Rituximab +/− Bevacizumab for Patients with Previously Treated Follicular Non-Hodgkins Lymphoma: A Randomized Phase II Trial of the Sarah Cannon Research Institute.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2749-2749
Author(s):  
John D. Hainsworth ◽  
Dana S. Thompson ◽  
F. Anthony Greco ◽  
Eric Raefsky ◽  
Scott Lunin ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Off Label ◽  
Overall Response ◽  
Randomized Phase Ii ◽  
Previously Treated ◽  
Grade 3 ◽  
Tumor Types

Abstract Abstract 2749 Background: Single-agent rituximab produces an overall response rate of approximately 50% and a median PFS of 9 months in patients with previously treated follicular NHL. Since resistance to rituximab eventually develops in nearly all patients, a number of novel agents are currently being evaluated in combination with rituximab to improve treatment efficacy. Vascular endothelial growth factor (VEGF) promotes angiogenesis and is increased in many tumor types. In NHL, high levels of VEGF are correlated with disease progression. Bevacizumab, a monoclonal antibody inhibiting VEGF, has extended PFS in several solid tumor types when added to combination chemotherapy. In this randomized phase II trial, we compared the efficacy and toxicity of bevacizumab + rituximab versus single-agent rituximab, in patients with previously treated follicular NHL. Methods: Eligible patients had follicular NHL (grade 1 or 2); NHL progression after either 1 or 2 prior chemotherapy regimens; measurable or evaluable disease; and ECOG PS 0–2. Prior rituximab treatment was allowed as long as progression occurred > 6 months following completion of treatment. Patients were randomized to receive single-agent rituximab (Regimen A) or rituximab plus bevacizumab (Regimen B). All patients received 375 mg/m2IV of rituximab weekly for 4 weeks. Regimen B patients also received bevacizumab 10 mg/kg IV on days 3 and 15 during the 4-week course of rituximab. Response evaluations were performed at weeks 6 and 12 as well as 4 weeks after the completion of all therapy. Patients with objective response or stable disease at week 12 received 4 additional doses of rituximab administered at months 3 (week 12), 5, 7, and 9; in addition, regimen B patients received bevacizumab 10 mg/kg IV every 2 weeks for a total of 16 doses (also beginning week 12). Addition of bevacizumab was hypothesized to improve the median PFS from 15 months to 20 months. Accrual of 90 patients (45/arm) was initially planned; the study was stopped early due to slow accrual. Results: Between 8/2005 and 3/2012, 60 patients were enrolled (Regimen A, 30; Regimen B, 29). Key clinical characteristics including age, performance status, FLIPI score, and previous treatment were comparable in the 2 treatment groups. 95% of patients had received 2 previous regimens, and 78% had received previous rituximab. After a median followup of 36 months, 92% of patients have either completed (40%) or discontinued treatment (lymphoma progression 30%, toxicity 12%, patient/physician decision 8%). The overall response rates were 42% in Regimen A (CR rate 10%) and 45% in Regimen B (CR rate 17%). The median progression-free survivals for Regimens A and B were 10.4 and 18.4 months, respectively (HR 0.33, p=0.0090). Median OS has not been reached for either group; at 3 years, the estimated OS rates are 54% (Regimen A) and 81% (Regimen B) (p=0.12). Grade 3/4 hematologic toxicity was uncommon, with no grade 4 neutropenia or thrombycytopenia, and 1 episode of febrile neutropenia (Regimen B). No grade 4 non-hematologic toxicity occurred; grade 3 non-hematologic toxicity occurred in 3 patients (10%) on Regimen A (infusion reaction 1, hyperglycemia 1, pneumonia 1) and 7 patients (24%) on Regimen B (hypertension 3, epistaxis 1, abdominal wall hematoma 1, wound dehiscence 1, confusion 1). All 7 patients who discontinued treatment due to toxicity (3 during the first 12 weeks) were on regimen B; 5 had bevacizumab-related toxicity. There were no treatment-related deaths. Conclusion: The addition of bevacizumab to rituximab was feasible with a modest increase in toxicity in this group of patients with previously-treated follicular NHL. The toxicities observed were consistent with the known profiles of each agent. While response rates were similar between regimens, the addition of bevacizumab lengthened the progression-free survival when compared to rituximab alone (median 18.4 vs. 10.4 months). Although results of this study must be interpreted with caution due to its small size, further study of VEGF- targeted therapies in NHL may be warranted. Disclosures: Off Label Use: Off-label bevacizumab use for treatment of follicular non-Hodgkin's lymphoma. Reeves:Celgene: Equity Ownership.

