Results of phase I clinical trials of Coramsine in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2070-2070
Author(s):  
M. Millward ◽  
A. Powell ◽  
P. Daly ◽  
S. Tyson ◽  
R. Ferguson ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase Ii ◽  
Single Agent ◽  
Unknown Primary ◽  
Pharmacokinetic Parameters ◽  
Membrane Glycoproteins ◽  
Phase I Clinical Trials ◽  
Minor Response ◽  
Phase Ii Studies

2070 Background: Coramsine (C) is a 1:1 mixture of solasonine and solamargine, plant glycoalkaloids found in the species Solanum Linneanum, with single agent and synergistic combination in vitro and in vivo preclinical efficacy in various tumor models through interaction with rhamnose-containing cell membrane glycoproteins and subsequent internalization. Methods: C initially as a 2-hr IV infusion daily × 5 every 2 weeks to define the MTD, recommended Phase II dose, toxicity and pharmacokinetics. Based on preclinical toxicology the infusion duration was increased to 4 hours and 24 hours (120 hr continuous infusion). Doses studied range from 0.75 mg/kg/day to 3.0 mg/kg/day. Results: 27 pts were treated. DLT occurred in 2/2 pts at 1.5 mg/kg/day (2 hr) and 2/2 pts each at 3.0 mg/kg/day (4 hr and 24 hr). Preceding dose levels 1.0 mg/kg (2 hr) and 1.5 mg/kg (4 hr) produced DLT in 2/6 pts each with no grade IV. Over 24 hr, 2.25 mg/kg/day produced DLT in 4/6 patients. Limiting toxicity at all schedules was grade III/IV transaminitis with grade I-III increases of bilirubin and grade I-II creatinine. Hepatotoxicity was maximal at days 3–5, resolved over 10–21 days, was clinically asymptomatic apart from grade I-II fatigue, and was not cumulative. No myelosuppression or other serious drug-related toxicity was recorded. Partial responses were documented in 2 pts (renal, NSCLC) and minor response in 1 pt with unknown primary. Responses were seen using both 2 hr and 4 hr infusions. Pharmacokinetic parameters for solasonine and solamargine are linear across the narrow range of doses studied with elimination T1/2 of 5.57 ± 1.27 hr (solasonine), 8.40 ± 2.00 hr (solamargine) and Cl of 5.6 ± 1.6 L/hr (solasonine), 3.0 ± 0.7 L/hr (solamargine). Peak levels of both exceed active in vitro levels (>2,000 ng/ml). Conclusions: Coramsine produces dose-limiting hepatotoxicity at doses above 1.0 mg/kg/day over 2 hours or 1.5 mg/kg/day over 4 hours. 2.25 mg/kg/day over 24 hours exceeds the MTD. Activity has been seen against resistant solid tumors. Phase II studies in renal cancer and melanoma will be performed using 1.5 mg/kg/day over 4 hours. [Table: see text]

Phase II Trial of Irinotecan in Children With Refractory Solid Tumors: A Children's Oncology Group Study

2007 ◽  
Vol 25 (29) ◽  
pp. 4622-4627 ◽  
Author(s):  
Lisa R. Bomgaars ◽  
Mark Bernstein ◽  
Mark Krailo ◽  
Richard Kadota ◽  
Soma Das ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase Ii ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Relative Extent ◽  
Grade 3 ◽  
Ugt1a1 Genotype

