Phase I pharmacokinetic(PK)/food effect and safety study of satraplatin in patients (pts) with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12014-12014
Author(s):  
B. J. George ◽  
A. D. Ricart ◽  
E. Calvo ◽  
Q. Chu ◽  
J. Sarantopoulos ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Phase Iii ◽  
Fed State ◽  
Fasted State ◽  
Heavily Pretreated ◽  
Effect Of Food ◽  
Hormone Refractory ◽  
Grade 3 ◽  
Tumor Types

12014 Background: Satraplatin (S) is a novel oral platinum analog that has demonstrated preliminary activity in hormone refractory prostate cancer (HRPC). A large (950 pts) worldwide, randomized phase III trial evaluating S as 2nd line therapy for HRPC recently completed enrollment. The current study was designed to determine the PKs of S under fasted and fed conditions, as well as treatment efficacy and toxicity. Methods: S was administered orally at 80 mg/m2/day (d) on d1–5 q 35 days, with prophylactic antiemetics. For the 1st cycle, pts were randomized to receive d1 and d5 doses of S in either the fed or fasted state when PK sampling was performed. The fed/fasted state was reversed for the 2nd cycle. Subsequent doses of S were given in the fasted state. Results: 17 pts were enrolled (9M/8F), median age 62 (range 33–78) and tumor types: HRPC (7), breast (3), 1 each with anal, parotid, leiomyosarcoma, Merkel cell, ovarian, mesothelioma, and neuroendocrine tumor. The median no. of prior regimens was 3 (range 1–8). A total of 58 cycles of S were given. Grade 3–4 hematologic toxicities (1st 2 cycles) included: neutropenia (11%), thrombocytopenia (24%) and anemia (24%). The hematologic nadir occurred during week 4. There was no grade 3–4 nausea, vomiting or diarrhea. No significant cardiac, renal, hepatic, or neurologic toxicity was observed. The peak plasma concentration (Cmax) for platinum in plasma ultrafiltrate (PUF) was decreased by 20% when S was administered following a high fat meal compared to the fasting condition. There was no effect of food on AUC0–24 hr. The time of Cmax (Tmax) was delayed in the fed state. Table shows PK parameters. One PR (HRPC) and 4 SD ≥ 5 months (breast, ovarian, parotid and HRPC) were confirmed. Conclusions: There is an effect of food on the Cmax, however the clinical implications are unknown at this time. For this reason, it is recommended that S be administered to pts in the fasting state. At the dose of 80 mg/m2/day, S was well tolerated in this group of heavily pretreated patients. [Table: see text] [Table: see text]

A phase I dose escalation safety and pharmacokinetic (PK) study of SSR244738 administered as a one-hour intravenous (IV) infusion twice-weekly during a 3-week cycle in patients (pts) with refractory solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2539-2539
Author(s):  
N. Isambert ◽  
G. Spitaleri ◽  
P. Fumoleau ◽  
C. Noberasco ◽  
C. Ramazeilles ◽  
...  
Keyword(s):  
Repeated Administration ◽  
Individual Variability ◽  
Distribution Volume ◽  
Weekly Schedule ◽  
Cell Cycle Inhibitor ◽  
Terminal Half Life ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Tumor Types