scholarly journals Updated Results from a Phase II Study of the Fc Engineered CD19 Antibody MOR208 in Combination with Lenalidomide for Patients with Chronic Lymphocytic Leukemia (CLL) and Richter's Transformation or Ibrutinib for Patients with Ibrutinib-Resistant Clones

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4386-4386 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Amy S. Ruppert ◽  
Farrukh T. Awan ◽  
Jeffrey Jones ◽  
Leslie A. Andritsos ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Variant Allele Frequency ◽  
Advisory Committees ◽  
Previously Treated ◽  
Grade 3

Abstract MOR208 is an Fc engineered CD19 monoclonal antibody with preliminary efficacy in CLL as a single agent (Woyach et al, Blood 2014). Compared to non-engineered antibodies, MOR208 has significantly enhanced antibody dependent cellular cytotoxicity (ADCC), which can be further augmented in vitro with the addition of lenalidomide. Given the potential synergy of these agents, acceptable individual safety profiles, and efficacy of each as a single agent, we chose to combine MOR208 and lenalidomide in patients (pts) with previously treated and previously untreated CLL and in pts who have undergone Richter's Transformation (RT). Because recent data show poor outcomes in pts who relapse after the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib and the presence of mutations in BTK prior to relapse, we included a cohort of ibrutinib-treated pts with identified resistance mutations but no clinical relapse where MOR208 was added to ibrutinib. This study is a single institution phase II trial of MOR208 in combination with lenalidomide or MOR208 in combination with ibrutinib with an initial safety run-in as part of each cohort. In combination with lenalidomide, MOR208 was given at a dose of 1 mg/kg on cycle 1 day 1, 9 mg/kg on days 2, 8, 15, and 22 of cycle 1, and day 1 of cycles 2-12. Lenalidomide was started at a dose of 2.5 mg daily on cycle 1 day 8 and given continuously. The dose of lenalidomide could be escalated up to 10 mg daily in pts without toxicity. After 12 cycles, lenalidomide could be continued indefinitely in responding pts. In combination with ibrutinib, ibrutinib was continued at a dose of 420 mg daily, and MOR208 was given at a dose of 1 mg/kg on cycle 1 day 1, 12 mg/kg on days 2, 8, 15, and 22 of cycle 1, then weekly during cycles 2 and 3, and every other week through cycle 12. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events (AE) v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. For pts on MOR208 plus ibrutinib, variant allele frequency of mutant BTK was measured every 3 cycles. In the previously untreated cohort, 11 pts have been enrolled, with a median age of 62 (range 44-75). 1 pt had both del(17p) and del(11q) on FISH. Grade 3/4 adverse events regardless of attribution have been uncommon and have included hypertension (3 pts), infusion reaction (2 pts), and fatigue, neutropenia, colitis, hyperglycemia, dyspnea, and sinusitis (1 pt each). After a protocol amendment augmenting steroid premedication, no further grade 3 infusion reactions were observed. In the previously treated cohort, 11 pts have been enrolled, with a median age of 70 (range 62-75). 2 pts each had del(17p) and del(11q) on FISH, and 8 have Zap-70 methylated disease. Grade 3/4 toxicities regardless of attribution have included neutropenia (6), hyperglycemia (2), hypertension (2), and thrombocytopenia, fatigue, anemia, upper respiratory infection, catheter related infection, hypercalcemia, hypophosphatemia, infection, respiratory failure, and sepsis in 1 pt each. In the RT cohort, 5 pts have been enrolled, with a median age of 60 (range 55-70). Four had previously treated CLL, and one was previously untreated. Three had del(17p) and 2 had del(11q) on FISH. Grade 3/4 toxicities included hyperglycemia (3) and hyponatremia, thrombocytopenia, and neutropenia in 1 pt each. In the cohort of pts with molecular progression on ibrutinib, 7 pts have been enrolled, with a median age of 62 (range 45-77). Five have del(17p), 1 of whom also has del(11q). Grade 3/4 toxicities have included hypertension (2) and hyperglycemia and hyperuricemia in 1 pt each. Four pts have been on study for at least 3 cycles. One pt had an increase in BTK C481S variant allele frequency (VAF) from 66.3% to 78.8% while the others all have decreased (15.1% to 3.7%, 46.4% to 34.9%, and 67.2% to 18.1%). No pt has developed progressive disease. In conclusion, this Phase II trial in progress demonstrates preliminary safety and activity of the combination of MOR208 and lenalidomide in pts with CLL. This combination also has the potential to positively modulate the immune system, and detailed correlative studies will evaluate T- and NK-cell function. MOR208 appears safe in combination with ibrutinib, and preliminary evidence of activity against CLL cells with BTK C481S has been observed. Trial accrual is ongoing and updated results will be presented at the meeting. Disclosures Woyach: Morphosys: Research Funding; Karyopharm: Research Funding; Acerta: Research Funding. Awan:Innate Pharma: Research Funding; Novartis Oncology: Consultancy; Pharmacyclics: Consultancy. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Lozanski:Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding.

