Phase I and Pharmacokinetic Study of Irinotecan Administered as a Low-Dose, Continuous Intravenous Infusion Over 14 Days in Patients With Malignant Solid Tumors

1999 ◽  
Vol 17 (6) ◽  
pp. 1897-1897 ◽  
Author(s):  
Virginie M.M. Herben ◽  
Jan H.M. Schellens ◽  
Martha Swart ◽  
Gabriela Gruia ◽  
Laurent Vernillet ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Intravenous Infusion ◽  
High Performance ◽  
Infusion Pump ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Continuous Intravenous Infusion ◽  
Infusion Schedule ◽  
Grade 3

PURPOSE: To evaluate the feasibility of administering irinotecan as a continuous intravenous infusion for 14 to 21 days. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapy received continuous infusions of irinotecan by means of an ambulatory infusion pump. The starting dosage was 12.5 mg/m2/d for 14 days every 3 weeks. After identification of the maximum-tolerated dose for the 14-day infusion schedule, the protocol was amended to prolong the infusion duration to 17 and 21 days. Pharmacokinetics of irinotecan and SN-38 and its glucuronide were determined using high-performance liquid chromatography and noncompartmental modeling. RESULTS: Thirty-three patients received 85+ courses. At the first dose level (12.5 mg/m2/d), cumulative grade 3 or 4 diarrhea and grade 3 or 4 neutropenia occurred in three of five patients. At a dosage of 10 mg/m2/d, 14-day administration resulted in grade 4 diarrhea in two of six patients and one episode of grade 4 vomiting occurred, whereas with 17-day administration, one episode of grade 3 nausea and two episodes of grade 3 or 4 diarrhea were observed in six patients. Increasing the number of days of infusion to 21 days was not feasible because of cumulative diarrhea. Hematologic toxicity was rare. The mean metabolic SN-38 area under the curve/irinotecan area under the curve ratio was 16% ± 6% compared with 3% to 5% after short infusion schedules involving therapeutic dosages. Partial responses were observed in two patients with extraovarian and colorectal cancer. CONCLUSION: The recommended dosage is 10 mg/m2/d for 14 days, repeated every 3 weeks. Enhanced metabolism of irinotecan to SN-38 may explain in part the low recommended dose for this schedule.

Phase I and Pharmacokinetic Study of a Daily Times 5 Short Intravenous Infusion Schedule of 9-Aminocamptothecin in a Colloidal Dispersion Formulation in Patients With Advanced Solid Tumors

1999 ◽  
Vol 17 (6) ◽  
pp. 1906-1906 ◽  
Author(s):  
Virginie M.M. Herben ◽  
Roel van Gijn ◽  
Jan H.M. Schellens ◽  
Margaret Schot ◽  
Jan Lieverst ◽  
...  
Keyword(s):  
Solid Tumors ◽  
High Performance ◽  
Plasma Concentrations ◽  
Colloidal Dispersion ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Time Curve ◽  
Infusion Schedule ◽  
Recommended Phase Ii Dose ◽  
Dose Levels

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of 9-aminocamptothecin (9-AC) in a colloidal dispersion (CD) formulation administered as a 30-minute intravenous (IV) infusion over 5 consecutive days every 3 weeks. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapy were entered onto the study. The starting dose was 0.4 mg/m2/d. The MTD was assessed on the first cycle and was defined as the dose at which ≥ two of three patients or ≥ two of six patients experience DLT. Pharmacokinetic measurements were performed on days 1 and 5 of the first cycle and on day 4 of subsequent cycles using high-performance liquid chromatography. RESULTS: Thirty-one patients received 104+ treatment courses at seven dose levels. The DLT was hematologic. At a dose of 1.3 mg/m2/d, three of six patients experienced grade 3 thrombocytopenia. Grade 4 neutropenia that lasted less than 7 days was observed in four patients. At a dose of 1.1 mg/m2/d, four of nine patients had grade 4 neutropenia of brief duration, which was not dose limiting. Nonhematologic toxicities were relatively mild and included nausea/vomiting, diarrhea, obstipation, mucositis, fatigue, and alopecia. Maximal plasma concentrations and area under the concentration-time curve (AUC) increased linearly with dose, but interpatient variation was wide. Lactone concentrations exceeded 10 nmol/L, the threshold for activity in preclinical tumor models, at all dose levels. Sigmoidal Emax models could be fit to the relationship between AUC and the degree of hematologic toxicity. A partial response was observed in small-cell lung cancer. CONCLUSION: 9-AC CD administered as a 30-minute IV infusion daily times 5 every three weeks is safe and feasible. The recommended phase II dose is 1.1 mg/m2/d.

