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

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.

Cisplatin, Gemcitabine, and Ifosfamide As Weekly Therapy: A Feasibility and Phase II Study of Salvage Treatment for Advanced Transitional-Cell Carcinoma

2002 ◽  
Vol 20 (13) ◽  
pp. 2965-2970 ◽  
Author(s):  
Lance C. Pagliaro ◽  
Randall E. Millikan ◽  
Shi-Ming Tu ◽  
Dallas Williams ◽  
Danai Daliani ◽  
...  
Keyword(s):  
Transitional Cell Carcinoma ◽  
Cell Carcinoma ◽  
Phase Ii ◽  
Transitional Cell ◽  
Hematologic Toxicity ◽  
Nonhematologic Toxicity ◽  
Metastatic Urothelial Carcinoma ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

PURPOSE: We investigated the feasibility, safety, and antitumor activity of weekly gemcitabine given in combination with low doses of cisplatin and ifosfamide in previously treated patients with advanced transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with measurable, metastatic or unresectable TCC who had received one or two prior chemotherapy regimens were eligible. On a 28-day course, doses of cisplatin 30 mg/m2, gemcitabine 800 mg/m2, and ifosfamide 1 g/m2 were given on day 1 and then repeated on day 8 and day 15 unless there was dose-limiting hematologic toxicity. RESULTS: Fifty-one patients were registered; 10 patients participated in a pilot study, after which 41 patients were registered onto the phase II protocol. Forty-eight patients (94.1%) had dose-limiting hematologic toxicity on day 8 or day 15. Nonhematologic toxicity of grade 3 or greater consisted mainly of nausea and vomiting (seven patients, 13.7%) and infection (seven patients, 13.7%). Responses could be assessed in 49 of 51 eligible patients; two complete responses (4.1%) and 18 partial responses (36.7%) were observed for an overall response rate of 40.8% (exact 95% confidence interval, 27% to 56%). CONCLUSION: This regimen of cisplatin, gemcitabine, and ifosfamide is not feasible for weekly administration because of hematologic toxicity. Nevertheless, there was promising activity with only two doses per 28-day cycle. On the basis of these results, we have initiated a phase II trial of this combination given as a single dose every 14 days in patients with untreated, metastatic urothelial carcinoma.

Trial of sequential trimetrexate, fluorouracil, and high-dose leucovorin in previously treated patients with gastrointestinal carcinoma.

1994 ◽  
Vol 12 (4) ◽  
pp. 695-700 ◽  
Author(s):  
J A Conti ◽  
N Kemeny ◽  
K Seiter ◽  
E Goker ◽  
W Tong ◽  
...  
Keyword(s):  
Rest Period ◽  
Maximum Tolerated Dose ◽  
High Dose ◽  
Gastrointestinal Carcinoma ◽  
Significant Toxicity ◽  
Previously Treated Patients ◽  
Advanced Colorectal Carcinoma ◽  
Previously Treated ◽  
Grade 3 ◽  
Almost All

PURPOSE Trimetrexate (TMTX) is a dihydrofolate reductase inhibitor, which, like methotrexate (MTX), has been shown to potentiate fluorouracil (FU) cytotoxicity by increasing phosphoribosylpyrophosphate (PRPP) levels. We investigated the safety and efficacy of a sequential TMTX/FU/leucovorin (LV) combination. PATIENTS AND METHODS Forty-one patients with advanced gastrointestinal carcinoma (mostly colorectal) received variable doses of TMTX followed 24 hours later by FU/LV (500 mg/m2 of each drug). Almost all patients had received previous chemotherapy. The initial 19 patients were treated on a 3-week-on/1-week-off schedule without any significant toxicity; the remaining patients were treated for 6 consecutive weeks followed by a 2-week rest period. TMTX was escalated in 30-mg/m2 increments from 20 to 110 mg/m2 in separate patient cohorts. When the 110-mg/m2 dose of TMTX was reached, the FU dose was escalated from 500 mg/m2 to 600 mg/m2. RESULTS The partial response (PR) rate in assessable patients with colorectal cancer (all previously treated) was 20% (seven of 35; 95% confidence interval, 7% to 33%), and with other gastrointestinal cancers was one of four patients. Median survival has not been reached with a median follow-up of 13.5 months. The maximum-tolerated dose (MTD) was 110 mg/m2 for TMTX, 500 mg/m2 for FU, and 500 mg/m2 for LV on a 6-weeks-on/2-weeks-off cycle. The principal toxicities were grade 3 or 4 diarrhea, which occurred in 17% of patients, and hypersensitivity reactions, which occurred in 26% of patients. CONCLUSION TMTX can be administered at maximal doses in combination with FU and LV without increasing toxicity. The PR rate of 20% in advanced colorectal carcinoma patients previously treated with chemotherapy is encouraging and merits further study.

