dose level of 40 mg/m2. Only one DLT occurred, a grade 2 increase in ALT/AST. The only other drug-related toxicity was a self limited infusion-related skin reaction (grade 1-2) in 10 pts. EP-100 was rapidly cleared from circulation, mean half life ranged from 7.1 ± 3.8 min to 15.9 ± 3.6 min. Best response was stable disease for >12 weeks in 5 pts. In 3 pts rapid, sustained decreases in LH/FSH levels were noted. Antibody production against EP-100 was absent in all pts. Conclusions: The study has completed accrual, the phase II dose is 30-40 mg/m2 twice a week x 3 weeks.EP-100is safe, well tolerated and not antigenic/immunogenic. Preclinical studies indicated synergy with paclitaxel and doxorubicin. A phase II study of EP-100 plus paclitaxel in ovarian cancer is planned.

Phase I study of c-Met inhibitor ARQ197 in combination with FOLFOX for the treatment of patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2544-2544
Author(s):  
Suzanne Fields Jones ◽  
Carla Kurkjian ◽  
Manish R. Patel ◽  
Jeffrey R. Infante ◽  
Howard A. Burris ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Stable Disease ◽  
Phase I Study ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Unknown Primary ◽  
Advanced Solid Tumors ◽  
Grade 3

2544 Background: C-Met protein is a receptor tyrosine kinase which is overexpressed or mutated in a variety of tumor types, causing cell proliferation, metastasis, and angiogenesis. Tivantinib is an orally bioavailable small molecule which binds to the c-Met protein. This phase I study was designed to determine the maximum tolerated dose (MTD) of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors. Methods: Patients with advanced solid tumors for which FOLFOX (5-FU IV 400 mg/m2 day 1; 5-FU CIV 2400 mg/m2 day 1; Leucovorin IV 400 mg/m2 day 1; Oxaliplatin IV 85 mg/m2 day 1) would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design. Dose-limiting toxicities (DLTs), non-dose-limiting toxicities (NDLTs), safety, and preliminary efficacy were evaluated. Results: Fourteen patients (50% colorectal) were treated across 3 dose levels: 120 mg (n=3); 240 mg (n=5); 360 mg (n=6). No DLTs were observed until the 3rd dose level (treatment delay ≥3 days, secondary to grade 3 neutropenia). Common related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (36%; 0%), neutropenia (0%; 29%), nausea (14%; 14%), vomiting (14%; 14%), dehydration (14%; 7%), and thrombocytopenia (14%; 0%). To date, 7 patients have been evaluated for response including 4 (57%) with stable disease evident at the 8-week evaluation (CRC, 2 patients; unknown primary favoring CRC, 1 patient; esophageal, 1 patient) and 3 (21%) with disease progression. The 4 patients with stable disease are continuing on treatment; three (CRC and unknown primary) had received prior FOLFOX. Conclusions: The addition of tivantinib to standard therapy FOLFOX appears tolerated up to its recommended phase II monotherapy dose of 360 mg. Preliminary efficacy is encouraging, and a phase II study is proceeding with this regimen for the first line treatment of advanced gastroesophageal patients. Clinical trial information: NCT01611857.

Phase I/II trial of gemcitabine (Gem) plus irinotecan (CPT-11) for metastatic pancreatic cancer (MPC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 301-301
Author(s):  
Takuo Yamai ◽  
Tatsuya Ioka ◽  
Hironari Sueyoshi ◽  
Ryoji Takada ◽  
Nobuyasu Fukutake ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Phase I ◽  
Phase Ii ◽  
Combination Chemotherapy ◽  
Phase I Study ◽  
Progressive Disease ◽  
Metastatic Pancreatic Cancer ◽  
Refractory Ascites ◽  
Recommended Phase Ii Dose

301 Background: Treatment options for patients with metastatic pancreatic cancer are still limited. Recently, new strategies to prolong disease control are reported. We conducted phase I/II trial of GEM+CPT-11 combination chemotherapy for MPC to evaluate the effectiveness and safety. Methods: As phase I study, traditional 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose. Four escalating dose levels of GEM/CPT-11 (800/60 mg/m2, 1000/60 mg/m2, 1000/80 mg/m2, and 1000/100 mg/m2) were studied. As results of this investigation, the recommended phase II dose was GEM 1000 mg/m2 and CPT-11 100 mg/m2, biweekly. Phase II eligibility included naïve MPC, PS0-2, Pathological diagnosis, no refractory ascites and pleural effusion, and adequate organ function. Primary endpoint was overall survival. Results: Eighteen patients were entered phase I study. The DLTs were anorexia, and nausea/vomiting. Severe neutropenia was rare. MTDs were determined GEM 1000 and CPT-11 100 mg/m2. After that, we investigated phase II trial in 40 patients. There were 6 partial response, 14 stable disease, 18 progressive disease and 2 in-evaluable. Response rate was 16%. The median overall survival was 7.5 months; progressive disease 4.0 months. Grade 3 to 4 toxicity included neutropenia (7%), anemia (7%), diarrhea (7%), ALT elevation (10%), pneumonitis(7%). There was no treatment-related death. Conclusions: This combination chemotherapy is not effective as first-line chemotherapy for metastatic pancreatic cancer. But this is safe and generally well tolerated. This chemotherapy could be effective of salvage chemotherapy with low toxicity after standard chemotherapy such as FOLFIRINOX.

