A Phase I Study of OMN54 (Aneustat™) in Patients with Advanced Malignancies

2020 ◽  
Vol 7 (2) ◽  
pp. 125-132
Author(s):  
Karen A. Gelmon ◽  
Christian Kollmannsberger ◽  
Stephen Chia ◽  
Anna V. Tinker ◽  
Teresa Mitchell ◽  
...  
Keyword(s):  
Phase I ◽  
Salvia Miltiorrhiza ◽  
Performance Status ◽  
Parent Drug ◽  
Maximum Tolerated Dose ◽  
Ecog Performance Status ◽  
Advanced Malignancies ◽  
Gi Toxicity ◽  
Adequate Organ Function ◽  
Recommended Phase Ii Dose

Background/Objective: With the increasing interest in natural products, a phase I openlabel study of OMN54 (Aneustat™) in patients with advanced malignancies was initiated to determine toxicity, maximum tolerated dose (MTD), dose limiting toxicities (DLT), and pharmacokinetics (PK). OMN54 is a multitargeted agent, combining three Chinese botanicals; Ganoderma lucidium, Salvia miltiorrhiza and Scutellaria barbata. Methods: Eligible patients (pts) were >18 years of age with advanced solid tumors, able to swallow oral capsules, ECOG performance status < 2, measurable disease as defined by RECIST 1.1 and adequate organ function. Results: Twenty-two patients were enrolled in 6 dose levels, 2 with daily dosing and 4 with twicedaily dosing ranging from 1 to 5 grams daily. All were evaluated for toxicity and 20 for response. No treatment-related dose-limiting toxicities (DLTs) were reported and the recommended phase II dose (RP2D) was determined to be 2.5 g twice daily. Seven adverse events in 5 patients were reported as possibly drug-related; 6 were GI toxicity and 1 was a skin disorder. All were grade 1 except one grade 2 vomiting. No RECIST responses were seen. Six pts were treated with > 2 cycles; one for 8 cycles. Four patients had reductions in TGF –β and EGF, exploratory biomarkers possibly suggestive of a drug effect. Plasma half-lives of 1 -2 hours were noted for all parent drug chemical markers with no accumulation over time. Conclusion: OMN54 was well tolerated, with no DLTs observed. Further studies at the RP2D will assess the biological activity.

Phase I study of docetaxel injection concentrate for nano-dispersion (DICN), a novel polysorbate 80-free formulation of docetaxel.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2592-2592
Author(s):  
Minish Mahendra Jain ◽  
Chetan Dilip Deshmukh ◽  
Shailesh Arjun Bondarde ◽  
Niraj Bhatt ◽  
Ganesh Divekar
Keyword(s):  
Phase I ◽  
Small Cell Lung Carcinoma ◽  
Performance Status ◽  
Metastatic Breast ◽  
Maximum Tolerated Dose ◽  
Polysorbate 80 ◽  
Cell Lung Carcinoma ◽  
Advanced Malignancy ◽  
Adequate Organ Function ◽  
Recommended Phase Ii Dose