Phase II trial of gemcitabine and irinotecan in previously treated patients with small-cell lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7718-7718
Author(s):  
M. Nishio ◽  
F. Ohyanagi ◽  
A. Horikike ◽  
Y. Okano ◽  
Y. Satoh ◽  
...  
Keyword(s):  
Survival Time ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Single Agent ◽  
Refractory Disease ◽  
Platinum Based Chemotherapy ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

7718 Background: Gemcitabine and irinotecan has been shown to have an antitumor activity as a single agent against previously treated SCLC. The objective of this study was to assess the efficacy and safety of gemcitabine combined with irinotecan in patients with refractory or relapsed SCLC. Methods: Patients with histologically or cytologically confirmed SCLC, 20 to 74 years in age, performance status 0–2, with a history of receiving one platinum-based chemotherapy were eligible for the study. Treatment consisted of gemcitabine (1,000 mg/m2) and irinotecan (150 mg/m2) on days 1 and 15 of a 28-day cycle.The primary endpoint was the response rate (RR), and planned sample size for this phase II study was 30 patients (Simon's two-stage minimax design). Results: Thirty-one patients were enrolled and 30 patients (24 males/6 females, 10 refractory/20 sensitive, median age, 65 years) receive protocol treatment in this phase II trial. The median treatment cycles were 3 (1–10). The overall response rates was obtained in 39.3% (95% CI: 18.1% to 60.5%) of the patients, including two patients with refractory disease and 9 patients with sensitive disease. The median overall survival time was 14.4 months, and the 1-year survival rate was 51%. The median survival time of the patients with refractory disease was 7.4 months, compared with 14.4 months for patients with sensitive disease. The chief grade 3/4 toxicities included neutropenia (42%), thrombocytopenia (3%), diarrhea (9%), and liver dysfunction (3%). The only grade 4 toxicities were one case of grade 4 neutropenia (3.3%) and one case of grade 4 thrombocytopenia (3.3%). Conclusion: Gemcitabine plus irinotecan is an active regimen that seems to be well- tolerated by patients with previously treated SCLC. No significant financial relationships to disclose.