2539 Background: SSR244738 is a new cytotoxic agent (G2-cell cycle inhibitor). In this first in man study the original schedule of administration was an IV infusion once every 3 weeks (Q3W); and due to the high clearance variability, 1300 mg/m2 was considered the maximum administered dose (MAD). The study was amended to test the twice weekly schedule (D1-D4-D8-D11-D15, every 3 weeks). Methods: Standard escalation was used in cohorts of 3–6 pts. PK profiles (up to T48h or T96h) were obtained in each pt after the 1st and the 5th administration (D1 and D15) of Cycle 1. In the Q3W, there was a trend to lower clearance (CL) in CYP2C9 *3/*3 and *1/*3 genotype pts therefore genotype samples were analyzed at baseline to identify poor metabolizers (PM) and adjust-dosing accordingly. Results: 22 heavily pretreated patients received SSR244738 at doses of 200 (3 pts), 280 (4 pts), 400 (3 pts), 560 (3 pts), 780 (3 pt), 1000 (6 pts; one pt was a PM and received 500 mg/m2). 15 females, 7 males, median age: 60 years (29–82), ECOG: (0:12, 1:9, Unk:1). Main tumor types: ovary, lung, breast, colon and prostate. Nb cycles/pts: > 2 cycles/21 (95%), > 4 cycles/9 (41%), > 6 cycles/6 (27%), > 8 cycles/2 (9%). The most common reason for treatment discontinuation was disease progression. DLT was seen in 2 pts at 1000 mg/m2 dose level: one patient had febrile neutropenia associated with Grade 3 mucositis and the second patient had Grade 3 neutropenia, which caused a treatment delay. Both pts showed high SSR244738 plasma exposures on D15. SD was reported in 11 patients. No CRs or PRs were observed. SSR244738 exhibited an overall low plasma CL (mean [range]: 0.9 [0.3–2.1] L/h). CL slightly decreased with repeated administration. The distribution volume was low [Vss mean (CV%): 11.6 L (30%)] and the terminal half life was long [mean (CV%): 15.6 h (58%)]. No deviation from dose proportionality could be observed, despite the moderate-to-high inter-individual variability (CV<64%) in exposure. Conclusions: SSR244738 is well tolerated with PK profile similar to the Q3W schedule; by changing the schedule of administration we were able to reach the MAD dose (5000 mg/m2/cycle). [Table: see text]

Single-Dose Pharmacokinetics of Indinavir and the Effect of Food

1998 ◽  
Vol 42 (2) ◽  
pp. 332-338 ◽  
Author(s):  
Kuang C. Yeh ◽  
Paul J. Deutsch ◽  
Heidi Haddix ◽  
Michael Hesney ◽  
Vicki Hoagland ◽  
...  
Keyword(s):  
Single Dose ◽  
Renal Clearance ◽  
Dose Range ◽  
Systemic Circulation ◽  
Tubular Secretion ◽  
Fed State ◽  
Fasted State ◽  
Indinavir Sulfate ◽  
Effect Of Food ◽  
Intrinsic Solubility

ABSTRACT Indinavir sulfate is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor indicated for treatment of HIV infection and AIDS in adults. The purpose of this report is to summarize single-dose studies which characterized the pharmacokinetics of the drug and the effect of food in healthy volunteers. Indinavir concentrations in plasma and urine were obtained by high-pressure liquid chromatography and UV detection assay methods. The results indicate that indinavir was rapidly absorbed in the fasting state, with the time to the maximum concentration in plasma occurring at ∼0.8 h for all doses studied. Over the 40- to 1,000-mg dose range studied, concentrations in plasma and urinary excretion of unchanged drug increased greater than dose proportionally. The nonlinear pharmacokinetics were attributed to the dose-dependent oxidative metabolism of first-pass metabolism as well as to metabolism in the systemic circulation. Renal clearance slightly exceeded the glomerular filtration rate, suggesting a net tubular secretion component. At high concentrations in plasma, tubular secretion appeared to be lowered because there was a trend for a decreased renal clearance. Administration of 400 mg of indinavir sulfate following a high-fat breakfast resulted in a blunted and decreased absorption (areas under the concentration-time curves [AUCs], 6.86 μM·h in the fasted state versus 1.54 μM·h in the fed state; n = 10). However, two types of low-fat meals were found to have no significant effect on the absorption of 800 mg of indinavir sulfate (AUCs, 23.15 μM·h in the fasted state versus 22.71 and 21.36 μM·h, respectively, in the fed state; n = 11). Immediately following dosing, the concentrations of indinavir in urine often exceeded its intrinsic solubility. To reduce the risk of nephrolithiasis, it is recommended that indinavir sulfate be administered with water.

A multicentric phase II randomized trial of docetaxel (D) plus estramustine (E) versus docetaxel (D) as first line chemotherapy for patients (pts) with hormone-refractory advanced prostate cancer (HRPC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4625-4625 ◽  
Author(s):  
O. Caffo ◽  
T. Sava ◽  
E. Comploj ◽  
A. Fariello ◽  
F. Zustovich ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Synergistic Activity ◽  
Eligibility Criteria ◽  
Psa Progression ◽  
Hormone Refractory ◽  
Grade 3 ◽  
Anticoagulant Prophylaxis ◽  
Ecog Ps