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.

Final results from a phase I trial of ixabepilone in patients with advanced malignancies and lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2039-2039
Author(s):  
C. Aghajanian ◽  
O. O’Connor ◽  
M. Cohen ◽  
R. Peck ◽  
H. Burris
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase Ii Studies ◽  
Grade 3

2039 Background: Ixabepilone is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixabepilone has shown clinical activity in a broad range of tumors. Methods: This Phase I trial was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), efficacy, safety, pharmacokinetics and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or lymphoma. Eligible patients were aged ≥18 years with histologically/cytologically confirmed non-hematologic cancer, or a pathologic diagnosis of relapsed/primary refractory non-Hodgkin’s lymphoma (NHL) or relapsed/primary refractory mantle cell lymphoma, with ≤CTC Grade 1 neuropathy. Ixabepilone doses ranged from 7.5–65 mg/m2. Response was assessed every 6 weeks using RECIST. DLT was defined as Grade 4 neutropenia and/or febrile neutropenia, thrombocytopenia, ≥Grade 3 nausea/vomiting and non-hematologic toxicity, or treatment delay of >2 weeks due to delayed recovery. Results: Of 61 patients (median age 58, range 18–81), 75% had solid tumors; 25% had lymphoma. 98% and 67% of patients had received one or ≥ two prior chemotherapy regimens, respectively. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The most common DLTs were neutropenia, myalgia, arthralgia and stomatitis/pharyngitis. A total of eight patients (13%) achieved a durable objective response. Complete responses were achieved in two patients with primary peritoneal cancer and NHL. A partial response was seen in six patients. The most common Grade 3/4 treatment-related adverse events (only observed at doses ≥40 mg/m2) were sensory neuropathy (13%), fatigue (13%), myalgia (10%), arthralgia (7%), nausea (5%), febrile neutropenia (5%) and neutropenia (5%). Recovery to baseline or ≤Grade 1 neuropathy occurred in some patients. Conclusions: The recommended dose of ixabepilone for the initiation of Phase II studies based on this study is 50 mg/m2 over 1 hour every 3 weeks. Ixabepilone demonstrates promising safety in patients with solid tumors or lymphoma who have failed standard therapy. Encouraging activity was reported in several tumor types. [Table: see text]

Effective Dosing of Topotecan With Carboplatin in Relapsed Ovarian Cancer: A Phase I/II Study

2001 ◽  
Vol 19 (13) ◽  
pp. 3255-3259 ◽  
Author(s):  
A. Bowman ◽  
T. Rye ◽  
G. Ross ◽  
A. Wheatley ◽  
J. F. Smyth
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Nonhematologic Toxicity ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3 ◽  
Carboplatin Auc

PURPOSE: This phase I/II study was performed to evaluate the feasibility of administering the topoisomerase inhibitor topotecan in combination with carboplatin. PATIENTS AND METHODS: Topotecan was given as a 30-minute infusion daily for 5 days, with carboplatin given immediately after topotecan on day 5. Treatment was repeated every 21 days. Carboplatin and then topotecan were escalated in sequential cohorts of three to six patients. Four dosage combinations of topotecan days 1 to 5 and carboplatin (day 5) were tested: 0.5 mg/m2/d and carboplatin area under the curve (AUC) of 4, topotecan 0.5 mg/m2/d and carboplatin AUC of 5, topotecan 0.75 mg/m2/d and carboplatin AUC of 5, and topotecan 1.0 mg/m2/d and carboplatin AUC of 5. RESULTS: Grade 3 and 4 neutropenia was common at doses of 0.75 mg/m2/d and above, but dose-limiting hematologic toxicity occurred in only one patient. The most common reason for dose reduction or delay was failure of myelosuppression to resolve by day 21. Nonhematologic toxicity was generally mild. The maximum-tolerated dose as defined in the protocol was not reached, but topotecan dose escalation was stopped at 1.0 mg/m2/d, because delayed neutrophil recovery precluded re-treatment on a 21-day schedule. CONCLUSION: Hematologic toxicity was common but rarely serious, and the combination of topotecan with carboplatin on this schedule was safe and well tolerated. Giving carboplatin to patients after topotecan on day 5, rather than on day 1, allowed dose escalation beyond the levels reported in other studies. The recommended doses for previously treated patients are topotecan 0.75 mg/m2/d, days 1 to 5, with carboplatin at an area under the curve (AUC) of 5 following topotecan on day 5. The combination of topotecan 1 mg/m2/d, days 1 to 5, followed on day 5 by carboplatin at an AUC of 5, merits further examination in untreated patients.