Phase II trial of oral gimatecan in adults with recurrent glioblastoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2009-2009
Author(s):  
J. Hu ◽  
P. Y. Wen ◽  
L. E. Abrey ◽  
C. Fadul ◽  
J. Drappatz ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Single Agent ◽  
Recurrent Glioblastoma ◽  
Hematologic Toxicity ◽  
Radiographic Response ◽  
Daily Dose ◽  
Grade 3 ◽  
Experienced Grade

2009 Background: Gimatecan is a highly lipophilic oral camptothecin analogue with impressive preclinical activity in glioma models. Methods: We conducted a multicenter two-stage phase II trial to evaluate the efficacy of gimatecan in adults with recurrent glioblastoma. Eligibility criteria included ≤1 prior treatment for recurrent disease, age ≥18, ECOG performance status 0 or 1, and normal organ function. Patients taking enzyme-inducing anti-seizure medications were excluded. Gimatecan 1.22 mg/m2 was given orally once daily for 5 consecutive days during each 28-day cycle. Radiographic response was evaluated by MRI after every second cycle. The primary endpoint of the study was 6 months PFS. A Simon's 2-stage design was used in which 19 patients were evaluated in the first stage, with an additional 36 patients accrued if > 4 patients in stage 1 achieved 6 month PFS. Results: A total of 29 patients were enrolled in the study, with median age of 58 years (range, 25–77 years); 58.6% female; all of whom had received prior surgery, radiation therapy, and at least one regimen of chemotherapy. The daily dose was reduced to 1.0 mg/m2 after four of the first 10 patients experienced grade 4 hematologic toxicity. One patient was removed from trial due to toxicity (grade 3 leukopenia and thrombocytopenia). Treatment delay occurred in 11 patients (38%) and dose reduction was necessary in eight patients (28%). Treatment-related grade 3/4 toxicities included thrombocytopenia (17.2%), leukopenia (17.2%), and neutropenia (10.3%). Only 1/19 patients treated with 1.0 mg/m2/day experienced grade 3/4 hematologic toxicity. The 18% reduction in the daily dose resulted in a 19% decrease in the concentration of total gimatecan in plasma prior to administration of the fifth daily dose (56 ± 23 vs. 45 ± 20 ng/mL) and a 33% decrease in the AUC for dose 5 (8.0±4.8 vs. 5.3±4.2 ng*h/mL). Only one patient had a partial radiographic response by the modified Macdonald criteria and stable disease was the best response in 13 patients. All other patients had progressive disease after two cycles of therapy. Only three patients (12%) were progression-free at 6 months. Median time to progression was 12.0 weeks (95% CI: 7.0, 17.0). Conclusions: Treatment with single-agent gimatecan 1.0 mg/m2/day for 5 days, repeated every 28-days showed minimal efficacy. [Table: see text]

Lenalidomide and Prednisone for Primary and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (MF): An Eastern Cooperative Oncology Group (ECOG) Phase II Trial.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1753-1753 ◽  
Author(s):  
Ruben A. Mesa ◽  
Xiaopan Yao ◽  
Larry D. Cripe ◽  
Chin Yang Li ◽  
Ayalew Tefferi ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Phase Ii ◽  
Stable Disease ◽  
Phase Ii Trial ◽  
Alternative Therapy ◽  
Single Agent ◽  
Eastern Cooperative Oncology Group ◽  
Hematologic Toxicity ◽  
First Line ◽  
Grade 3