4625 Background: D is presently considered a standard treatment for HRPC pts. E has shown a synergistic activity with D in vitro, however the role of D+E combination remains to be defined in the clinical practice. We attempted to evaluate the activity, in terms of PSA decline (PSA↓), the safety and quality of life (QoL) of D ± E in HRPC pts. Methods: eligibility criteria were: HRPC diagnosis, hormone-refractory advanced disease (PSA progression after at least two hormonal therapy), ECOG PS ≤ 2, adequate renal, hepatic and hematological functions. Pts were randomized to D 70 mg/m2 IV d1 q3w (arm A) or D 70 mg/m2 IV d1 q3w + E 280 mg/TID PO starting 1 day prior to D, for 5 consecutive days (arm B). The treatments were planned until best PSA response achievement or PSA progression. No anticoagulant prophylaxis was planned in ARM B pts. Qol was assessed by self-filled questionnaires during the treatment. Results: Between 04/2003 and 09/2005, 95 pts (median age 69 years, range 48–86, median PSA 80 ng/ml, range 5–2166 and measurable disease in 45) were randomized to arm A (49) or arm B (46). To date, 9 pts and 6 pts are still on treatment in arm A and B respectively. In arm A, pts received 257 cycles (median 5, range 1–14) with only 10 (3.9%) delays ≥ 7 days. In arm B, pts received 317 cycles (median 7, range 0–20) with only 15 (4.7%) delays. Median follow-up was 19.5 months. Grade 3–4 hematological toxicities consisted of neutropenia, 4% in arm A and 8% in B, anemia, 0% and 2% respectively and 1 pt with febrile neutropenia and grade 3 diarrhea (Arm B). Grade 3−4 non-hematologic toxicities were vomiting (1 pt) in arm A, stomatitis (2 pts) and vomiting (1 pt) in arm B. Two cases of stroke were reported in arm A. Responses, in terms of PSA↓ >50% were: 43% in arm A and 70% in arm B with PSA normalization in 8% and 38% respectively. Progression free survival (biochemical) was 20 weeks in arm A and 31 in B. Analysis concerning QoL outcomes is planned at the treatment completion of all pts. Conclusions: D-based regimens are active in HRPC with a low toxicity profile. From this preliminary data, DE combination appears promising, in terms of activity and tolerability so, front-to-front formal comparison in a phase III trial can be recommended. No significant financial relationships to disclose.

Lubiprostone: A Chloride Channel Activator for Treatment of Chronic Constipation

2007 ◽  
Vol 41 (6) ◽  
pp. 957-964 ◽  
Author(s):  
Emily M Ambizas ◽  
Regina Ginzburg
Keyword(s):  
Chloride Channel ◽  
Chronic Constipation ◽  
Peak Plasma ◽  
Pediatric Population ◽  
Peak Plasma Concentration ◽  
Data Sources ◽  
Phase Iii ◽  
Controlled Study ◽  
Efficacy And Safety ◽  
Channel Activator

OBJECTIVE: To review lubiprostone's pharmacology, pharmacokinetics, efficacy, and safety in the treatment of chronic constipation. DATA SOURCES: A literature search was conducted using PubMed/MEDLINE (1966–January 2007), IngentaConnect, and International Pharmaceutical Abstracts (1977–January 2007). Key words used included lubiprostone, Amitiza, and chronic constipation. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources that were published in English were evaluated. DATA SYNTHESIS: Lubiprostone is a chloride channel activator approved by the Food and Drug Administration for the treatment of chronic constipation. A randomized, double-blind, parallel-group, placebo-controlled study evaluating the effect of lubiprostone on gastric function showed slowed gastric emptying and increased small bowel and colonic transit time. Peak plasma concentration was shown to be around 1.14 hours, with a majority of the drug excreted in the urine within 48 hours. Phase III trials have noted that most patients with chronic constipation have a spontaneous bowel movement within 24 hours after taking lubiprostone. The most common adverse events in these trials were nausea, diarrhea, abdominal pain, and headache. Lubiprostone use has not been studied in the pediatric population. CONCLUSIONS: Lubiprostone may be a reasonable alternative for use in patients who either fail or are intolerant of standard therapy for chronic constipation. Head-to-head comparison studies with conventional therapy are needed to contrast clinical efficacy and safety of this medication.