Phase I Trial of Imexon in Patients With Advanced Malignancy

2007 ◽  
Vol 25 (13) ◽  
pp. 1779-1784 ◽  
Author(s):  
Tomislav Dragovich ◽  
Michael Gordon ◽  
David Mendelson ◽  
Lucas Wong ◽  
Manuel Modiano ◽  
...  
Keyword(s):  
Phase Ii ◽  
High Performance ◽  
Metastatic Cancer ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
Advanced Malignancy ◽  
Phase Ii Studies ◽  
Heavily Pretreated ◽  
Grade 3

Purpose Imexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers. Patients and Methods Forty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days (one course) every other week (days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays. Results There were 13 dose levels evaluated, from 20 mg/m2/d to 1,000 mg/m2/d. The MTD recommended for phase II studies was 875 mg/m2/d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m2/d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose- and area under the curve–dependent decrease in cystine levels 8 hours after dosing at ≥ 750 mg/m2/d. Conclusion The phase II recommended dose of imexon is 875 mg/m2/d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure.

Phase I Study of Combination Topotecan and Carboplatin in Pediatric Solid Tumors

2002 ◽  
Vol 20 (1) ◽  
pp. 88-95 ◽  
Author(s):  
Uma H. Athale ◽  
Clinton Stewart ◽  
John F. Kuttesch ◽  
Albert Moghrabi ◽  
William Meyer ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Pediatric Solid Tumors ◽  
Group A ◽  
Group B

PURPOSE: We conducted a phase I trial of escalating doses of topotecan (TOPO) in association with a fixed systemic exposure of carboplatin (CARBO) with or without granulocyte colony-stimulating factor (G-CSF) in children. PATIENTS AND METHODS: Two separate cohorts of patients (pts) with solid tumors were studied: (A) pts with refractory or recurrent disease and (B) pts with no prior myelosuppressive therapy or newly diagnosed tumors for which there was no standard chemotherapy. CARBO was given on day 1 at an area under the curve of 6.5, followed by TOPO as a continuous infusion for 3 days; the starting dose of TOPO was 0.50 mg/m2/d. Cycles were repeated every 21 days. G-CSF was given at a dose of 5 μg/kg/d starting on day 4. RESULTS: Forty-eight of 51 pts were assessable for toxicity. In group A, dose-limiting myelosuppression persisted despite de-escalation of TOPO to 0.3 mg/m2/d and use of G-CSF. In group B, the maximum-tolerated dose of TOPO was 0.5 mg/m2/d for 3 days, and 0.6 mg/m2/d for 3 days with G-CSF. No significant nonhematologic toxicities were observed. Among 46 pts assessable for response, one had complete response, five had partial response, and 18 had stable disease. CONCLUSION: Although this combination possesses antineoplastic activity in pediatric solid tumors, hematologic toxicity precluded any meaningful TOPO dose escalation. The addition of G-CSF did not alter this. The potential for preservation of activity and diminution of toxicity with alternative sequences and schedules of administration (topoisomerase followed by alkylating or platinating agents) should be evaluated.

Phi-53: (NCI#7251): Phase I trial of belinostat (PXD101) in combination with 13-cis-retinoic acid (13c-RA) in advanced solid tumor malignancies—A California Cancer Consortium NCI/CTEP sponsored trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2526-2526 ◽  
Author(s):  
Thehang H. Luu ◽  
Paul Henry Frankel ◽  
Dean Lim ◽  
Mihaela C. Cristea ◽  
Jan Hendrik Beumer ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Phase I ◽  
Solid Tumors ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Qtc Interval ◽  
Advanced Solid Tumors ◽  
Eligibility Criteria ◽  
Grade 3