Irinotecan (Iri) and buparlisib (B) in previously treated patients (pts) with metastatic colorectal cancer (mCRC).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 655-655 ◽  
Author(s):  
Joaquina Celebre Baranda ◽  
Greg Reed ◽  
Stephen K. Williamson ◽  
Raymond P. Perez ◽  
Maxine L. Stoltz ◽  
...  
Keyword(s):  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Complete Analysis ◽  
Dose Titration ◽  
Human Trial ◽  
Ffpe Samples ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3 ◽  
Clinical Trial Information

655 Background: The PIK3CA pathway has oncogenic role in mCRC. Buparlisib is an oral pan-class PIK3CA inhibitor. It is currently being studied in combination trials for various malignancies. The primary objective of this phase I trial was to identify the maximum tolerated dose (MTD) for Iri plus B in pts with previously treated mCRC, with or without previous Iri therapy. We also performed PK analysis of each drug alone and in combination, determined clinical response to the combination, and evaluated achieval FFPE samples for somatic mutations in a panel of cancer associated genes, including PIK3CA for clinical correlation. Methods: A 3+3 dose titration method was used. Iri was administered intravenously every 14 days (one cycle) and B orally daily. Pts received the first dose of Iri on Cycle1 Day1. B was started 24 hours after the first dose of Iri. Safety and toxicity assessments were performed every cycle. Results: Twenty patients were enrolled: 4 in cohort 0 (Iri 120 mg/m2 + B 50 mg/d), 11 in cohort 1 (Iri 150 mg/m2 + B 50 mg/d), 5 in cohort 2 (Iri 150 mg/m2 + B 80 mg/d). The most common Grades 3/4 adverse events were neutropenia and abdominal pain. The MTD was Iri 150 mg/m2 + B 50 mg/d. The DLTs include male genital mucositis, grade 3 diarrhea, and asymptomatic grade 3 hyponatremia. In cohort 1, one pt experienced grade 2 delirium and a pt in cohort 2 had grade 3 psychosis. Of the 4 pts who received 4 cycles of therapy 2 had stable and 2 had progressive disease. No objective responses were seen. There is no significant change in the PK of Iri between Cycles 1 and 2. B at 50 mg had no consistent effect on the disposition of Iri given at 120 mg/m2 and 150 mg/m2. The Cmax and AUC for B show clear dose proportionality. Using targeted re-sequencing, a 48-gene panel that included AKT1, BRAF, KRAS, and PTEN was performed. The complete analysis of the correlative study will be presented in the meeting. Conclusions: This first human trial established that Buparlisib (50 mg qd) and Iri (150 mg/m2 q14d) are tolerable in combination. However, it is too early to determine the activity of this combination in the treatment of mCRC. Clinical trial information: NCT01304602.