2592 Background: A polysorbate 80-free formulation of docetaxel may preclude the need for dexamethasone pre-medication and may also reduce toxic effects associated with polysorbate 80. DICN is a novel polysorbate 80-free formulation of docetaxel stabilized with lipid and polymer using NanotectonTM technology. We studied safety, tolerability, and the pharmacokinetics (PK) of DICN in patients with advanced solid malignancies. Methods: Entry criteria included: age 18-65 years, histologically/cytologically confirmed advanced malignancy, performance status ≤ ECOG 2, estimated survival ≥ 12 weeks, and adequate organ function. A standard phase I 3+3 dose escalation schema was employed with an increase of 12.5 to 50% over previous DICN dose level as per safety profile. The infusion was 60 min for 1 cycle and major objectives were to determine maximum tolerated dose (MTD), and PK and safety profiles. Premedication to prevent hypersensitivity was not administered to patients receiving DICN. Three patients were treated with docetaxel 75 mg/m2 to gather PK data. Plasma was analyzed for docetaxel level using a validated assay. Results: Twenty-seven patients treated with DICN had a mean age of 48.8 yrs (range 29-65); 21 were females; and entered with metastatic breast cancer (MBC; n=14), non-small cell lung carcinoma (NSCLC; n=6), ovarian (n=2), and other (n=5). Doses (mg/m2) studied were 60 (n=7), 75 (n=5), 100 (n=3), 125 (n=3), 150 (n=6), and 170 (n=3). Despite lack of dexamethasone premedication, no patient receiving DICN reported a hypersensitivity reaction. Two DLTs (febrile neutropenia) were reported at DICN 170 mg/m2. DICN PK (AUC0-24, AUC0-∞, and Cmax) increased in a dose proportionate manner from 60 to 170 mg/m2. Compared with docetaxel 75 mg/m2, Cmax and AUC0-24 of DICN 75 mg/m2 was 1.4 and 1.2 times higher, respectively, and 1.9 and 1.8 times higher, respectively for DICN 150 mg/m2. The median Tmax of DICN 75 mg/m2 and docetaxel 75 mg/m2 were 1.00 and 0.517 hours, respectively. Conclusions: In this study,DICN demonstrated acceptable tolerability and a favorable PK profile. A 150 mg/m2 is the recommended phase II dose for DICN.

Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of intravenous dimethane sulfonate (DMS612, NSC 281612) in advanced malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2553-2553
Author(s):  
Susan Elaine Bates ◽  
Sanjeeve Balasubramaniam ◽  
Robert A Parise ◽  
Christina Bryla ◽  
William Bonner ◽  
...  
Keyword(s):  
Dna Damage ◽  
Phase I ◽  
Intravenous Infusion ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Lymphocytes ◽  
Ecog Performance Status ◽  
Alkylating Activity

2553 Background: DMS612 is a dimethane sulfonate compound that was identified as preferentially cytotoxic to renal cell carcinoma (RCC) cell lines in a chemical screen of the NCI-60 panel. DMS612 has bifunctional alkylating activity in vitro. Objectives of this first-in-human phase I study included determining the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), PK and PD of DMS612 administered by 10 minute intravenous infusion on day 1, 8 and 15 of a 28 day cycle. Methods: Eligibility criteria included adults with advanced solid malignancies or lymphoma with ECOG performance status 0-2, life expectancy > 3 months and adequate organ and marrow function. Patients were enrolled using a standard “3+3” dose escalation scheme. Plasma PK of DMS612 and metabolites was assessed by LC-MS/MS. DNA damage PD was assessed by γ-H2AX immunofluorescence. Results: 35 subjects were enrolled (22 male, 13 female) with median age 59 years (41-75). Tumor types included colorectal (8), RCC (4), cervix (2), and urothelial (2). Doses administered were 1.5, 3, 5, 7, 9 and 12 mg/m2. The MTD was determined to be 9 mg/m2, with only one DLT of grade 4 thrombocytopenia in 12 subjects enrolled. The maximum administered dose of 12 mg/m2 was considered to be intolerable after 1 of 3 subjects had grade 4 neutropenia and 1 had prolonged grade 3 thrombocytopenia. Prolonged thrombocytopenia in later cycles was observed in other subjects, including one patient naïve to prior cytotoxic chemotherapy. One subject with RCC had a confirmed partial response at 7 mg/m2. DMS612 was rapidly converted into carboxy, chloroethyl and hydroxyethyl analogues and their glucuronides, some of which retained alkylating activity in vitro. Dose-dependent pharmacodynamic evidence of DNA damage induced by DMS612 in vivo was observed by γ-H2AX immunofluorescance in both peripheral blood lymphocytes and plucked scalp hairs. Conclusions: The MTD of DMS12 administered by intravenous infusion on day 1, 8 and 15 of a 28-day cycle was 9 mg/m2. Pre-clinical and clinical observations suggest that further study of DMS612 in RCC is warranted.

