Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients.

1995 ◽  
Vol 13 (1) ◽  
pp. 210-221 ◽  
Author(s):  
D Abigerges ◽  
G G Chabot ◽  
J P Armand ◽  
P Hérait ◽  
A Gouyette ◽  
...  
Keyword(s):  
Phase I ◽  
Head And Neck ◽  
Phase Ii ◽  
Dose Escalation ◽  
Half Life ◽  
Topoisomerase I ◽  
Nausea And Vomiting ◽  
High Dose ◽  
Phase Ii Studies ◽  
Grade 3

PURPOSE A phase I study was undertaken to determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacokinetics of the novel topoisomerase I inhibitor irinotecan (CPT-11). PATIENTS AND METHODS Sixty-four patients meeting standard phase I eligibility criteria were included (24 women, 40 men; median age, 51 years; primary sites: colon, head and neck, lung, pleura; 60 of 64 had been previously treated). Pharmacokinetics was determined by high-performance liquid chromatography (HPLC). RESULTS One hundred ninety CPT-11 courses were administered as a 30-minute intravenous (IV) infusion every 3 weeks (100 to 750 mg/m2). Grade 3 to 4 nonhematologic toxicities included diarrhea (16%; three hospitalizations), nausea and vomiting (9%), asthenia (14%), alopecia (53%), elevation of hepatic transaminases (8%), and one case of skin toxicity. An acute cholinergic syndrome was observed during CPT-11 administration. Diarrhea appeared dose-limiting at 350 mg/m2, but this was circumvented by using a high-dose loperamide protocol that allowed dose escalation. Dose-dependent, reversible, noncumulative granulocytopenia was the dose-limiting toxicity (nadir, days 6 to 9; median recovery time, 5 days). Grade 3 to 4 anemia was observed in 9% of patients. One patient died during the study, 8 days after CPT-11 treatment. Two complete responses (cervix, 450 mg/m2; head and neck, 750 mg/m2) and six partial responses in fluorouracil (5-FU)-refractory colon cancer were observed (260 to 600 mg/m2). Pharmacokinetics of CPT-11 and active metabolite SN-38 were performed in 60 patients (94 courses). CPT-11 plasma disposition was bi- or triphasic, with a mean terminal half-life of 14.2 +/- 0.9 hours (mean +/- SEM). The mean volume of distribution (Vdss) was 157 +/- 8 L/m2, and total-body clearance was 15 +/- 1 L/m2/h. The CPT-11 area under the plasma concentration versus time curves (AUC) and SN-38 AUC increased linearly with dose. SN-38 plasma decay had an apparent half-life of 13.8 +/- 1.4 hours. Both CPT-11 and SN-38 AUCs correlated with nadir leukopenia and granulocytopenia, with grade 2 diarrhea, and with nausea and vomiting. CONCLUSION The MTD of CPT-11 administered as a 30-minute IV infusion every 3 weeks is 600 mg/m2, with granulocytopenia being dose-limiting. At 350 mg/m2, diarrhea appeared dose-limiting, but high-dose loperamide reduced this toxicity and allowed dose escalation. For safety reasons, the recommended dose is presently 350 mg/m2 every 3 weeks; more experience must be gained to establish the feasibility of a higher dose in large multicentric phase II studies. However, when careful monitoring of gastrointestinal toxicities is possible, a higher dose of 500 mg/m2 could be recommended in good-risk patients. The activity of this agent in 5-FU-refractory colorectal carcinoma makes it unique and mandates expedited phase II testing.

Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study.

1994 ◽  
Vol 12 (12) ◽  
pp. 2743-2750 ◽  
Author(s):  
A A Miller ◽  
J B Hargis ◽  
R C Lilenbaum ◽  
S Z Fields ◽  
G L Rosner ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Grade 3 ◽  
Dose Levels

PURPOSE The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

Phase I and Pharmacokinetic Study of Docetaxel and Irinotecan in Patients With Advanced Solid Tumors

2000 ◽  
Vol 18 (20) ◽  
pp. 3545-3552 ◽  
Author(s):  
Corinne Couteau ◽  
Marie-Laure Risse ◽  
Michel Ducreux ◽  
Florence Lefresne-Soulas ◽  
Alessandro Riva ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Topoisomerase I ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m2, 50/175 mg/m2, 60/210 mg/m2, 60/250 mg/m2, 60/275 mg/m2, 60/300 mg/m2, and 70/250 mg/m2. Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m2 and 60/300 mg/m2; the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study. CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m2, respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.