Purpose A phase II study was performed to determine the efficacy of irinotecan (IRN) in children with refractory solid tumors. Secondary objectives were to evaluate toxicity, pharmacokinetics, pharmacodynamics, and UGT1A1 genotype. Patients and Methods A total of 181 patients were enrolled, of whom 171 were eligible. Patients received IRN 50 mg/m2/d for 5 days repeated every 3 weeks. Pharmacokinetic studies and UGT1A1 genotyping were performed. Results Of 161 patients assessable for response, one patient with hepatoblastoma had a complete response, with partial responses observed in patients with medulloblastoma (n = 4), rhabdomyosarcoma (n = 1), neuroblastoma (n = 1), and germinoma (n = 1), for an overall response rate of 5%. Grade 4 neutropenia and grade 3 to 4 diarrhea occurred in less than 7% of the courses administered. Pharmacokinetic studies were available for 79 patients. The mean ± standard deviation IRN plasma clearance was 374 ± 148 mL/min/m2, with median relative extent of conversion and relative extent of glucuronidation of 0.05 (range, 0.01 to 0.25) and 2.24 (range, 0.39 to 9.6), respectively. No association between UGT1A1 genotype (n = 61) and toxicity or pharmacokinetic parameters was observed. Conclusion IRN 50 mg/m2/d for 5 days every 21 days is well tolerated, but was not effective as a single agent in a spectrum of solid tumors, with the possible exception of patients with medulloblastoma (16% response rate). There was no association between UGT1A1*28 genotype and toxicity or pharmacokinetic parameters.

Trabectedin phase II clinical trials: Pooled analysis of safety in patients with solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13510-e13510 ◽  
Author(s):  
A. Cioffi ◽  
A. LeCesne ◽  
J. Blay ◽  
S. Delaloge ◽  
A. Yovine ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase Ii ◽  
Specific Binding ◽  
Single Agent ◽  
Antineoplastic Agent ◽  
Dose Intensity ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Phase Ii Studies ◽  
Breast And Prostate Cancer

e13510 Background: Trabectedin is an originally marine-derived antineoplastic agent. Its unique antitumor properties, attributed to specific binding to the small groove of DNA, have been demonstrated activity against soft-tissue sarcoma (STS), ovarian, breast and prostate cancer. Trabectedin treatment has been authorized by EMEA for STS after failure of standard treatment and shows efficacy in relapsed ovarian cancer in a phase III study. This retrospective report on safety includes single-agent trabectedin phase II studies in patients (pts) with solid tumors. Methods: A total of 1,132 pts were treated with trabectedin in 19 international trials (Feb’99 - Apr’08). Three schedules were analyzed: 24-hour infusion every 3 weeks (wk) (570 pts), 3-h every 3 wk (258 pts), and 3-h for 3 out of 4 wk (304 pts). Safety analyses included pts who received at least part of 1 infusion. MedDRA and NCI-CTC v1.0/2.0 were used to code and grade treatment-emergent adverse events (AEs). Results: Median pt age was 54 years with ECOG 0–1 (>99%). Diagnosis included sarcoma (56%), ovary (26%) and breast (7%) cancer, for which 90% of pts had received chemotherapy, 37.5% radiotherapy, and 96.0% surgery. Trabectedin lasted for a median of 3 cy (9.4 wks) and 28% of pts received ≥ 6 cycles, with a median dose intensity of 0.4 (0.1–0.6) mg/m2/wk. The overall rate of discontinuations due to toxicity was 10.3%, similar between all three dose schedules. Most common trabectedin-related AEs (≥ 20% of pts) were nausea, fatigue and vomiting. Most common lab abnormalities were reversible myelosuppression, mainly neutropenia (37% grade3–4) though G-CSF was given to less than 10% of pts; and transient transaminase increases (grade3–4: ALT, 45%; AST, 30%). Of note, only 3.7% and 5.7% of pts had alopecia or mucositis/stomatitis, respectively. Fifteen drug-related deaths (1.3%) occurred. Conclusions: Single-agent trabectedin was reasonably well tolerated, with low rates of drug-related discontinuations and deaths. Sustained clinical benefit in the absence of relevant cumulative toxicities allows its administration to patients for prolonged periods of time. [Table: see text]

scholarly journals ACTR-34. SINGLE AGENT ONC201 IN PREVIOUSLY-TREATED, PROGRESSIVE ADULT H3 K27M-MUTANT GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi20-vi21 ◽  
Author(s):  
Isabel Arrillaga-Romany ◽  
Sylvia Kurz ◽  
Ashley Sumrall ◽  
Nicholas Butowski ◽  
Rebecca Harrison ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Receptor Expression ◽  
Phase Ii Trials ◽  
Minor Response ◽  
Expanded Access ◽  
Dismal Prognosis ◽  
Best Response