Phase I trial of metronomic cyclophosphamide (CTX) and lenalidomide (LEN) in patients with castration-resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 164-164
Author(s):  
Jue Wang ◽  
Timothy R. McGuire ◽  
James K. Schwarz ◽  
Jane L Meza ◽  
James E E Talmadge
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Patient Characteristics ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Level 1 ◽  
Grade 3

164 Background: Angiogenesis and suboptimal antitumor immune response are important in the progression of CRPC. Both LEN and metronomic CTX have known anti-angiogenic and immunomodulatory activities. A phase I study of a novel combination of metronomic CTX with LEN in patients with CRPC who have failed prior docetaxel therapy was initiated to assess safety and effects on potential biomarkers. Methods: CTX was given 50 mg PO QD(day 1-28) and LEN 10-25 mg PO QD(day 1-21) on a 28 day cycle. Dose limiting toxicity was defined as any treatment-related grade 4 hematologic event or grade 3 / 4 non-hematologic event during cycles one. Quantification of circulating tumor cells (CTC), plasma cytokines, analgesic consumption and quality of life assessments were performed. Measurement of Treg and MDSCs were performed in some patients. Results: 17 patients with CRPC have been enrolled in L0-4; all patients are evaluable for toxicity. Patient characteristics include: ECOG performance status 0/1= 4/13; median age=77 (range 50–86); median PSA=36.7 (range 1.36–2287). Dose level 1 (CTX 50 mg/d, LEN 10 mg/d) was expanded to 6 patients after one out of three initial patients was removed from the study for Gr 3 gastrointestinal bleeding (in cycle 1). Dose level 1 (CTX 25 mg/d, LEN 10 mg/d) had no DLT’s. The maximum tolerated dose has not yet been reached. Other Grade 3/4 toxicities observed after cycle 1 included grade 3 pain (N=1), grade 3 neutropenia (N=4), grade 3 thrombocytopenia (N=2), grade 4 neutropenia (N=2). Most frequent grade 1 and 2 toxicities included anemia, fatigue, neutropenia, and hypocalcemia. Overall, 9 of 14 patients (64%) have experienced a reduction in PSA. One patient had partial response after one cycle. Stable disease was documented in 5 of 14 (36%) evaluable patients. Two inflammatory cytokines, IL-6 (N = 19; r = 0.64; p = 0.0035) and IL-8 (N = 9; r = 0.86; p = 0.0028), were found to significantly correlated with PSA. Conclusions: The combination of metronomic CTX and LEN can be safely administered. Preliminary clinical activity was observed in this heavily-pretreated patient population. Enrollment to this study continues and clinical and biomarker studies are ongoing.

Vorinostat in combination with gemcitabine and cisplatinum in patients with advanced non-small cell lung cancer (NSCLC): A Phase I dose-escalation study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8049-8049 ◽  
Author(s):  
J. Trédaniel ◽  
R. Descourt ◽  
D. Moro-Sibilot ◽  
J. Misset ◽  
E. Gachard ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Ecog Performance Status ◽  
Dose Escalation Study ◽  
Platinum Agent ◽  
Elevated Creatinine ◽  
Expansion Cohort ◽  
Dose Levels