Combination of Oxaliplatin Plus Irinotecan in Patients With Gastrointestinal Tumors: Results of Two Independent Phase I Studies With Pharmacokinetics

1999 ◽  
Vol 17 (6) ◽  
pp. 1751-1751 ◽  
Author(s):  
Ernesto Wasserman ◽  
Caroline Cuvier ◽  
François Lokiec ◽  
François Goldwasser ◽  
Salima Kalla ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Two Phase ◽  
Phase I Studies ◽  
Phase Ii Studies ◽  
Minute Period ◽  
Grade 3 ◽  
Febrile Episodes

PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS: Patients with a performance status (PS) of ≤2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m2 for oxaliplatin and 150 to 250 mg/m2 for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m2 plus irinotecan 200 mg/m2 in one study and oxaliplatin 110 mg/m2 plus irinotecan 250 mg/m2 in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2. At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU–resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

Pilot study of fixed-dose bevacizumab (200 mg) for solid malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14600-e14600
Author(s):  
S. K. Reddy ◽  
M. Curti ◽  
M. Janis ◽  
R. Minow
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Optimal Dose ◽  
Median Number ◽  
Fixed Dose ◽  
Phase I Studies ◽  
Phase Ii Studies ◽  
Prospective Phase ◽  
Grade 3 ◽  
Grade Iii

e14600 Background: We report our initial experience with fixed dose bevacizumab at 200mg (approximately 3mg/kg). Phase I studies suggested that an optimal dose for phase II studies with bevacizumab is 3mg/kg and that circulating VEGF was undetectable at 0.3mg/kg. (Gordon et al. JCO 2001) We proposed a fixed-dose regimen of bevacizumab which we hypothesized would yield equivalent response rates with reduced toxicities and cost versus higher-dose regimens. Patients with advanced malignancies for whom bevacizumab would be indicated were analyzed. Methods: 15 patients were treated with 200mg bevacizumab in combination with antineoplastic therapy. 6 patients had NSCLCa, 8 patients had Colorectal cancer, and 1 patient had BRCA. Results: 15 patients are evaulable for response and have completed a total of 234 doses of bevacizumab (median number of doses =13) with no grade III/IV toxicity, or bevacizumab associated toxicities seen. No grade III or greater hypertension was observed. Proteinuria was not formally assessed, but no grade 3 or greater proteinuria was reported. All patients are evaluable for response with overall response rate of 33% (5/15). With a median follow-up (from the start of bevacizumab) of 452 days (222–1,699 days), median survival has not been reached with only 2 deaths. Conclusions: Fixed dose bevacizumab appears to be effective, less toxic, significantly less expensive and supported by biologic rationale and prior phase I studies and warrants further investigation. Additional patients will be accrued in a prospective phase II trial. [Table: see text]

Phase I/II trial of combination nab-paclitaxel and pemetrexed in advanced solid tumor patients (pts) with emphasis on non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19147-e19147
Author(s):  
Jonathan Riess ◽  
Cheryl Ho ◽  
Angela M. Davies ◽  
Derick Lau ◽  
Primo Lara ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Advanced Nsclc ◽  
Patient Characteristics ◽  
Maximum Tolerated Dose ◽  
Prior Therapy ◽  
Early Closure ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