Abstract H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no established or effective treatments at recurrence. ONC201 is the first clinical bitopic DRD2 antagonist/ClpP agonist and is under evaluation in Phase II trials for gliomas and other cancers. We previously reported in vitro studies suggesting dysregulated dopamine receptor expression and enhanced ONC201 sensitivity among H3 K27M-mutant gliomas. Following these observations, adults with midline H3 K27M-mutant glioma patients were enrolled to a dedicated Phase II clinical trial (NCT03295396), a multi-arm Phase II trial (NCT0252569), and expanded access protocols under the Sponsor’s IND. An integrated radiographic analysis with an objective response rate primary endpoint in patients who received ONC201 monotherapy with confirmed H3 K27M-mutant glioma (not primarily in the pons or spinal cord and without leptomeningeal spread) that was progressive and measurable disease by RANO criteria, >90 days from completion of prior radiation, and had KPS >60. As of December 15, 2018, 15 patients have received single agent ONC201 who meet these criteria (n=9 NCT03295396; n=5 NCT0252569; n=1 expanded access). ONC201 was orally administered at 625 mg weekly, except for one patient dosed once every 3 weeks. As midline gliomas can exhibit a mixture of contrast-enhancing and non-contrast-enhancing disease, objective response was assessed by blinded independent central review using RANO-HGG and RANO-LGG criteria for each patient. Best response to date by RANO-HGG criteria is at least 27%: 1 CR, 3 PR, 7 SD, and 4 PD; by RANO-LGG is at least 36%: 1 CR, 1 PR, 3 minor response (MR), 4 SD, 5 PD, 1 unevaluable. By RANO-HGG, median onset of response is 2.6 months (range 1.3–3.4); median duration of response has not been reached with a median follow-up of 7.7 months (range 1.8–29.8). Updated radiographic response, pharmacodynamics, safety, and other clinical outcomes will be reported.

Efficacy and safety profile of oxaliplatin and docetaxel in patients with advanced non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17061-17061
Author(s):  
E. S. Santos ◽  
L. E. Raez ◽  
M. Rosado ◽  
G. Lopes ◽  
E. Roman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Single Agent ◽  
Small Cell ◽  
Efficacy And Safety ◽  
Small Cell Lung ◽  
Phase Ii Studies

17061 Background: Platinum-based doublets are used as treatment for advanced or metastatic non-small cell lung cancer (NSCLC), but chemotherapy must be tailored to decrease side effects. Oxaliplatin is more potent than cisplatin, requiring fewer DNA adducts to provide equivalent cytotoxicity in vitro studies. Oxaliplatin was active as a single agent and in combination with vinorelbine, paclitaxel, and gemcitabinein phase II studies of patients with NSCLC. A phase II study was conducted to evaluate the efficacy and safety of oxaliplatin combined with docetaxel for NSCLC. Methods: Patients with stage-IIIB or -IV, chemotherapy-naive NSCLC received docetaxel 70 mg/m2, oxaliplatin 130 mg/m2, and pegfilgrastim 6 mg every 21 days for up to 6 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints were progression-free and overall survival (PFS and OS), and safety. Results: Twenty-nine patients were treated; 15 (51.7%) were women, 25 (76%) were white, 17 (58.6%) were hispanic, 21 (72.4%) had adenocarcinomas, 24 (83%) had a PS ECOG 1, 93% had stage-IV disease and 28% had brain metastases. There were 10 partial responses in 27 evaluable patients for an ORR of 37% (90% confidence interval [CI], 21.7%–54.7%). Median PFS for 29 treated patients was 4.6 months (95% CI, 2.6–6.5 months); 12-month PFS was 14.8% (95% CI, 3.4%– 34.0%). Median OS was 10.9 months (95% CI, 8.9–16.8 months); 12-month OS was 40% (95% CI, 18.5%–60.8%) and 18-month OS was 16% (95% CI, 1.4%–45.7%). There were no unusual or unexpected adverse events. The most common grade-3 and -4 toxicities were anemia (14% of patients) and hyperglycemia (10%). There were only 2 reports of neutropenia; both were grade 1 or 2. Conclusions: These phase II findings suggest that the combination of oxaliplatin and docetaxel is active and well tolerated, and offers a feasible treatment alternative for patients with advanced or metastatic NSCLC. [Table: see text]

scholarly journals A Review of Docetaxel: Its Use in the Treatment of Gastric Cancer