A phase I study of axitinib (AG-013736), a potent inhibitor of VEGFRs, in combination with gemcitabine (GEM) in patients (pts) with advanced pancreatic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13092-13092 ◽  
Author(s):  
J. Spano ◽  
M. Moore ◽  
S. Kim ◽  
K. F. Liau ◽  
B. Hee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Tyrosine Kinases ◽  
Phase I Study ◽  
Phase Ii Study ◽  
Tumor Regression ◽  
Epigastric Pain ◽  
Cell Cancer ◽  
Advanced Pancreatic Cancer

13092 Background: Axitinib (AG-013736) is a novel small molecule inhibitor of the receptor tyrosine kinases with picomolar potency against VEGFR 1, 2 & 3 and nanomolar potency against PDGFR-beta and KIT. A phase I study in solid tumors identified 5 mg BID as the therapeutic dose; a phase II study in renal cell cancer demonstrated significant efficacy with a response rate (RR) of 46% (Rini et al, ASCO 2005). This study examined the safety, PK and preliminary efficacy of AG-013736 (AG) in combination with gemcitabine (GEM) as first-line therapy for advanced pancreatic cancer. Methods: A randomized phase II study was preceded by a phase I component. All patients (pts) in the phase I portion received 1000 mg/m2 GEM by 30-minute infusion on days 1, 8, and 15 followed by one week of rest from treatment. AG 5 mg p.o. BID was given beginning Cycle 1, Day 3 (C1D3). Eligible pts had no prior chemotherapy for advanced disease, ECOG 0–2, and no previous treatment with VEGF/VEGFR inhibitors, or anti-angiogenesis treatment. Full PK profiles were collected on C1D1 (GEM alone), C1D14 (steady state, AG alone), and C1D15 (GEM + AG). In the phase II trial, pts are randomized to AG or AG plus GEM beginning C1D1. Results: 8 pts were treated on the phase I portion of this trial. Toxicity: The primary Gr. 3/4 toxicity was hematologic: Gr. 4 anemia and Gr.3 thrombocytopenia in 1 pt and Gr. 3 neutropenia in 1 pt requiring a dose reduction for GEM in Cycle 3. Gr. 2 non-hematologic adverse events include pruritus (1 pt), abdominal pain (2 pts), epigastric pain (1 pt), melena (1 pt), and asthenia (2 pts). Gr. 2 hypertension was observed in 3 pts. Efficacy: Radiological assessment suggests 2 pts with partial response and 4 pts with stable disease: response assessments are ongoing. The median number of cycles is 3 [1,6]. Treatment for 4 pts is still ongoing: Cycle 6 (2 pts) and Cycle 2 (2 pts). Conclusions: This combination is safe and appears to be an effective treatment for advanced pancreatic cancer with significant tumor regression observed in 2 pts. Therapy was well tolerated with manageable toxicity. Additional investigation of AG-013736 in combination with GEM in the phase II setting for advanced pancreatic cancer is warranted. [Table: see text]

Stage III non small lung cancer (NSCLC): Docetaxel (D), gemcitabine (G), and cisplatin (C) as induction chemotherapy, an Italian phase I study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18201-18201
Author(s):  
S. De Santis ◽  
V. Donato ◽  
M. R. Migliorino ◽  
B. Tedesco ◽  
S. Condo ◽  
...  
Keyword(s):  
Phase I ◽  
Induction Chemotherapy ◽  
Phase Ii ◽  
Phase I Study ◽  
Objective Response ◽  
Stage Iii ◽  
Stage Iiia ◽  
Phase Ii Studies ◽  
Stage Iii Nsclc ◽  
Grade 3