8049 Background: Preclinical data indicate that vorinostat, a histone deacetylase inhibitor, enhances the efficacy of gemcitabine and platinum chemotherapy agents. This study investigated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of vorinostat plus gemcitabine and a platinum agent in patients (pts) with advanced NSCLC. Methods: Eligible pts (aged ≥18 years; stage IIIB/IV NSCLC, ECOG performance status ≤1, no prior systemic chemotherapy [except adjuvant]) were sequentially enrolled on escalating doses of vorinostat plus gemcitabine and a platinum agent (standard 3+3 design) for ≤6 cycles ( Table ). Carboplatin regimens were to be investigated if dose levels 1 or 2 exceeded the MTD. Results: 28 pts enrolled to date (M/F: 22/6; median age: [range] 55 [34–70] years; 20 chemonaïve) at 5 dose levels ( Table ). Two pts had DLTs: elevated creatinine leading to cisplatin dose reduction (dose level 2) and febrile neutropenia (dose level 5) ( Table ). Dose level 5 was achieved without reaching the MTD; however, based on clinical tolerability, dose level 4 was chosen as the recommended dose (RD). 24 pts had adverse events (AEs): 86% mild/moderate, 53% not considered treatment-related. The most common drug-related Grade 3/4 AEs were thrombocytopenia (19 events) and neutropenia (14 events). Serious AEs occurred in 15 pts, and 5 deaths occurred (1 ‘probably‘ and 4 ‘definitely not‘ treatment-related). Of 19 evaluable pts at 5 dose levels, 9 (47%) had a partial response, 8 stable disease, and 2 disease progression ( Table ). Updated results of pts treated at the RD in an expansion cohort will be presented. Conclusions: These phase I data suggest that vorinostat can be administered with standard doses of gemcitabine and cisplatin and the combination is active in the initial treatment of metastatic NSCLC: randomized trials are needed to determine whether addition of vorinostat improves outcomes in such pts. [Table: see text] [Table: see text]

Phase I study of a novel capecitabine schedule based on Norton-Simon mathematical modeling

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1045-1045 ◽  
Author(s):  
M. Theodoulou ◽  
T. A. Traina ◽  
U. Dugan ◽  
D. Lake ◽  
M. Fornier ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Metastatic Breast ◽  
Maximum Tolerated Dose ◽  
Ecog Performance Status ◽  
Safe Delivery ◽  
Optimal Dosing ◽  
Ecog Ps

1045 Background: We have previously described a mathematical method to optimize chemotherapy dose and schedule (Norton et al, AACR 2005). Capecitabine (C) has activity in breast cancer when conventionally dosed for 14 days (d) q3 weeks (14/7). However, the predicted optimal dosing schedule for C using our model is 7d followed by a 7d rest (biweekly, 7/7). We tested this hypothesis in a Phase I/II study described below. Methods: Eligible patients (pts) have measurable, metastatic breast cancer (MBC), ECOG performance status (PS) =2 and normal organ function. There is no limit to number of prior chemotherapy (CRx) regimens. Pts with prior fluoropyrimidine for MBC are excluded. HER2+ pts must not be candidates for trastuzumab. C is given in divided daily doses for 7d followed by a 7d rest. A standard “3+3” dose escalation scheme employs flat dosing which begins at 1,500mg BID and increases by 500mg/dose level. Primary endpoint is the maximum tolerated dose (MTD), defined as the highest dose for which the incidence of dose-limiting toxicity (DLT) is <33%. Results: 19 pts are now accrued; 17 pts have been treated, 2 withdrew prior to receiving C. Medians: age 47 y (range 34–62 y) and ECOG PS 0 (range 0–2). Sites of MBC: bone 8, viscera 16, soft tissue 11. ER/PR+ 11. HER2+ or unknown 2. Prior adjuvant tx: CRx 17, hormone tx 10. Six pts had adjuvant fluoropyrimidine-based tx. Three pts had 1 prior CRx for MBC; 12 pts received first-line hormone tx for MBC. Fifteen pts had prior anthracycline and taxane. Treatment-related toxicities after a median of 4 cycles (range 1–10) are shown in the table . The MTD has not been reached. Pts continue accrual to the 2500mg/2500mg dose level. Conclusions: Capecitabine 7/7 is well tolerated and allows for safe delivery of higher daily doses than routinely used in practice, as predicted by the mathematical model. Capecitabine 7/7 will be tested in a Phase II program at MSKCC in combination with targeted agents. [Table: see text] No significant financial relationships to disclose.