2526 Background: Belinostat has a reported maximum tolerated dose (MTD) of 1,000 mg/m2 given days 1 to 5 every 21 days as a single agent, although in one study in hepatocellular carcinoma belinostat was given at 1,400 mg/m2on the same schedule. Pre-clinical evidence suggests HDAC inhibitors enhance retinoic acid signaling with a synergistic impact in a variety of solid tumors. We conducted a phase I study of belinostat and 13c-RA in advanced solid tumors. Methods: Dose limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity: ≥grade 3 that not resolved to <grade 1 within 1 week or non-hematologic toxicity: ≥grade 3. We sought the MTD of belinostat days 1-5 with 13-cRA days 1-14, every 21 days, in patients (pt) with advanced solid tumors. Eligibility criteria included normal organ function and QT/QTc interval; 4 weeks from previous therapy. Results: 51 pt were treated: median age 61 (range 40-80); 29 men; 57% ECOG 0, 41% ECOG 1, 2% ECOG 2; 13 lung, 11 breast, 8 colorectal, 3 pancreatic. 11 dose levels (DL) were tested starting from belinostat 600 mg/m2/day and 13c-RA 50 mg/m2/day to belinostat 2000 mg/m2/day and 13c-RA 100 mg/m2/day. Only two DLTs were observed: a grade 3 hypersensitivity reaction with dizziness and hypoxia at DL 8 (belinostat 1700 mg/m2/day, 13c-RA 100 mg/m2/day); and a grade 3 allergic reaction in a patient with an ECOG PS 2 at DL 11 (belinostat 2000 mg/m2/day, 13c-RA 100 mg/m2/day). The MTD was not reached. Pharmacokinetics of belinostat suggests dose proportionality. Median number of cycles: 2 (range 1–56). 10 patients had SD including: 1 neuroendocrine pancreatic stable for 56 cycles; 1 breast pt for 12 cycles; 1 lung pt 8 cycles. 2 pt had PRs: a keratinizing squamous cell carcinoma (tonsil) and a lung cancer pt. Conclusions: Belinostat 2000 mg/m2 days 1-5and 13-cis-Retinoic acid 100 mg/m2days 1-14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single agent MTD. Future studies building on this combination to belinostat are warranted. Support: U01CA062505 and P30CA033572 (City of Hope); U01CA099168 and P30CA047904 (University of Pittsburgh).

Phase 1/2 study of veliparib (V) combined with carboplatin (Cb) and etoposide (E) in patients (pts) with extensive-stage disease (ED) small cell lung cancer (SCLC) and other solid tumors: Phase 1 results.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8530-8530 ◽  
Author(s):  
Florence Atrafi ◽  
Harry J.M. Groen ◽  
Lauren Averett Byers ◽  
Elena Garralda ◽  
Martijn P. Lolkema ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Term Tolerability ◽  
Grade 3 ◽  
Dose Levels ◽  
Continuous Dosing

8530 Background: The majority of SCLC cases are diagnosed as ED, for which there is a poor prognosis and no curative treatment (Tx). V, a potent PARP inhibitor, has been shown in preclinical studies to enhance the antitumor activity of platinum-based agents and E against SCLC. The presented phase 1 dose-escalation (NCT02289690) evaluated V combined with Cb/E. Methods: Pts (≥18 years) with ED SCLC or other advanced/metastatic solid tumors with ≤1 line of prior cytotoxic therapy and ECOG performance score 0/1 were included. This study followed a 3+3 design. V starting dose and schedule were 80 mg BID PO administered on days (D) –2 to 5 in combination with Cb AUC 5 mg/mL•min administered on D 1 and E 100 mg/m2 administered on D 1 to 3 via intravenous infusion in 21-D cycles. V schedules of D –2 to 12 and continuous dosing were also explored. Primary objectives were to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for V combined with Cb/E, and to evaluate the pharmacokinetic (PK) interaction between V and E. Results: Thirty-nine pts (n = 24 ED SCLC; n = 15 other solid tumors) with median age of 62 years (range 43–79) received study Tx. Most common adverse events (AEs; ≥40%) were nausea (54%), fatigue (51%), alopecia (46%), and anemia (44%); grade 3/4 AEs (≥30%) were decreased neutrophil count, neutropenia (31% each), and anemia (26%). Dose-limiting toxicity occurred in 1 pt (n = 1 grade 3 fatigue) at V 240 mg BID D –2 to 5. The MTD was not reached; RP2D for V was set at 240 mg BID on D –2 to 12 based on long-term tolerability. Continuous dosing of V 240 mg BID with Cb/E resulted in unacceptable Cb/E dose delays due to hematologic toxicity. Coadministration of V (80 to 240 mg BID) with Cb/E exhibited dose-proportional kinetics with no impact on the E PK. Confirmed responses: ED SCLC 63% (15/24 pts) across all dose levels and in 83% (5/6) at RP2D; other tumor types: 13% (2/15) across all dose levels. Conclusions: V + Cb/E had an acceptable safety profile in pts with ED SCLC, with an RP2D of 240 mg BID D –2 to 12. Coadministration of V with Cb/E had no effect on E PK. Responses were seen across all dose levels. A phase 2 study of V with Cb/E in ED SCLC is ongoing. Clinical trial information: NCT02289690.