18201 Background: Based on the several clinical trials, combined modality therapy became the standard of care for patients with stage III NSCLC “unresectable” with good performance status (Kathy S. Albain, Educational Book ASCO 2006, 453–461; Thomas E. Stinchcombe, Oncologist 2006, 11, 809–823). The most effective induction chemotherapy has yet to be determined. The objective of this prospective phase I study was to define the maximum tolerated dose (MTD), and to evaluate the activity and safety of one of the third generation triplets as a full dose neoadjuvant regimen in patients (pts) with unresectable Stage III NSCLC. Methods: In this study, chemotherapy-naïve pts with stage IIIA-N2 bulky and IIIB (except malignant pleural effusion) NSCLC were eligible. Inclusion into the trial and treatment decisions were done by multidisciplinary panel involving surgeons, medical oncologists and radiotherapists. All drugs were given intravenously on days 1 and 8, and repeated every 3 weeks up to 2 cycles followed by concurrent chemoradiation. D (30–35 mg/m2) was given first, followed by C (35 mg/m2) and G (1000 mg/m2). Results: From Jan ‘06 to Jul ‘06 twelve eligible pts were enrolled, 10/2 m/f gender; median age 63 (50–72), 1 patient with ECOG PS 0, 11 pts with PS 1; 5 pts with stage IIIA-N2 bulky, 7 pts with stage IIIB NSCLC; nine pts were smokers. All pts were evaluable for toxicity. Toxicity grade 3–4 by CTC criteria was: grade 3 neutropenia in 2/3 patients and grade 3 thrombocytopenia in 1/3 patients on the second dose level of chemotherapy (i.e. docetaxel 35 mg/m2), and was considered dose-limiting. Of 9 pts treated at the MTD (i.e. docetaxel 30 mg/m2), only 1 patient developed grade 4 neutropenia and 1 patient grade 3 thrombocytopenia; 3 patients (30%) had grade 2 neutropenia and grade 2 stomatitis. Of 12 evaluable pts for response, after induction chemotherapy eighty-three percent of patients (9/12 pts) had an objective response and 16,6% (2/9 pts) stable disease. Phase II is continuing for larger patient accrual. Conclusions: The recommended doses for further phase II studies are D (30 mg/m2) followed by C (35 mg/m2) and G (1000 mg/m2) every 3 weeks. This regimen is well tolerated and effective, and appears to be an excellent choice for stage III NSCLC. No significant financial relationships to disclose.

Biomodulation of capecitabine by weekly paclitaxel and carboplatin in patients with advanced solid tumor malignancies: A dose-escalating phase I study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2569-2569
Author(s):  
M. B. Lustberg ◽  
J. Nuovo ◽  
J. P. Thomas ◽  
P. J. Monk ◽  
S. Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Dihydropyrimidine Dehydrogenase ◽  
Weekly Paclitaxel ◽  
Unknown Primary ◽  
Cancer Tissue ◽  
Phase Ii Trials ◽  
Two Phase ◽  
Phase Ii Studies

2569 Background: A principal determinant of the therapeutic index with capecitabine-based treatment is the grade of thymidine phosphorylase (TP) activity in malignant tissue. The beneficial interactions of paclitaxel and carboplatin in upregulation of TP promise to make capecitabine more tumor specific and to provide the expected synergy. On the basis of the time-dependency and transiency for this upregulation we performed a phase I study of capecitabine in combination with weekly paclitaxel and carboplatin (CTX). Methods: Patients with advanced solid tumors received carboplatin on day 1, paclitaxel on days 1, 8, 15 and capecitabine orally twice a day on days 8–21, every 4 weeks. There were 5 planned dose levels (DL 1–5). Paclitaxel was escalated from 60 mg/m2 to 80 mg/m2 (DL 4) then 100 mg/m2 (DL 5). Capecitabine from 500 mg/m2 bid to 750 mg/2 bid (DL 2) then 1000 mg/m2 bid (DL 3–5). Carboplatin dose was fixed at AUC 6. Paraffin-embedded tissue was evaluated for expression of TP, thymidylate synthase and dihydropyrimidine dehydrogenase by immunohistochemistry. Results: 32 patients from Ohio State University (OSU) were enrolled. 84% had prior therapy. The most common grade 3/4 toxicities were neutropenia (59%), leukopenia (56%), and fatigue (16%). DLTs included neutropenic fever (1), prolonged neutropenia or thrombocytopenia (2) and diarrhea (1). The MTD was at DL 2. There were 10 confirmed responses [4 CR (esophagus, stomach, unknown primary and ampullary); 6 PRs (Pancreas (3), unknown primary, anal and esophagus] and stabilization of disease > 3 months in 12 patients. In normal tissue, there was no difference in expression levels of both TS and TP. On the other hand, in cancer tissue, TP levels seem to correlate with response whereas TS did not. Conclusions: CTX demonstrates acceptable tolerability. The recommended doses for phase II studies are capecitabine 750 mg/m2 bid, paclitaxel 60 mg/m2/week and carboplatin AUC=6. The acceptable toxicity profile in this dose schedule, and the promising antitumor activity observed warrant further evaluation of this regimen. Two phase II trials are already underway at OSU using this regimen for patients with pancreatic cancer and adenocarcinomas of unknown primary, the latter already actively enrolling patients. Pretreatment tumoral TP levels may help predict patients that are more likely to respond to CTX. Correlation of IHC data with responses will be presented at the meeting. [Table: see text]

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