Phase Ib study of drozitumab combined with cetuximab (CET) plus irinotecan (IRI) or with FOLFIRI with or without bevacizumab (BV) in previously treated patients (pts) with metastatic colorectal cancer (mCRC).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 532-532 ◽  
Author(s):  
A. D. Baron ◽  
C. L. O'Bryant ◽  
Y. Choi ◽  
S. Royer-Joo ◽  
C. C. Portera
Keyword(s):  
Dose Escalation ◽  
Death Receptor ◽  
Agonistic Interaction ◽  
Death Receptor 5 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

532 Background: Drozitumab is a monoclonal antibody that triggers tumor cell apoptosis by selective agonistic interaction with the Apo2 ligand/TNF-related apoptosis-inducing ligand death receptor 5. This study assessed the safety of drozitumab combined with two standard IRI- containing regimens in previously treated mCRC pts. Methods: Multicenter, open-label, dose-escalation study with treatment until disease progression or treatment intolerance. For CET+IRI regimen (Cohorts 1-4), a 21-day cycle (cy) = drozitumab on Day 1 at escalating doses of 1, 4, 10, or 15mg/kg, IRI on Day 1, and CET on Days 1, 8, and 15. For FOLFIRI (Cohort 5), a 14-day cy = drozitumab on Day 1 given as a 10 mg/kg loading dose followed by 7 mg/kg in continuing cys, with FOLFIRI (plus BV in pts not previously treated with BV) on Day 1. Dose-limiting toxicity (DLT) was assessed through 2 doses of drozitumab (29 days for CET+IRI; 28 days for FOLFIRI). Adverse events (AE) were recorded through all cys. Response was assessed by RECIST. Results: 14 pts received a median of 6.5 cys (range 2-21) of drozitumab with CET+IRI and 6 pts received a median of 12 cys (range 3-21) of drozitumab with FOLFIRI. No DLTs occurred at the time of dose escalation. The most frequent AEs were diarrhea (85%), fatigue (80%), nausea (80%), alopecia (70%), neutropenia (70%), and decreased appetite (50%). Most of the toxicities were grades 1-2. The most frequent grade ≥3 AEs were neutropenia (60%), diarrhea (15%), hypokalemia (15%), and leukopenia (15%). Two pts discontinued due to AEs: 1 grade 2 fatigue, 1 grade 3 pyrexia. Among the 20 total pts, best responses included 3 partial responses (2 confirmed, 1 unconfirmed), 12 stable disease and 5 progressive disease. The study enrollment was stopped early by the sponsor for reasons unrelated to safety or efficacy. Conclusions: The addition of drozitumab to two standard second-line IRI-containing regimens (CET+IRI or FOLFIRI ± BV) was well tolerated in mCRC pts. AEs were similar to those previously reported for the chemotherapy alone. Tumor responses suggest no adverse interactions between drozitumab and the chemotherapy evaluated in this study. [Table: see text]

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 Pharmacokinetics Trial of ABI-007, a Novel Nanoparticle Formulation of Paclitaxel in Patients With Advanced Nonhematologic Malignancies

2005 ◽  
Vol 23 (31) ◽  
pp. 7785-7793 ◽  
Author(s):  
David W. Nyman ◽  
Kimberley J. Campbell ◽  
Evan Hersh ◽  
Kristen Long ◽  
Kelly Richardson ◽  
...  
Keyword(s):  
Castor Oil ◽  
Dose Range ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Endothelial Cell Surface ◽  
Pretreated Patients ◽  
Previously Treated ◽  
Albumin Receptor ◽  
Grade 3 ◽  
Dose Levels

Purpose ABI-007 is a novel solvent-free, albumin-bound, 130-nm particle formulation of paclitaxel designed to avoid solvent-related toxicities and to deliver paclitaxel to tumors via molecular pathways involving an endothelial cell-surface albumin receptor (gp60) and an albumin-binding protein expressed by tumor cells and secreted into the tumor interstitium (secreted protein acid rich in cysteine). This study determined the maximum-tolerated dose (MTD) of ABI-007 monotherapy administered weekly (three weekly doses, repeated every 4 weeks) and assessed the pharmacokinetics of paclitaxel administered as ABI-007. Patients and Methods Patients with advanced nonhematologic malignancies received ABI-007 without premedication at dose levels from 80 to 200 mg/m2 as a 30-minute intravenous infusion once a week for 3 weeks, followed by 1 week of rest (one cycle). Results Thirty-nine patients were treated with an average of five cycles of ABI-007; 33% of patients received ≥ six cycles of treatment. MTDs for heavily and lightly pretreated patients were 100 and 150 mg/m2, respectively; and the dose-limiting toxicities were grade 4 neutropenia and grade 3 peripheral neuropathy, respectively. Maximum paclitaxel concentration and area under the curve increased linearly with dose. Dose-dependent changes in plasma clearance did not occur. Partial responses were observed in five patients with breast, lung, and ovarian cancers, all of whom had previously been treated with paclitaxel containing polyoxyethylated castor oil in the formulation. Conclusion This study demonstrated that weekly ABI-007 can be administered at doses exceeding those typically used for paclitaxel containing polyoxyethylated castor oil. Pharmacokinetics were linear over the dose range studied. Antitumor responses occurred in patients previously treated with paclitaxel containing polyoxyethylated castor oil.

Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer.

1989 ◽  
Vol 7 (7) ◽  
pp. 890-899 ◽  
Author(s):  
S M Swain ◽  
M E Lippman ◽  
E F Egan ◽  
J C Drake ◽  
S M Steinberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Objective Response ◽  
Metastatic Breast ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Tumor Biopsy ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

The efficacy and toxicity of leucovorin 500 mg/m2 administered intravenously (IV) over 30 minutes daily for five days followed in one hour by fluorouracil (5-FU) 375 mg/m2 administered IV daily for five days, each given every 3 weeks, was assessed in 54 previously treated patients with metastatic breast cancer. An overall objective response rate of 24% was achieved (95% confidence interval, 13% to 38%), with an additional 56% of patients maintaining stable disease. Eleven of 12 patients who responded had received previous 5-FU therapy. Toxicity of this regimen included grade 3 diarrhea in 13%, grade 3 or 4 mucositis in 33%, grade 3 or 4 granulocytopenia in 65%, and grade 3 or 4 thrombocytopenia in 19%. Delay of treatment was required for hematologic toxicity in 44 patients. Thirty-eight patients required dose reductions due to toxicity. Biochemical evaluation of tumor biopsy specimens obtained from 17 patients used as their own controls with and without leucovorin was performed. These studies reveal an increased stabilization of the 5-fluorodeoxyuridylate (FdUMP)-thymidylate synthase (TS) folate ternary complex with the addition of leucovorin. There was a 71% +/- 14% occupancy or inhibition of the enzyme with the use of both 5-FU and leucovorin, v 30% +/- 13% for 5-FU alone (P2 less than .037). The percent TS bound in responding patients was substantially higher than in those patients with progressive disease. Finally, the mean total tumor TS pre-therapy in seven patients was 31 fmol/mg compared with a mean of 81 fmol/mg in these same seven patients 24 hours after therapy. This 2.6-fold increase suggests that there is an induction of the enzyme, TS, with 5-FU treatment.

Dose-escalation trial of cladribine using five daily intravenous infusions in patients with advanced hematologic malignancies.

1996 ◽  
Vol 14 (1) ◽  
pp. 188-195 ◽  
Author(s):  
R A Larson ◽  
R Mick ◽  
R T Spielberger ◽  
S M O'Brien ◽  
M J Ratain
Keyword(s):  
Platelet Count ◽  
Dose Escalation ◽  
Performance Status ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Dose Escalation Study ◽  
Intravenous Infusions ◽  
Drug Concentrations ◽  
Nonhematologic Toxicity