A phase I/II study of S-1 plus cisplatin alternating with S-1 plus docetaxel in patients with advanced gastric cancer (AGC).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 101-101
Author(s):  
A. Hosokawa ◽  
K. Ogawa ◽  
S. Kajiura ◽  
Y. Tsukioka ◽  
T. Kobayashi ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Survival Data ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
First Line ◽  
Ecog Performance Status ◽  
Eligibility Criteria ◽  
Starting Dose ◽  
Grade 3

101 Background: S-1 plus cisplatin has been regarded as standard first-line chemotherapy for patients with AGC in Japan, and S- 1 plus docetaxel showed promising results for AGC in clinical trials. To investigate the usefulness of S-1 plus cisplatin alternating with S-1 plus docetaxel as first-line treatment in patients with AGC, we conducted a phase I/II study to determine the maximum tolerated dose (MTD), the recommended dose (RD), preliminary efficacy and toxicity. Methods: Eligibility criteria included pathologically confirmed AGC; no prior chemotherapy; Age 20 to 74, ECOG performance status (PS) of 0 to 2; adequate organ function; and written informed consent. Cisplatin was administered on day1 and the dose was escalated by 10 mg/m2 from starting dose of 40 mg/m2 in phase I part. S-1 was given orally at 80 mg/m2 on day1-14. Docetaxel was administered at 40 mg/m2 on day 22 in combination with S-1 80 mg/m2 on days 22-35. The treatment was repeated every 6 weeks. The RD was studied in every 3-6 patients cohort and determined according to the pre-defined DLTs. Primary endpoint of phase II was the response rate (RR). Results: Between Aug 2006 and Jul 2010, 33 pts were enrolled. Nine patients entered the phase I part and 24 enrolled in phase II part. In the phase I part, the MTD of cisplatin was presumed to be 50 mg/m2, because 50% of patients (3/6) developed DLTs. Therefore, the RD of cisplatin was estimated as 40 mg/m2, and the 27 patients received the treatment at RD level. Patients characteristics were as follows: median age=65 years (range 48-74), Male: female=21:6, PS 0:1:2=11:16:0, diffuse: intestinal=19:8, initially unresectable: recurrent=24:3. The RR was 59.2% (95% CI, 40.7-77.7). Median follow-up period was 14.6 months, median PFS was 7.9 months, and median survival time was 17.2 months, although survival data remain to be confirmed. Major grade 3/4 toxicities were neutropenia (63%), leucopenia (41%), and anemia (33%). These toxicities were tolerable and manageable. No treatment-related death was observed. The updated analysis will be presented at the meeting. Conclusions: This alternating treatment seems to be effective and well tolerated in the first-line treatments in patients with AGC. No significant financial relationships to disclose.

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

1998 ◽  
Vol 16 (7) ◽  
pp. 2494-2499 ◽  
Author(s):  
A M Langevin ◽  
D T Casto ◽  
P J Thomas ◽  
S D Weitman ◽  
C Kretschmar ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Malignant Tumors ◽  
Hepatic Metabolism ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Recommended Phase Ii Dose

PURPOSE A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717.

1986 ◽  
Vol 4 (8) ◽  
pp. 1245-1252 ◽  
Author(s):  
A H Calvert ◽  
D L Alison ◽  
S J Harland ◽  
B A Robinson ◽  
A L Jackman ◽  
...  
Keyword(s):  
Phase I ◽  
Thymidylate Synthase ◽  
Renal Toxicity ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Radiation Recall ◽  
Heavily Pretreated ◽  
Recommended Phase Ii Dose ◽  
The One ◽  
Synthase Inhibitor