e19147 Background: Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in NSCLC. Preclinical evaluation has demonstrated additive cytotoxicity of pemetrexed and taxanes. We evaluated the safety and efficacy of combining nab-paclitaxel (nP) and pemetrexed (P) in solid tumors with a focus on NSCLC for the phase II expansion. Methods: A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: P 500 mg/m2 day 1 plus nP on day 1 at doses of 180, 220, and 260 mg/m2 every 21 days. Dose limiting toxicity (DLT) in cycle 1 was defined as: grade 4 platelets or grade 3 platelets with bleeding, neutropenia with fever or documented infection, or other grade ≥ 3 non-heme toxicity. Phase II eligibility included advanced NSCLC, ≤ 2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25%. Results: Planned dose escalation during the Phase I portion was completed without reaching the MTD. The RP2D was P 500 mg/m2 and nP 260 mg/m2. The phase II portion accrued 37 pts before early closure due to increasing use of first-line pemetrexed/platinum doublet therapy in non-squamous NSCLC. Phase II patient characteristics: median 63 (45-77); M:F 23:14; median cycles 3. In 31 assessable patients: 5 PR, 12 SD and 14 PD. Efficacy: RR =14%; disease control rate (DCR) = 46%; median survival time (MST) = 8.7 months. Pts in the DCR group had a MST of 15.4 vs 4 months in the PD group (p=0.02). Conclusions: P 500 mg/m2 day 1 with nP 260 mg/m2 was feasible and well tolerated. The phase II component demonstrated activity in second-line therapy of advanced NSCLC. Practice patterns have evolved; so further trials of this regimen are not planned. Clinical trial information: NCT00470548.

Pooled analysis of phase I dose-escalation and dose cohort expansion studies of IMP4297, a novel PARP inhibitor, in Chinese and Australian patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Junning Cao ◽  
Pin Zhang ◽  
Paul L. de Souza ◽  
Bo Gao ◽  
Mark Voskoboynik ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Response To Treatment ◽  
Clinical Activity ◽  
Dose Cohort ◽  
Phase Ii Studies ◽  
Grade 3

3059 Background: Poly (ADP-ribose) polymerase (PARP) enzymes play critical roles in DNA damage detection and repair. IMP4297 is a novel, potent PARP1/2 inhibitor (IC50 6.27nM/1.57nM) and has demonstrated to be 20-fold more potent than Olaparib in anticancer animal models. Two phase I studies were performed to evaluate and characterize the tolerability and safety, pharmacokinetics, and antitumor activity of single agent IMP4297 in Chinese and Australian patients with advanced ovarian, breast, prostate and other solid tumors. Methods: Dose escalation used a 3+3 design with a modified Fibonacci escalation. Dose cohort expansion was planned after efficacy was observed at the lowest dose level. Patients received IMP4297 monotherapy orally once a day until disease progression or unacceptable toxicity. Results: As of Jan 12, 2019, 56 patients, including 23 BRCA mutation carriers (BRCA+), had been enrolled at 2-100 mg dose level. No DLT was observed. In these two studies, the most frequent treatment-related adverse events (TRAEs) were leukopenia (20%), followed by anemia (18%), nausea (18%) and thrombocytopenia (14%). The majority of TRAEs were grade 1 or 2. Grade 3 TRAEs occurred in five patients (anemia, n=2; vomiting, n=1; thrombocytopenia, n=1; elevated AST, n=1). Only one patient had a dose reduction due to grade 3 thrombocytopenia. No serious TRAEs were observed. In 15 BRCA+ patients who had measurable lesions, the ORR was 33% and the DCR was 80%. There were 4 BRCA+, platinum-sensitive ovarian cancer patients with an ORR of 75% and a DCR of 100%. One patient with somatic BRCA mutated urothelial carcinoma showed a 76% decrease in tumor size. Conclusions: IMP4297 has been well-tolerated with significant anti-tumor activity. The 100 mg daily dose was selected as the RP2D based on safety, pharmacokinetics and clinical activity, and will be further characterized in dose expansion and phase II studies. Tumor response to treatment (RECIST 1.1) in patients with measurable lesions. Clinical trial information: NCT03508011 and NCT03507543. [Table: see text]