Abstract Background: Immunomodulatory therapy has been shown to be of benefit for the improvement of anemia, thrombocytopenia and splenomegaly in patients with myelofibrosis (MF) initially with thalidomide (Blood2000;96:4007), and further enhanced by combination therapy with corticosteroids (Blood2003;101:2534). We sought to further enhance our previously reported efficacy of single agent lenalidomide for MF patients (Blood2006;108:1158) by combination therapy with prednisone. Methods: Symptomatic patients with MF (all with baseline anemia, hemoglobin <10g/dL or transfusion dependent) were enrolled in the single arm Phase II trial. Adequate neutrophils (>1 x 109/L) and platelets (>100 x 109/L) were required for trial entry. Lenalidomide was administered at 10 mg daily with a 3 month prednisone taper (30mg/daily, 15 mg daily, 15 mg every other day months 1,2, and 3, respectively). Patients with at least stable disease remained on single agent lenalidomide for an additional 3 months. Responses were assessed by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Response Criteria (Blood2006;108:1498). Results: Patients 28 patients were enrolled in the first step of the trial, and a total of 48 patients were enrolled (3 were ineligible because of proximity of prior therapy with 43 deemed evaluable). The enrolled eligible patients (56 % males) had a median age of 64 (range 18–83). At baseline, 52% were red cell transfusion dependent, and the median hemoglobin amongst those non transfusion dependent patients was 8.8 g/dL (range 5.9–12.4). By entry criteria neutrophils (median 5.1 x 109/L (range 1.0–79.4)) and platelets (median 234 x 109/L (range 40–1253)) were adequate. Therapy and Toxicity: A median of 6 cycles of therapy was administered, 10 patients received 3 months, and 25 patients the full 6 months of therapy. Premature discontinuation of therapy occurred in 19 patients; progressive disease (3), toxicity (7), patient withdrawal (5), death from disease (1), comorbidities (2), or seeking alternative therapy other (1). Myelosuppression was the main toxicity with 45% experiencing ≥ grade 3 hematologic toxicity (16%/2% and 23%/26%, grade 3/4 thrombocytopenia and/or neutropenia, respectively) and with 34% of patients having ≥ grade 3 non-hematologic toxicity. Less severe toxicities (< grade 3) were again mainly secondary to myelosuppression (34%) or gastrointestinal (i.e. diarrhea). No significant steroid induced toxicities were observed. Response: Among 43 patients eligible for response assessment the best confirmed response observed was a partial response in 11 (26%), stable disease (54%), and progression during trial in 8 (18%), 1 was not evaluable because no medication was taken. Among the latter responses improvement in anemia was seen in 9 (21%) (IWG-MRT clinical improvement (CI)-sustained normalization of hemoglobin, >2 g/dL increase, or transfusion independence for >2 months), and major reductions in spleen size in 4 (9%) (IWG-MRT CI - sustained >50% decrease). Serial marrow analysis was available in a subset which did not show any significant resolution of disease related fibrosis, hypercellularity or increased angiogenesis typical of MF. Conclusions: 1) Lenalidomide plus a corticosteroid taper was active in patients with MF primarily in those who suffer from anemia, but myelosuppression (particularly neutropenia is common) 2) Response rates observed with combination therapy are almost identical to our previously reported response rate seen with single agent lenalidomide (22% single agent, 21% in this trial), 3) Current results would suggest that given the myelosuppression observed, and rates of efficacy, thalidomide and prednisone would be first line for treating MF associated cytopenias with lenalidomide being considered second line (first line if a del(5q) present).

A Phase II Study of the Fc Engineered CD19 Antibody MOR208 in Combination with Lenalidomide for Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2953-2953
Author(s):  
Jennifer A. Woyach ◽  
Amy S. Ruppert ◽  
Farrukh Awan ◽  
Jeffrey A. Jones ◽  
Sharon Waymer ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Treatment Naïve ◽  
Infusion Reactions ◽  
Grade 3 ◽  
Relapsed Disease