Phase III, randomized, open-label study of triweekly docetaxel versus biweekly docetaxel as treatments for advanced hormone-refractory prostate cancer: Findings from an interim safety analysis of the Finnish Uro-oncological Group Study 1-2003.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 129-129
Author(s):  
P. Hervonen ◽  
H. Joensuu ◽  
T. K. Joensuu ◽  
P. Nyandoto ◽  
M. Luukkaa ◽  
...  
Keyword(s):  
Adverse Events ◽  
Performance Status ◽  
Safety Analysis ◽  
Similar Efficacy ◽  
Multicenter Trial ◽  
Phase Iii ◽  
Open Label ◽  
Serious Adverse Events ◽  
Hormone Refractory ◽  
Grade 3

129 Background: Docetaxel (T) administered at every three weeks is standard treatment for advanced HRPC. We compared 2-weekly to 3-weekly T as first- or second-line chemotherapy of advanced HRPC in this prospective randomized multicenter trial. Methods: 360 pts were randomly allocated to receive T 75 mg/m2 i.v. d1 q3 wks (tT) or 50 mg/m2 i.v. d1 and d 14, q4 wks (bT) from March 2004 to May 2009. Prednisolon 10 mg/day was administered in both groups. The groups were well balanced according to the WHO performance status, mean age (70 vs. 68, range 45–87), and the median serum PSA level at study entry (109 vs. 98 μ g/L, range 11–1,490). The primary endpoint was TTF. Study identifier: NCT00255606 . Results: 158 pts (tT, 79; bT, 79) were included in this preplanned interim safety analysis. 567 and 487 cycles were administered in the tT and bT groups, respectively. The most common grade 3–4 adverse events (expressed as %/cycles) in tT /bT were neutropenia 20%/14%, infection with/without neutropenia 8%/3%, fatigue 3%/ 3%, febrile neutropenia 2%/1%, and bone pain 2%/1%. Serious adverse events occurred more frequently in tT (n=60, 10.6% of cycles) than in bT (n=29, 6.0%, p=0.012). One pt. died from coronary infarction and one was diagnosed with ALL (both in bT group). 30 pts (38%) in bT group and 22 pts (28%) in tT group were receiving treatment at 6 months. (p=0.176). Conclusions: Biweekly T has been better tolerated than the conventional triweekly T with fewer serious adverse events and may be associated with similar efficacy. [Table: see text]

scholarly journals Effects of Food on the Relative Bioavailability of Lapatinib in Cancer Patients

2009 ◽  
Vol 27 (8) ◽  
pp. 1191-1196 ◽  
Author(s):  
Kevin M. Koch ◽  
Nandi J. Reddy ◽  
Roger B. Cohen ◽  
Nancy L. Lewis ◽  
Bonnie Whitehead ◽  
...  
Keyword(s):  
Systemic Exposure ◽  
Random Order ◽  
Relative Bioavailability ◽  
High Fat ◽  
Low Fat ◽  
Time Curve ◽  
Fed State ◽  
Fasted State ◽  
Concentration Time ◽  
Effect Of Food

Purpose This study was conducted to characterize the effect of food on the relative bioavailability of lapatinib. Patients and Methods A single 1,500-mg, oral dose of lapatinib was administered to 27 patients with advanced solid tumors on each of three occasions that were 1 week apart, in random order: after an overnight fast, with a low-fat breakfast, and with a high-fat breakfast. Results The low-fat breakfast produced mean increases in lapatinib area under the concentration-time curve (AUC) of 167% (2.67-fold) and maximum concentration (Cmax) of 142% (2.42-fold). The high-fat breakfast produced mean increases in lapatinib AUC of 325% (4.25-fold) and Cmax of 203% (3.03-fold) compared with the fasted state. Increased bioavailability in the fed state did not significantly decrease relative variability. Therefore, absolute variability in systemic exposure was increased. Conclusion These large increases in lapatinib bioavailability and absolute variability support the recommendation for dosing in the fasted state to achieve consistent therapeutic exposure. Prescribers and patients should consider the potential consequences of toxicity or diminished efficacy that might result from dosing without regard to variations in diet.