Phase I Clinical Trial of Oxaliplatin in Children and Adolescents With Refractory Solid Tumors

2007 ◽  
Vol 25 (16) ◽  
pp. 2274-2280 ◽  
Author(s):  
Sheri L. Spunt ◽  
Burgess B. Freeman ◽  
Catherine A. Billups ◽  
Valerie McPherson ◽  
Raja B. Khan ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Solid Tumors ◽  
Pediatric Patients ◽  
Dose Intensity ◽  
Sensory Neuropathy ◽  
Maximum Tolerated Dose ◽  
Adverse Effect Profile ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Grade 3

Purpose To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors and to determine whether carbamazepine reduces oxaliplatin-induced neurotoxicity. Patients and Methods Three regimens of oxaliplatin (given intravenously over 2 hours) were tested: regimen A (100 mg/m2, 130 mg/m2, or 160 mg/m2 every 3 weeks to determine the MTD of oxaliplatin); regimen B (to determine whether carbamazepine starting 24 hours before and ending 48 hours after oxaliplatin reduced the dose-limiting neurotoxicity and increased the MTD of regimen A); and regimen C (to evaluate the safety of a fixed dose two-thirds the MTD of regimen A given every 2 weeks [more frequent administration but comparable dose intensity]). Results Twenty-six patients were enrolled on regimens A (n = 11), B (n = 6), and C (n = 9). The DLT was grade 3 pharyngolaryngeal dysesthesia, sensory neuropathy, and ataxia at 160 mg/m2. The MTD was 130 mg/m2 every 3 weeks. At the MTD, the median clearance rate of ultrafiltrable platinum was 9.7 L/h/m2 (range, 6.5 to 15.5 L/h/m2). Addition of carbamazepine permitted dose escalation to 160 mg/m2 without DLT. DLT was not observed with a fixed dose of 85 mg/m2 given every 2 weeks. On all regimens, hematologic toxicity was mild. No significant nephrotoxicity, ototoxicity, or cumulative neurologic toxicity was observed. Conclusion The DLT, MTD, PK, and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors are similar to those observed in adults. Carbamazepine may reduce the dose-limiting neurotoxicity of oxaliplatin.

scholarly journals Effective Dosing of Topotecan with Carboplatin in Relapsed Ovarian Cancer

2018 ◽  
Vol 29 (2) ◽  
pp. 31-36
Author(s):  
Md Dayem Uddin ◽  
Shafayat Habib ◽  
Shakera Sultana ◽  
Khan MMR ◽  
MN Islam ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Neutrophil Recovery ◽  
Nonhematologic Toxicity ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3 ◽  
Carboplatin Auc

Patients and Methods: Topotecan was given as a 30-minute infusion daily for 5 days, with carboplatin given immediately after topotecan on day 5. Treatment was repeated every 21 days. Carboplatin and then topotecan were escalated in sequential cohorts of three to six patients. Four dosage combinations of topotecan days 1 to 5 and carboplatin (day 5) were tested: 0.5 mg/m2/d and carboplatin area under the curve (AUC) of 4, topotecan 0.5 mg/m2/d and carboplatin AUC of 5, topotecan 0.75 mg/m2/d and carboplatin AUC of 5, and topotecan 1.0 mg/m2/d and carboplatin AUC of 5.Results: Grade 3 and 4 neutropenia was common at doses of 0.75 mg/m2/d and above, but dose-limiting hematologic toxicity occurred in only one patient. The most common reason for dose reduction or delay was failure of myelosuppression to resolve by day 21. Nonhematologic toxicity was generally mild. The maximum-tolerated dose as defined in the protocol was not reached, but topotecan dose escalation was stopped at 1.0 mg/m2/d, because delayed neutrophil recovery precluded re-treatment on a 21-day schedule.Conclusion: Hematologic toxicity was common but rarely serious, and the combination of topotecan with carboplatin on this schedule was safe and well tolerated. Giving carboplatin to patients after topotecan on day 5, rather than on day 1, allowed dose escalation beyond the levels reported in other studies. The recommended doses for previously treated patients are topotecan 0.75 mg/m2/d, days 1 to 5, with carboplatin at an area under the curve (AUC) of 5 following topotecan on day 5. The combination of topotecan 1 mg/m2/d, days 1 to 5, followed on day 5 by carboplatin at an AUC of 5, merits further examination in untreated patients.TAJ 2016; 29(2): 31-36

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