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.

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.

Multi-Institutional Phase I/II Trial of Paclitaxel, Cisplatin, and Etoposide With Concurrent Radiation for Limited-Stage Small-Cell Lung Carcinoma

2000 ◽  
Vol 18 (5) ◽  
pp. 1102-1102 ◽  
Author(s):  
Nathan Levitan ◽  
Afshin Dowlati ◽  
Donald Shina ◽  
Mark Craffey ◽  
Wilma Mackay ◽  
...  
Keyword(s):  
Phase I ◽  
Overall Response Rate ◽  
Response Rate ◽  
Small Cell Lung Carcinoma ◽  
Maximum Tolerated Dose ◽  
High Response Rate ◽  
Thoracic Radiotherapy ◽  
Cell Lung Carcinoma ◽  
Dose Limiting Toxicity

PURPOSE: To determine the feasibility of adding paclitaxel to standard cisplatin/etoposide (EP) and thoracic radiotherapy. PATIENTS AND METHODS: Thirty-one patients were enrolled onto this study. During the phase I section of this study, the dose of paclitaxel was escalated in groups of three or more patients. Cycles were repeated every 21 days. For cycles 1 and 2, paclitaxel was administered according to the dose-escalation schema at doses of 100, 135, or 170 mg/m2 intravenously over 3 hours on day 1. Once the maximum-tolerated dose (MTD) of paclitaxel (for cycles 1 and 2, concurrent with radiation) was determined, that dose was used in all subsequent patients entered onto the phase II section of this study. For cycles 3 and 4, the paclitaxel dose was fixed at 170 mg/m2 in all patients. On day 2, cisplatin 60 mg/m2 was administered for all cycles. On days 1, 2, and 3, etoposide 60 mg/m2/d (cycles 1 and 2) or 80 mg/m2/d (cycles 3 and 4) was administered. Chest radiation was given at 9 Gy/wk in five fractions for 5 weeks beginning on day 1 of cycle 1. Granulocyte colony-stimulating factors were used during cycles 3 and 4 only. RESULTS: Twenty-eight patients were assessable. The MTD of paclitaxel was 135 mg/m2, with the dose-limiting toxicity being grade 4 neutropenia. Cycles 1 and 2 were associated with grade 4 neutropenia in 32% of courses, with fever occurring in 7% of courses and grade 2/3 esophagitis in 13%. Cycles 3 and 4 were complicated by grade 4 neutropenia in 20% of courses, with fever occurring in 6% of courses and grade 2/3 esophagitis in 16%. The overall response rate was 96% (complete responses, 39%; partial responses, 57%). After a median follow-up period of 23 months (range, 9 to 40 months), the median survival time was 22.3 months (95% confidence interval, 15.1 to 34.3 months) CONCLUSION: The MTD of paclitaxel with radiation and EP treatment is 135 mg/m2 given over 3 hours. In this schedule of administration, a high response rate and acceptable toxicity can be anticipated.

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.

Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors

2010 ◽  
Vol 28 (25) ◽  
pp. 3965-3972 ◽  
Author(s):  
Timothy A. Yap ◽  
Laura Vidal ◽  
Jan Adam ◽  
Peter Stephens ◽  
James Spicer ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Small Cell Lung Carcinoma ◽  
Maximum Tolerated Dose ◽  
Phase Iii ◽  
Advanced Solid Tumors ◽  
Irreversible Inhibitor ◽  
Cell Lung Carcinoma ◽  
Bibw 2992

Purpose Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy. Patients and Methods Patients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state. Results Fifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non–small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting ≥ 6 months. Conclusion Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.

Phase I study of repeated cycles of high-dose cyclophosphamide, etoposide, and cisplatin administered without bone marrow transplantation.