A Phase 1, Open Label Study To Evaluate The Drug Interaction Potential With Ketoconazole and The Effect Of Food On The Plasma Pharmacokinetics Of The Smoothened Inhibitor PF-04449913

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3857-3857
Author(s):  
M.Naveed Shaik ◽  
Robert R LaBadie ◽  
Dan Rudin ◽  
Wendy J. Levin
Keyword(s):  
Geometric Mean ◽  
Random Effect ◽  
Geometric Mean Ratio ◽  
Open Label ◽  
Post Dose ◽  
Fed State ◽  
Fasted State ◽  
Effect Of Food ◽  
Plasma Pharmacokinetics ◽  
Anti Fungal

Abstract Introduction PF-04449913 is a potent and selective inhibitor of the Hedgehog signaling pathway through binding to the target, Smoothened (SMO). PF-04449913 inhibits Hedgehog (Hh) signaling ex vivo and has demonstrated anti-tumor activity in vivo. PF-04449913 is currently under clinical evaluation in the AML and high risk MDS patient populations, who receive anti-fungal agents routinely as prophylaxis. The preferred anti-fungal agents are azoles which are known strong CYP3A4 inhibitors. Preliminary assessment using individual recombinant P450 enzymes suggests that CYP3A4 plays a major role in mediating the metabolism of PF-04449913. Preliminary results show that PF-04449913 does not inhibit CYPs .Thus, one of the goals of this study was to understand the potential drug-drug interaction (DDI) impact of a strong CYP3A4 inhibitor (ketoconazole) on PF-04449913 plasma exposure to provide dosing guidance. An additional objective was to estimate the effect of a high fat, high calorie meal on single dose PF-04449913 plasma pharmacokinetics (PK). Methods This was an open label, 2-sequence, 3-period, 3-treatment arm, single dose, crossover study in healthy volunteers. Subjects were randomized to receive single doses of 200 mg PF-04449913 in either the fasted or fed state during Periods 1 or 2 with a washout period of at least 8 days between treatments. Subsequently, in Period 3, all subjects received a fixed regimen of ketoconazole (400 mg/day) from Days 1 to 7 and a co-administered single 200 mg PF-04449913 dose on Day 4. Serial blood sampling to determine plasma concentrations of PF-04449913 was performed to 120 hours post dose in Periods 1 and 2, and to 144 hours post dose in Period 3. PF-04449913 in the fasted state was the Reference treatment for both comparisons, while PF-04449913 in the fed state and PF-04449913 + ketoconazole were the Test treatments. Natural log transformed AUCinf (area under the plasma concentration versus time curve from time zero to infinity) and Cmax (maximum observed plasma concentration) for PF-04449913 were analyzed using a mixed effects model with sequence, period and treatment as fixed effects and subject within sequence as a random effect for the effect of food. For the DDI, natural log transformed AUCinf and Cmax for PF-04449913 were analyzed using a mixed effects model with treatment as a fixed effect and subject as a random effect. The adjusted mean differences and 90% confidence intervals (CIs) for the differences from both models were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. Results PF-04449913 exposure was increased in the presence of ketoconazole, with a geometric mean ratio for AUCinf of 2.40 (90% CI: 2.15 -2.68) and for Cmax of 1.40 (90% CI: 1.24-1.58). For PF-04449913 alone and with ketoconazole, Cmax occurred 1.0 and 2.0 hours after dosing, respectively. The geometric mean ratio for AUCinf for fed state compared to the fasted state was 0.87 (90% CI: 0.78 -0.97) and for Cmax was 0.66 (90% CI: 0.56-0.78). In the fasted and fed state, the PF-0444913 Cmax occurred at 1.0 and 4.0 hours after dosing, respectively. All adverse events (AE) were mild in severity except for one case of moderate AE accelerated idioventricular rhythm in an individual with underlying cardiac issues, which was classified as non-treatment related. Conclusions PF-04449913 plasma exposures and peak concentrations were increased (2.40-fold for AUCinf and 1.40-fold for Cmax) following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for the PF-04449913 plasma exposures expected with potent metabolic inhibition and define PF-04449913 dosing parameters in AML and high-risk MDS patient trials. While PF-04449913 plasma exposures and peak concentrations were decreased following administration of PF-04449913 in the fed state, the difference in exposures under the fed and fasted conditions was not considered clinically meaningful. Disclosures: Shaik: Pfizer: Employment, Stock Other. LaBadie:Pfizer: Employment, Stock Other. Rudin:Pfizer: Employment. Levin:Pfizer Oncology Business Unit: Employment.