2010 ◽  
Vol 2 ◽  
pp. CMT.S5191
Author(s):  
Alessandro Inno ◽  
Michele Basso ◽  
Alessandra Cassano ◽  
Carlo Barone
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Poor Performance ◽  
Phase Iii ◽  
Poor Performance Status ◽  
Phase Ii Studies ◽  
Combination Regimens

Docetaxel, a member of the taxane family, promotes cell death by binding β-tubulin and has demonstrated activity against several human malignancies, both as a single agent and in combination therapy. It has been approved in Europe and the US as front-line treatment for advanced gastric cancer in combination with cisplatin and fluorouracil (DCF regimen). This approval was based on the results of a pivotal study (V325) which demonstrated that the addition of docetaxel to the reference regimen of cisplatin and fluorouracil improves overall survival and progression-free survival with a better quality of life despite increased toxicity (mainly haematological). Modifications of DCF regimen have been successfully investigated as a means of making the treatment more tolerable and suitable also for elderly patients or patients with poor performance status. Emerging data from several phase II studies suggest that other docetaxel-based combination regimens with anthracyclines or irinotecan have interesting activity with acceptable toxicity profiles, but the true efficacy of these regimens needs to be assessed in large randomized phase III studies. Thus, the best docetaxel-containing regimen has yet to be identified. Docetaxel also represents a good candidate for combination with novel molecular target agents. In light of the high response rates observed in phase II-III studies, a docetaxel-based chemotherapy regimen might also be considered a treatment option as perioperative or adjuvant therapy in potentially curable gastric cancer and further studies with or without biological agents are eagerly awaited in this setting.

scholarly journals Phase II Study of Temsirolimus in Women With Recurrent or Metastatic Endometrial Cancer: A Trial of the NCIC Clinical Trials Group

2011 ◽  
Vol 29 (24) ◽  
pp. 3278-3285 ◽  
Author(s):  
Amit M. Oza ◽  
Laurie Elit ◽  
Ming-Sound Tsao ◽  
Suzanne Kamel-Reid ◽  
Jim Biagi ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Partial Response ◽  
Phase Ii ◽  
Median Duration ◽  
Stable Disease ◽  
Mutational Analysis ◽  
Single Agent ◽  
Protein Translation ◽  
Mtor Inhibition ◽  
Phase Ii Studies

Purpose Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting. Patients and Methods Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles. Results In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome. Conclusion mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs.

Sequential Phase II Studies of Flavopiridol by 72-Hour Continuous Infusion and 1-Hour Intravenous Bolus for the Treatment of Relapsed B-Cell Chronic Lymphocytic Leukemia: Results from CALGB Study 19805.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3485-3485
Author(s):  
John C. Byrd ◽  
Bercedis L. Peterson ◽  
Janice L. Gabrilove ◽  
Olatoyosi M. Odenike ◽  
Michael R. Grever ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Phase Ii ◽  
Tumor Lysis Syndrome ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Intravenous Bolus ◽  
Phase Ii Studies ◽  
Grade 3