1990 ◽  
Vol 8 (10) ◽  
pp. 1728-1738 ◽  
Author(s):  
J A Neidhart ◽  
W Kohler ◽  
C Stidley ◽  
A Mangalik ◽  
A Plauche ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Performance Status ◽  
Complete Response ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Tumor Type ◽  
Advanced Malignancy ◽  
Prior Therapy ◽  
And Performance

Forty-two patients with advanced malignancy judged unlikely to respond to standard treatment received high-dose combination chemotherapy with cyclophosphamide, etoposide, and cisplatin in a phase I trial. Twenty-two of these patients who had at least a partial response (PR) to the first cycle of therapy received a second cycle, and eight patients received three or more cycles of therapy. Bone marrow replacement was not used. The maximum-tolerated doses (MTDs) were cyclophosphamide 2.5 g/m2 on days 1 and 2; etoposide 500 mg/m2 on days 1, 2, and 3; and cisplatin 50 mg/m2 on days 1, 2, and 3. Hematologic toxicity was not dose-limiting by study design. Recovery to an absolute granulocyte count above 100/microL occurred at a median of 9 days from onset (range, 3 to 23 days) at the MTD. Recovery was delayed after the third cycle. Only one patient on his third cycle failed to recover peripheral blood counts and died of sepsis an day 43. Hematologic toxicity was not dose-dependent. Nonhematologic toxicities included emesis, fatigue, alopecia, diarrhea, and anorexia and were generally well tolerated. The dose-limiting toxicities were fatal pulmonary or cardiac toxicities in five of nine patients treated at the highest dose level. Patients likely to do well can be selected by tumor type, response to prior therapy, and performance status. Nine of 36 assessable patients had a complete response (CR) and 13 a PR for a response rate of 61%. Five patients (12%) remain alive and free of disease at 15 to 32 months. Repeated cycles of dose-intensive combination therapy can produce long-term disease-free remissions in patients with refractory tumor types. The toxicity of the regimen is acceptable if patients are carefully selected.

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.

A phase I trial of high-dose diaziquone and autologous bone marrow transplantation: an Illinois Cancer Council study.

1991 ◽  
Vol 9 (8) ◽  
pp. 1487-1494 ◽  
Author(s):  
P J Stiff ◽  
R S McKenzie ◽  
L D Potempa ◽  
K Albain ◽  
D Koch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Renal Failure ◽  
Phase I ◽  
Small Cell Lung Carcinoma ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Liver Function Tests ◽  
Cns Tumors ◽  
High Dose ◽  
Cell Lung Carcinoma

Diaziquone (AZQ), a synthetic quinone with demonstrated activity against acute nonlymphocytic leukemia (ANLL), primary CNS tumors, and non-Hodgkin's lymphoma (NHL), is virtually devoid of nonhematopoietic toxicity at conventional doses. As a prelude to its inclusion into bone marrow transplant (BMT) preparative regimens, a phase I study of high-dose AZQ with autologous BMT (ABMT) was performed. Patients with refractory solid tumors and lymphomas were treated with a single 24-hour infusion of AZQ at 50 to 355 mg/m2 in dose escalations of 20%. Fifty-six patients received 69 courses. Those receiving greater than 60 mg/m2 had nadir granulocyte and platelet counts less than 500/microL and 20,000/microL, respectively. Nausea, vomiting, stomatitis, and diarrhea were mild, transient, and not dose-related. Transient minimal elevations of liver function tests were seen in five patients and were also not dose-related. The maximally tolerated dose (MTD) of high-dose AZQ was found to be 245 mg/m2, with nephrotoxicity being dose-limiting. Significant azotemia was seen in four of 12 patients treated at 295 and 355 mg/m2, including fatal anuric renal failure in three of these patients. Reversible proteinuria also occurred in 24 of 26 courses above 150 mg/m2, including nephrotic range proteinuria in eight courses, all at doses of 205 to 355 mg/m2. The proteinuria was also associated with multiple proximal tubular defects including generalized aminoaciduria and proximal renal tubular acidosis. There were six early deaths including two of early renal failure (295 and 355 mg/m2), two of sepsis (205 and 245 mg/m2), one of a pulmonary embolus (85 mg/m2), and one of progressive disease (60 mg/m2). Of 50 patients who were assessable for response, there were seven responses including two of 10 with primary CNS tumors, one of 12 with malignant melanoma, one of five with non-small-cell lung carcinoma, two of two with breast carcinoma, and one of one with ovarian carcinoma. Because of its activity in ANLL and NHL and its unique toxicity spectrum, high-dose AZQ may improve the efficacy of current BMT preparative regimens without significantly increasing their nonhematopoietic toxicity.

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