scholarly journals Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2154-2154
Author(s):  
Noa Biran ◽  
Shijia Zhang ◽  
Scott D. Rowley ◽  
David H. Vesole ◽  
Michele L. Donato ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Conditioning Regimen ◽  
High Dose ◽  
Advisory Committees ◽  
Common Grade ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Background: A regimen of escalating doses of thalidomide, in combination with bortezomib and high dose melphalan (Mel/Vel/Thal) was evaluated as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM) in a phase I/II study. Methods: Patients received Mel/Vel/Thal as a second of tandem ASCT if they achieved <CR to their first ASCT (tandem), or as conditioning for a salvage ASCT (salvage). Exclusion criteria were dose-intense therapy within 56 days, uncontrolled infections, severe organ dysfunction, Karnofsky score <70%, or painful grade 2 or greater peripheral neuropathy. Conditioning consisted of Vel 1.6 mg/m2 intravenously on days -4 and -1 with Mel 200 mg/m2 on day -2. Thal was given on days -5 through -1 and was administered in a planned step-wise dose escalation of 600, 800 and 1000 mg (in cohorts of 3 pts). Dexamethasone (Dex) 10-20 mg was given prior to Vel and Mel. All pts received G-CSF every other day starting day +3 until engraftment. Serious adverse events (SAEs) were graded according to CTCAE version 3. Results: Twenty-nine pts were enrolled: 9 in the phase 1 dose-escalation phase and an additional 20 pts in phase 2. In the phase I portion, all pts experienced somnolence, with grade 3 occurring in 1 pt at the 800 mg/day dose. Subsequently, Dex 40 mg was given with first dose of Thal at the 1000 mg level with decreased severity of somnolence. No dose limiting toxicities defined as ≥ grade 4 non-hematological SAEs occurred in the phase I portion, allowing full dose escalation with 9 pts enrolled. The maximum tolerated dose for Thal was not reached and the 1000 mg dose was chosen for the phase 2 dose expansion. No regimen related mortality occurred in either phase I or phase II portion of the study. All SAEs except lethargy and dizziness occurred after ASCT and were not attributed to Thal. The most common grade 1 and 2 non-hematologic toxicities included nausea (65.5%), mucositis (51.7%), diarrhea (48.3%), somnolence (48.3%), lethargy (27.6%), and vomiting (17.2%). The most common grade 3 non-hematologic adverse events (AEs) were neutropenic fever (58.6%), mucositis (6.9%), and somnolence (13.8%), which increased risk of falls. SAEs included somnolence (13.8%), tumor lysis syndrome (3.4%), and engraftment syndrome (3.4%). All transplant-related SAEs resolved by day +28 after ASCT. All pts achieved prompt hematological recovery with the median time to ANC >500/uL 10 days (range, 8-14 days), and platelet >20,000 12 days (range 9-26 days). All pts received at least one ASCT prior to enrolling on the study. Seventeen pts (59%) had interim salvage chemotherapy between their upfront and Mel/Vel/Thal ASCT (i.e. received a salvage ASCT), with median time from first to salvage ASCT 29 months. The remaining 12 (41%) went directly from an upfront ASCT Mel-based ASCT to the Mel/Vel/Thal ASCT (tandem ASCT) within 6 months of the first ASCT. Twenty-seven (93%) were Durie-Salmon stage III, and 13 (44%) had >2 prior lines of therapy. Of those who had Mel/Vel/Thal as a salvage ASCT, 70% had ≥3 prior lines of therapy. The overall response rate (ORR) was 69% with 38% complete remission. ORR for Mel/Vel/Thal compared to upfront Mel ASCT was 69% versus 62% with 11 patients achieving CR with Mel/Vel/Thal compared to 5 patients with Mel alone (Figure 1). Ten of 27 evaluable patients (37%) had an upgrade in response in the Mel/Vel/Thal salvage ASCT compared to their upfront ASCT: 2 pts (7%) went from PD to PR, 1 (4%) from SD to CR, 1 (4%) from PR to VGPR; 3 (11%) from PR to CR and 2 (7%) from VGPR to CR. Median PFS and OS were 9.3 and 65.4 months, respectively, with a median follow-up of 17.8 months. Of those who underwent tandem Mel followed by Mel/Vel/Thal ASCT the median PFS was 14.9 months with a median OS not yet reached at time of analysis. For the 17 patients who received a salvage Mel/Vel/Thal ASCT, median PFS from their upfront ASCT was 11.9 months, compared to 9.1 months with the salvage Mel/Vel/Thal ASCT. Conclusions: High-dose Thal up to 1000 mg daily for 5 days can be safely combined with Vel and dose-intense Mel as an ASCT conditioning regimen with acceptable toxicities. Confirmation of potential synergistic effects of this combination regimen will require an appropriately designed phase III study. Figure 1 Figure 1. Disclosures Biran: BMS: Research Funding; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Siegel:Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Phase I and Pharmacologic Study of Oral (PEG-1000) 9-Aminocamptothecin in Adult Patients With Solid Tumors