Abstract Flavopiridol has in vitro activity in CLL and promotes apoptosis independent of p53 function or prior fludarabine exposure. We sought to determine if flavopiridol administered using two different schedules has activity in CLL. Patients with previously treated CLL were enrolled on two sequentially performed phase II studies. Patients in the first trial received flavopiridol (50 mg/m2 daily) as a continuous infusion (CI) over 72-hours every 2 weeks. Patients in the second trial received flavopiridol 50 mg/m2 as a 1-hour intravenous bolus (IVB) daily for three days repeated every 3 weeks. Patients received up to 6 (CI cohort) or 8 (IVB cohort) cycles of therapy. Fifteen patients enrolled in the 72-hour CI phase II trial; 6 (40%) had intermediate (Rai stage I or II) and 9 (60%) high (Rai stage III and IV) risk stages. No responses were noted in this group with 27% having stable disease (SD) and 73% progressive disease (PD). Thirty-six patients enrolled in the IVB study, with 13 (36%) having intermediate and 23 (64%) having high-risk disease. Four patients (11%) had partial responses, 19 (53%) SD, and 13 (36%) PD. The progression-free survivals for responders in the IVB study were 2.9, 3.2, 8.7, and 19.3 months. The median progression-free survival was 2.1 months (95% confidence interval [CI] 1.8 – 3.8) for patients in the CI study and 3.2 months (95% CI [2.5 – 7.4]) for the IVB study. The median overall survival was 27 months (95% CI [20–42]) for the CI study and 24 months (95% CI [18–31]) for the IVB study. Toxicity was manageable and included mainly myelosuppression (granulocytopenia and thrombocytopenia), infections, diarrhea and fatigue. Grade 3 and 4 toxicities were 20% and 27%, respectively, on the CI study and 39% and 33% on the IVB study. One patient on the IVB study had tumor lysis syndrome that was managed medically and did not require dialysis. There was one on-study death following a myocardial infarction on the IVB study. We conclude that flavopiridol has modest, schedule-dependent clinical activity in relapsed CLL and warrants future investigation utilizing alternative schedules of administration.

Combination of Sorafenib, Idarubicin, and Cytarabine Has a High Response Rate in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Younger Than 65 Years

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 768-768 ◽  
Author(s):  
Farhad Ravandi ◽  
Jorge Cortes ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Phase I ◽  
Cell Lines ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
High Response Rate ◽  
Clinical Activity ◽  
Mutation Burden

Abstract Background: Sorafenib is an orally active multi-kinase inhibitor with potent activity against the Raf/ERK/MEK pathway, VEGFR, PDGFR-β, and c-KIT. In vitro, it has growth-inhibitory effects in several AML cell lines with or without constitutive activation of ERK signaling. Sorafenib selectively induces cell growth arrest and apoptosis in FLT3-mutant human AML cell lines at nM concentrations. In a phase I study of single agent sorafenib in patients (pts) with AML escalating doses were well tolerated with no myelosuppression and with significant clinical activity predominantly (but not exclusively) in FLT3 mutated pts. Methods: This study was conducted to determine the tolerability and efficacy of combination of sorafenib with cytarabine 1.5 g/m2 iv over 24 hours daily × 4 (× 3 for pts over 60) and idarubicin 12 mg/m2 iv daily × 3. In the phase I portion of study, pts with relapsed AML were treated with escalating doses of sorafenib po (400 mg qod, 400 mg daily and 400 mg bid) for 7 days during induction, and 400 mg bid was established as a safe dose for phase II evaluation. Pts achieving CR receive up to 5 courses of consolidation with idarubicin 8 mg/m2 iv daily × 2 and cytarabine 0.75 g/m2 iv daily × 3 in addition to continuous sorafenib 400 mg po bid for up to 28 days per cycle. Maintenance with sorafenib 400 mg bid would continue for up to a year after consolidation. Results: Ten pts (median age 34 years, range 21–58) with relapsed AML (median prior therapy 2, range 1–6) were treated on the phase I portion. Seven had FLT3-ITD mutation (5 with high mutation burden, 2 with low), and 3 were negative. Four achieved CR, and 6 failed. In the phase II portion, 30 pts (including 8 with FLT3-ITD and 2 with FLT3-TKD) have been treated. Median age is 53 years (range 18 – 65) Cytogenetics were diploid in 13, +8 in 3, −5/−7 in 3, t(9;11) in 1, miscellaneous in 6, and unavailable in 4. The median presentation WBC was 4.6 × 109/L (range 1.5 –122.7 × 109/L). FLT3 mutation burden was low in blasts from 4 pts, and high in 6). Five pts were FLT3-ITD+/NPM1-. Among 25 evaluable pts, 22 (88%) have achieved CR (n=19), or CRi (n=3); 1 achieved PR, 1 died at induction from pneumonia, 1 was resistant; 5 pts are too early. The regimen is well tolerated and grade 3 adverse events thought to be possibly related to the study combination have included elevation of transaminases (3), hyperbilirubinemia (4), small bowel obstruction (1), diarrhea (2), rash (2), pericarditis (1), elevated creatinine (1), and atrial fibrillation (1). Median follow-up is 8 weeks (range, 1 – 28) with the probability of survival at 6 months of 87%; 2 pts have relapsed with CR durations of 2 and 3 months. Samples from 8 pts were studied prior to and 24–48 hours post sorafenib administration, and prior to chemotherapy. In six pts (75%), sorafenib alone induced apoptosis in peripheral blood blasts and in CD33/CD34 positive leukemia progenitor cells as determined by flow cytometry. Expression of phospho-ERK (pERK) was detectable by flow cytometry in 5 out of 7 samples tested at baseline; 24-hour exposure to sorafenib resulted in >50% downregulation of pERK in 3 of the 5 samples. Plasma inhibitory assay was performed using day 7 samples from 10 pts; mutant FLT3 was suppressed by all samples with 5-fold more potent suppression against mutant versus wildtype FLT3. Conclusions: Combination of sorafenib with idarubicin and cytarabine is safe and has a high CR rate in frontline therapy of younger pts with AML. Correlative studies confirm potent activity of sorafenib against ERK and FLT3 signaling.