Glufosfamide (GLU) plus gemcitabine (GEM) in advanced solid tumors: Phase 1 results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14022-14022
Author(s):  
E. G. Chiorean ◽  
T. Dragovich ◽  
J. T. Hamm ◽  
V. K. Langmuir ◽  
S. Kroll ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Karnofsky Performance Status ◽  
Phase 1 ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Heavily Pretreated ◽  
Isophosphoramide Mustard ◽  
Grade 3 ◽  
Tumor Types

14022 Background: Glufosfamide is glucose linked to isophosphoramide mustard, the active metabolite of ifosfamide. Cancer cells use glucose at a higher rate than normal cells, which may lead to preferential metabolic targeting by GLU. GLU has shown activity in patients (pts) with pancreatic cancer in Phase 1/2 studies with the dose-limiting toxicities (DLT) being nephrotoxicity and neutropenia. The MTD was 4500 mg/m2. In preclinical studies, GLU has shown additive activity when combined with GEM. The objectives of this study are to establish the maximum tolerated dose (MTD) and to evaluate the safety, efficacy and PK of GLU + GEM in advanced solid tumors. Methods: Eligible pts had Karnofsky Performance Status ≥70, no prior GEM, at least one lesion by RECIST, creatinine clearance (CrCL) ≥60 mL/min and acceptable hematologic and liver function. Cohorts of 3–6 patients were treated with GLU 1500–4500 mg/m2 IV over 4 hours on Day 1 and GEM 1000 mg/m2 IV over 30 minutes on Days 1, 8 and 15 of every 28-day cycle for up to 6 cycles. CT scans were obtained every 8 weeks. Detailed PK sampling was performed. Results: Nineteen pts with pancreatic (8), gall bladder (4) and other (7) cancers were enrolled. Two DLTs have occurred: Grade 3 fatigue at 2500 mg/m2 and Grade 4 thrombocytopenia at 4500 mg/m2. Both cohorts were expanded. No DLTs occurred in the 1500 or 3500 mg/m2 cohorts. Three pts completed all 6 cycles and 3 pts continue on study. Reasons for early discontinuation were progressive disease (10), clinical deterioration (1), AE (1) and death (1). Grade 3/4 neutropenia occurred in 7 pts (5 during Cycle 1) and Grade 3/4 thrombocytopenia in 5 pts (2 during Cycle 1). The CrCL fell below 60 mL/min in one patient. No objective tumor responses have been reported; 10 of 18 (56%) evaluable pts had stable disease (SD) at 8 weeks, including 1 pt with heavily pretreated ovarian cancer with ongoing SD after 8 months on therapy. PK analyses suggest no interaction between GLU and GEM. Conclusions: Phase 1 data indicate that full dose GLU (4500 mg/m2) can be given safely in combination with GEM. Both early and delayed Grade 3/4 thrombocytopenia and neutropenia have been observed. A Phase 2 cohort of 28 pts with pancreatic adenocarcinoma is currently enrolling. Studies with GEM/GLU in other tumor types are planned. [Table: see text]

Docetaxel (D) and estramustine (E) as first-line chemotherapy for patients (pts) with hormone-refractory advanced prostate cancer (HRPC): Final results of a multicentric phase II randomized trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15552-15552 ◽  
Author(s):  
O. Caffo ◽  
T. Sava ◽  
E. Comploj ◽  
M. Giampaolo ◽  
F. Zustovich ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Psa Response ◽  
Psa Progression ◽  
Hormone Refractory ◽  
Grade 3 ◽  
Ecog Ps