PURPOSE The optimal dose and schedule for cladribine (2CdA) therapy of malignant hematologic diseases have not been determined. This dose-escalation study was designed to assess toxicity when 2CdA is given using five daily 1-hour intravenous infusions. PATIENTS AND METHODS Forty-two adults with advanced hematologic malignancies were treated in one of nine cohorts, starting at 2.5 mg/m2/d for 5 days. Plasma drug concentrations were measured by high-performance liquid chromatography. Responses were assessed by bone marrow biopsy on day 15 of the first course and by clinical measurements after each course. Patients received one to four courses each. RESULTS Nonhematologic toxicity was mild, and dose-limiting nonhematologic toxicity was not observed, even at the highest dose level of 21.5 mg/m2/d. In particular, neurotoxicity was not observed. The maximum-tolerated dose (MTD) was not identified. However, prolonged cytopenias and severe infections were more common in the higher 2CdA dose cohorts. Logistic regression analysis suggested that severe hematologic toxicity was associated with pretreatment platelet count and performance status (PS). Good-risk patients were identified as having a PS of 0 and platelet count > or = 80,000/microL, PS of 1 and platelet count > or = 120,000/microL, or PS of 2 and platelet count > or = 160,000/microL. Sustained complete responses (CRs) and partial responses (PRs) were observed in eight patients. CONCLUSION 2CdA can be administered using five daily 1-hour infusions at 21.5 mg/m2/d without dose-limiting nonhematologic toxicity. Unlike continuous intravenous infusions, neurotoxicity was not observed using this schedule. Further dose escalation may be possible in good PS patients with adequate platelet counts.

Phase I/II study of carfilzomib plus melphalan-prednisone (CMP) in elderly patients with de novo multiple myeloma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8009-8009 ◽  
Author(s):  
Brigitte Kolb ◽  
Cyrille Hulin ◽  
Denis Caillot ◽  
Lotfi Benboubker ◽  
Mourad Tiab ◽  
...  
Keyword(s):  
Phase I ◽  
De Novo ◽  
Maximum Tolerated Dose ◽  
Toxicity Assessment ◽  
Hematologic Toxicity ◽  
Effective Combination ◽  
Nonhematologic Toxicity ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3

8009 Background: Melphalan-prednisone + thalidomide (MPT) or bortezomib (MPV) are approved in frontline MM patients (pts) >65 years. Both regimens demonstrated significant benefit over MP alone in terms of PFS and OS but this benefit could be hampered by the risk of peripheral neuropathy (PN). Carfilzomib (Cfz) is a novel proteasome inhibitor that has demonstrated promising activity and favorable toxicity profile, with low rates of PN. This phase I/II study was designed to determine the maximum tolerated dose (MTD) of CMP, to assess safety and evaluate efficacy of this combination in newly diagnosed MM >65. Methods: In Phase I, Cfz was the only escalating agent starting at 20 mg/m2 (level 1) with maximal planned dose 36 mg/m2 (level 3), given IV on days 1, 2, 8, 9, 22, 23, 29, 30 for nine 42-day cycles. Oral melphalan 9 mg/m² and prednisone 60mg/m² were given on days 1 to 4, for all dose levels. Based on toxicity assessment, the study was amended to add dose level 4 (Cfz 45 mg/m2). MTD determination was based on occurrence of Dose limiting toxicities (DLTs) during the first cycle only. DLTs were defined as any grade 4 hematologic toxicity or preventing administration of 2 or more of the 8 Cfz doses of the first treatment cycle except grade 4 thrombocytopenia without bleeding or grade 4 neutropenia lasting ≤ 7 days; or grade ≥ 3 febrile neutropenia; or any other grade ≥ 3 nonhematologic toxicity. Results: As of January 20th 2012, 24 pts have been enrolled in the phase I: 6 pts at level 1 (Cfz 20), 6 at level 2 (Cfz 27), 6 at level 3 (Cfz 36), and 6 at level 4 (Cfz 45). There were 2 DLTs at level 4 (fever and hypotension not related to sepsis) and the MTD was considered to be 36 mg/m². Then, 16 additional pts were included in the phase II at level 3. Overall, 40 pts have been enrolled into the phase I/II study and 26 pts are evaluable for response. The ORR was 92% including 42% at least VGPR. These results compare favorably to those achieved with MPV, MPT, MPR or lenalidomide-dex (ORR 71, 76, 80 and 85%, respectively) in the same population. Conclusions: Frontline carfilzomib (36 mg/m2) + MP is a tolerable and very effective combination in elderly MM pts. Treatment is ongoing, with updated toxicity and efficacy data to be presented at the meeting.

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