CB3717 is a quinazoline antifolate whose cytotoxic activity is mediated by inhibition of thymidylate synthase (TS). A phase I clinical trial commenced in September 1981 and 99 patients have received 296 treatments. Doses were dissolved in 0.15 mol/L NaHCO3 (pH 9.0) at a concentration of 4 mg/mL infused over one hour or in a total volume of 1 L infused over 12 hours. Doses were repeated every 3 weeks. The starting dose of 140 mg/m2 was escalated to 600 mg/m2. Renal toxicity, detected by a decrease in the 51Cr EDTA clearance, was dose-related and occurred in seven of ten patients receiving greater than 450 mg/m2. Reversible hepatic toxicity often associated with malaise occurred in 223 of 288 assessable courses (77%). Fifty-nine courses (20%) were associated with increases in alanine transaminase (ALT) levels to greater than 2.5 times the upper limit of the normal laboratory range. Increases in alkaline phosphatase levels also occurred, but were less marked. The severity and prevalence of these elevations were unaffected by the duration of the infusion. A self-limiting rash appeared in 12 patients and a radiation recall reaction was seen in two. Leukopenia developed in 17 patients (WBC less than 3 X 10(9)/L), and thrombocytopenia occurred in six patients (platelets less than 100 X 10(9)/L). The mean leucocyte nadir occurred on day 10 and was followed by recovery at 11 to 19 days. Neither the incidence nor the severity of any of these latter toxicities was dose related. The maximum tolerated dose was in the region of 600 mg/m2 with renal toxicity being dose limiting, although the inter-patient variation did not allow a precise definition. Seventy-six patients were evaluable for response. Responses occurred at doses greater than or equal to 200 mg/m2 and were ovary, one complete response (CR), one partial response (PR), seven minor responses (MR) in 30 cases; breast, two PRs and one MR in eight cases; adenocarcinoma of the lung, one MR in 5 cases; mesothelioma, one PR in five cases; and colon, two MRs in four cases. CB3717 has activity in heavily pretreated patients. The recommended phase II dose for good-risk patients is 400 mg/m2 using the one-hour infusion schedule of administration.

Phase I/II Trial to Evaluate the Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Combination With Gemcitabine in Patients With Pancreatic Cancer and an ECOG Performance Status of 2

2019 ◽  
Vol 37 (3) ◽  
pp. 230-238 ◽  
Author(s):  
Teresa Macarulla ◽  
Roberto Pazo-Cid ◽  
Carmen Guillén-Ponce ◽  
Rafael López ◽  
Ruth Vera ◽  
...  
Keyword(s):  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Phase Ii ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Ductal Adenocarcinoma ◽  
Tolerability Profile ◽  
Ecog Performance Status ◽  
Actuarial Survival ◽  
Number Of Patients

Purpose Gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel (GA) significantly improved survival compared with gemcitabine alone in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and a Karnofsky performance status (PS) of 70% or greater. Because of the low number of patients with reduced PS, the efficacy of this regimen in fragile patients remains unclear. This study aimed to evaluate the efficacy and tolerability of different GA dosing regimens in patients with a poor PS. Patients and Methods In the phase I part of this study, patients were randomly assigned to one of the following four parallel GA treatment arms (six patients per arm): a biweekly schedule of NAB-paclitaxel (150 mg/m2 [arm A] or 125 mg/m2 [arm C]) plus gemcitabine 1,000 mg/m2 or a standard schedule of 3 weeks on and 1 week off of NAB-paclitaxel (100 mg/m2 [arm B] or 125 mg/m2 [arm D]) plus gemcitabine 1,000 mg/m2. The two regimens with the better tolerability profile on the basis of predefined criteria were evaluated in the phase II part of the study, the primary end point of which was 6-month actuarial survival. Results Arms B and D were selected for the phase II part of the study. A total of 221 patients (111 patients in arm B and 110 patients in arm D) were enrolled. Baseline characteristics including median age (71 and 68 years in arms B and D, respectively), sex (51% and 55% men in arms B and D, respectively), and metastatic disease (88% and 84% in arms B and D, respectively) were comparable between arms. The most frequent grade 3 or 4 toxicities in arms B and D were anemia (12% and 7%, respectively), neutropenia (32% and 30%, respectively), thrombocytopenia (7% and 11%, respectively), asthenia (14% and 16%, respectively), and neurotoxicity (11% and 16%, respectively). In arms B and D, there were no significant differences in response rate (24% and 28%, respectively), median progression-free survival (5.7 and 6.7 months, respectively), and 6-month overall survival (63% and 69%, respectively). Conclusion NAB-paclitaxel administered at either 100 and 125 mg/m2 in combination with gemcitabine on days 1, 8, and 15 every 28 days is well tolerated and results in acceptable safety and efficacy in patients with metastatic pancreatic ductal adenocarcinoma and a poor PS.

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.

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