A phase II, multicenter study of bendamustine HCl plus rituximab in relapsed indolent B-cell and mantle-cell non-Hodgkin’s lymphoma (NHL)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7528-7528 ◽  
Author(s):  
M. E. Williams ◽  
P. Cohen ◽  
A. Tulpule ◽  
R. H. Van der Jagt ◽  
J. A. Herst ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Multicenter Study ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Mitotic Catastrophe ◽  
Hematologic Toxicity ◽  
Mantle Cell

7528 Background: Bendamustine HCl, a novel alkylating hybrid agent, has single-agent activity in multiple hematologic and solid tumors. In vitro data have demonstrated the multifunctional mechanisms of bendamustine by which cell death occurs via both apoptosis and mitotic catastrophe. Bendamustine has shown activity in NHL cell lines that are refractory to conventional alkylator chemotherapies. The combination of bendamustine and rituximab has shown a synergistic effect on NHL cells. The efficacy and safety of bendamustine in combination with rituximab in patients with relapsed NHL were evaluated. Methods: This phase II, multicenter study enrolled adult patients with relapsed, indolent, rituximab-sensitive B-cell or mantle-cell NHL. Patients received rituximab 375 mg/m2 IV on day 1 and bendamustine 90 mg/m2 IV on days 2 and 3 of a 28-day cycle for 4 to 6 cycles. An additional dose of rituximab 375 mg/m2 IV was given 1 week prior to the first cycle of bendamustine and 4 weeks after the last cycle. Results: The intent-to-treat population included 67 patients (57% males; median age, 60 years) with indolent NHL (81%) or mantle-cell NHL (16%) (data not available [3%]). A total of 81% of patients had stage III/IV disease. Patients had relapsed from a median of 1 prior therapy; 37% had prior treatment with rituximab. In the 57 evaluable patients, the overall objective response rate (ORR) was 87% (complete response [CR], 33%). The ORR for the 9 evaluable mantle-cell NHL patients was 89% (CR, 33%). For all patients, the median duration of response and progression-free survival had not been reached after a median follow-up of 3.7 months (range, 0–14.2 months). This therapy was well tolerated. Most commonly reported nonhematologic toxicities were grade 1/2 gastrointestinal events, with nausea being the greatest (38%). The primary grade 3/4 hematologic toxicity was neutropenia (29%), with 1 event of sepsis. Conclusions: Bendamustine in combination with rituximab was well tolerated and produced high response rates in patients with relapsed indolent and mantle-cell NHL. These results suggest bendamustine in combination with rituximab provides a potential benefit over single-agent rituximab therapy. [Table: see text]

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