15552 Background: Preclinical data showed a synergism between E and D and several studies supported an advantage in associating E and D. Nevertheless, D is considered a standard treatment for HRPC pts and the role of D+E combination remains controversial. Purpose of this study was to evaluate the activity, in terms of PSA decline (PSA↓), the safety and quality of life (QoL) of D±E in HRPC pts. Methods: Eligibility criteria included: HRPC diagnosis, hormone-refractory advanced disease (PSA progression after at least two hormonal therapy), ECOG PS < 2, adequate renal, hepatic and hematological functions, no prior chemotherapy. Pts were randomized to D 70 mg/m2 IV d1 q3w (arm A) or D 70 mg/m2 IV d1 q3w + E 280 mg/TID PO starting 1 day prior to D, for 5 consecutive days (arm B). The treatments were planned until best PSA response achievement or PSA progression. Toxicity was recorded according to NCIC criteria. Qol was assessed by self-filled questionnaires during the treatment. Results: Between 04/2003 and 09/2005, 95 pts (median age 69 years, range 48–86, median PSA 80 ng/ml, range 5–2,166 and measurable disease in 45) were randomized to arm A (49) or arm B (46). In arm A, pts received 321 cycles (median 6, range 0–28) with only 13 (4 %) delays = 7 days. In arm B, pts received 338 cycles (median 7, range 0–20) with only 16 (4.7%) delays. Grade 3–4 hematological toxicities consisted of neutropenia, 4% in arm A and 6% in B. One pt in arm B had febrile neutropenia and grade 3 diarrhea. Grade 3–4 non-hematologic toxicities were vomiting (1 pt in both arms), stomatitis (1 pt in arm A and 2 pts in B) and diarrhoea (1 pt in arm B). Two cases of stroke were reported in arm A. No treatment related death was recorded. Responses, in terms of PSA↓ >50% were: 40% in arm A and 75%in arm B with PSA normalization in 5% and 32% respectively. After a median follow-up of 17 months, 65 patients are died (31 in Arm A and 34 in Arm B). Progression free survival (biochemical) was 20 weeks in arm A and 30 in B. Conclusions: D-based regimens are active in HRPC with a manageable toxicity profile. From this preliminary data, DE combination appears promising, in terms of activity and tolerability so, front-to-front formal comparison in a phase III trial can be recommended. No significant financial relationships to disclose.

Atezolizumab (atezo) plus platinum-based chemotherapy (chemo) in non-small cell lung cancer (NSCLC): Update from a phase Ib study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9092-9092 ◽  
Author(s):  
Stephen V. Liu ◽  
D. Ross Camidge ◽  
Scott N. Gettinger ◽  
Giuseppe Giaccone ◽  
Rebecca Suk Heist ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Phase Iii ◽  
Clinical Activity ◽  
Multiple Tumor ◽  
Grade 5 ◽  
Platinum Based Chemotherapy ◽  
Potential Synergy ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Tumor Types

9092 Background: Platinum-based chemo is a standard first-line (1L) therapy for NSCLC lacking actionable gene alterations. Preclinical evidence suggests that chemo can play an immunomodulatory role and induce tumor antigen release, supporting combining chemo with immunotherapy. Atezo is a humanized and Fc-region-modified monoclonal anti-programmed death-ligand-1 (PD-L1) antibody that blocks interaction with PD1 or B7.1. The GP28328 study (NCT01633970) assessed safety and efficacy of atezo plus 1L chemo regimens in multiple tumor types. Methods: In this multicenter, multi-arm study, patients (pts) with locally advanced or metastatic NSCLC with no prior chemo for advanced disease received 15 mg/kg atezo IV q3w with standard doses of chemo (Arm C: carboplatin [carbo]+paclitaxel q3w; Arm D: carbo+pemetrexed q3w; Arm E: carbo+nab-paclitaxel qw) all for ≤6 cycles followed by atezo maintenance until loss of clinical benefit (+ pemetrexed maintenance until progression, Arm D). The primary endpoint was safety; secondary endpoints were overall response rate (ORR), PFS, and OS. Results: By the 30 Aug 2016 cut-off, 76 NSCLC pts were evaluable (n = 25, 25, 26 for Arms C, D, E, respectively). At this cut-off, the most common treatment-related grade 3–4 adverse events (AEs) were neutropenia (36% C, 36% D, 42% E) and anemia (16% C, 16% D, 31% E). Three potentially related grade 5 AEs were seen (arm C: pneumonia; arm D: systemic candida; arm E: autoimmune hepatitis). Confirmed ORRs were 36%, 64%, 46% for Arms C, D (1 CR), and E (4 CR). Median PFS (95% CI) was 7.1 months (4.2–8.3) for C, 8.4 months (4.7–11) for D, and 5.7 months (4.4–14.8) for E. Median OS (95% CI) was 12.9 months (8.8–not evaluable) for C, 19.3 months (14.7–27.4) for D, and 14.8 months (12.7–not evaluable) for E. Conclusions: Atezo was well tolerated when combined with various chemo regimens for advanced NSCLC. Clinical activity in terms of ORR was favorable supporting potential synergy between atezo and chemo. PFS and OS data show promising benefits, but are limited by small numbers and wide confidence intervals. Phase III studies that include chemotherapy and atezolizumab are currently ongoing. Clinical trial information: NCT01633970.

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