1999 ◽  
Vol 17 (7) ◽  
pp. 2219-2219 ◽  
Author(s):  
Maja J.A. de Jonge ◽  
Cornelis J.A. Punt ◽  
A. Hans Gelderblom ◽  
Walter J. Loos ◽  
Vera van Beurden ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Topoisomerase I ◽  
High Performance ◽  
Specific Inhibitor ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Time Curve ◽  
Phase Ii Studies

PURPOSE: 9-Amino-20(S)-camptothecin (9-AC) is a specific inhibitor of topoisomerase-I. Recently, a bioavailability of approximately 48% for the oral PEG-1000 formulation was reported. We conducted a phase I and pharmacokinetic study of the oral PEG-1000 formulation of 9-AC to define the maximum-tolerated dose, toxicity profiles, pharmacokinetic-dynamic relationships, and preliminary antitumor activity in patients with solid tumors. PATIENTS AND METHODS: Patients were treated with oral (PEG-1000) 9-AC given once a day for 7 or 14 days at doses ranging from 0.25 to 1.1 mg/m2/d; cycles were repeated every 21 days. For pharmacokinetic analysis, plasma sampling was performed on days 1 and 6 or 8 of the first course using a validated high-performance liquid chromatographic assay. RESULTS: Thirty patients were entered onto the study; three patients were not assessable for toxicity and response. Twenty-seven patients received a total of 89 courses. The dose-limiting toxicities (DLTs) were myelosuppression and diarrhea at a dose of 1.1 mg/m2/d for 14 days. Pharmacokinetics showed a substantial interpatient variation of the area under the plasma concentration-time curve (AUC) of 9-AC. The intrapatient variability was extremely small. A significant correlation was observed between the percentage decrease in WBC count and the AUC of 9-AC lactone (r2 = 0.86). One partial response was noted in a patient with metastatic colorectal cancer. CONCLUSION: DLTs in this phase I study of oral 9-AC daily for 14 days every 21 days were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m2/d. In view of the substantial interpatient variability in AUC and the availability of a limited sampling model, a pharmacokinetic guided phase II study should be considered.

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.

Phase I trial of combination becatecarin and oxaliplatin in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2561-2561
Author(s):  
S. Manda ◽  
C. Mauser ◽  
J. Bokar ◽  
M. Cooney ◽  
J. Brell ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Performance Status ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Level 2

2561 Background: Becatecarin (rebeccamycin analogue-RA) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase II and I as well as DNA intercalating properties. We performed a phase I trial to a) determine the maximum tolerated dose (MTD) of RA in combination with oxaliplatin; b) determine the dose limiting toxicities (DLT) (c) obtain data on pharmacokinetics and (d) observe for any antitumor activity. Methods: Eligibility criteria included patients with advanced solid tumors refractory to standard therapy; performance status 0–2; adequate hematologic, renal and liver function. Patients were treated with RA as a 1 hour infusion daily x 5 and oxaliplatin on day 5 only, after RA infusion. Treatment was repeated q 21 days. The following dose levels were evaluated: Dose level 1: RA 80 mg/m2/d and oxaliplatin 90 mg/m2; Dose level 2: RA 80 mg/m2/d and oxaliplatin 130 mg/m2; Dose level 3: RA 110 mg/m2/d and oxaliplatin 130 mg/m2. Results: A total of 15 evaluable patients were enrolled. Median age was 56 (8 male, 7 female). A variety of tumor types were enrolled. A total of 56 cycles were administered. DLT occurred at a dose of RA at 110 mg/m2/d x 5 days and oxaliplatin at 130 mg/m2 and consisted of grade 3 hypophosphatemia and grade 4 atrial fibrillation. At this dose level 2 of 3 enrolled patients also developed grade 3 neutropenia. The MTD and recommended phase II dose was RA at 80 mg/m2/daily x 5 along with oxaliplatin 130 mg/m2 day 5 q 21 days. Three confirmed partial responses were observed in patients with hepatocellular, gallbladder and esophageal cancers. Six patients experienced stable disease. Conclusions: At the MTD combination RA and oxaliplatin is well tolerated and given the response rate and stable diseases observed, phase II studies are recommended. Supported by Grants U01 CA62502, MO1-RR-00080, K23 CA109348–01 from the National Institutes of Health. No significant financial relationships to disclose.

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