Abstract MOR208 is an Fc engineered CD19 monoclonal antibody which has been shown in a Phase I trial in patients with relapsed and refractory CLL to be generally well tolerated and have preliminary efficacy, with an overall response rate (ORR) of 30% by IWCLL 2008 guidelines (Woyach et al, Blood 2014). Compared to non-engineered CD19 monoclonal antibodies, MOR208 has significantly enhanced antibody dependent cellular cytotoxicity (ADCC), which can be further augmented in vitro with the addition of lenalidomide. Given the in vitro synergy of these agents, acceptable individual safety profiles, and efficacy of each as a single agent, we chose to combine MOR208 and lenalidomide in patients with both previously treated and previously untreated CLL. This study is a single institution phase II trial of MOR208 in combination with lenalidomide with an initial safety run-in as part of each cohort. MOR208 was given at a dose of 1 mg/kg on cycle 1 day 1, then 9 mg/kg on days 2, 8, 15, and 22 of cycle 1, and then on day 1 of cycles 2-12. Lenalidomide was started at a dose of 2.5 mg daily on cycle 1 day 8 and given continuously. The dose of lenalidomide could be escalated up to 10 mg daily in patients without toxicity. After 12 cycles, lenalidomide could be continued indefinitely in responding patients. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response by IWCLL 2008 guidelines was assessed at cycle 7 day 1 and at the end of cycle 12. This study will enroll 20 patients with treatment-naïve CLL and 20 patients with relapsed/refractory CLL. At this time, 7 patients with relapsed/refractory disease and 5 patients with treatment-naïve disease have been enrolled and evaluated. The most common toxicities observed related to protocol therapy have been infusion related reactions, fatigue, thrombocytopenia, and neutropenia. In patients with relapsed disease, all toxicities except neutropenia have been grade 1 or 2, and 2 patients experienced grade 3 neutropenia. Of the 5 patients with treatment-naïve CLL, two experienced significant infusion reactions on cycle 1 day 1 that prevented further administration of MOR208. After a protocol amendment escalating steroid premedication, no further grade 3 infusion reactions have been observed. While the majority of patients were able to escalate lenalidomide to either 5 or 10 mg, all patients had lenalidomide eventually dose reduced to 2.5 mg daily due to cytopenias, rash, or fatigue. This combination has shown preliminary efficacy. In the cohort of patients with relapsed disease, two experienced progressive disease during cycle 2 and cycle 5 respectively. The remaining 5 patients achieved stable disease (SD, n=3) or a partial response (PR, n=2) at cycle 7 day 1, with one patient converting to PR by cycle 12. Three patients completed 12 cycles of therapy, and the remaining two completed 12 cycles and now remain on lenalidomide alone at cycle 18 and cycle 19 respectively. In the cohort of patients with treatment-naïve disease, three patients completed more than 1 day of therapy. All of these patients achieved a PR at cycle 7 day 1, and are now in cycle 10 (n=1) or cycle 11 (n=2). In conclusion, this Phase II trial in progress demonstrates preliminary safety and activity of the combination of MOR208 and lenalidomide in patients with CLL. This combination also has the potential to positively modulate the immune system, and detailed correlative studies are evaluating T cell and NK cell function in these patients. Trial accrual is ongoing and updated results will be presented at the meeting. Disclosures Jones: AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Byrd:Acerta Pharma BV: Research Funding.

A phase II trial of oxaliplatin and docetaxel in patients with androgen independent prostate cancer (AIPC) who have progressed to two prior regimens of chemotherapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15545-15545 ◽  
Author(s):  
T. Feinstein ◽  
L. J. Appleman ◽  
D. M. Friedland ◽  
S. A. Jacobs ◽  
W. A. Ferri ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Free Survival ◽  
Duration Of Response ◽  
Psa Response ◽  
Previously Treated ◽  
Grade 3

15545 Background: Single agent docetaxel has demonstrated survival benefit in AIPC. In a phase I study of single agent oxaliplatin at our institution, two patients with AIPC experienced a substantial and durable reduction in PSA. Thus, we hypothesised that a combination of oxaliplatin and docetaxel maybe beneficial in AIPC. Methods: This single arm phase II trial in patients with previously treated (0–2 regimens) and progressive AIPC commenced in June 2005, with the objectives of evaluating PSA response rates, progression free survival, and the toxicity (tolerance/safety) of the regimen. In patients with soft tissue disease, measurable responses were assessed by RECIST criteria. Using Simon stage II design, a total of 37 patients with AIPC will be accrued. No prior treatment with platinum was allowed. Treatment consisted of oxaliplatin (110 mg/m2) and docetaxel (60 mg/m2), administered intravenously every 21 days for a maximum of 6 cycles. Results: 27 men have been enrolled to date: median age 66 yrs (56–84). 21 of 27 men have completed at least two cycles of the above regimen, and are evaluable. Prior therapies included antiandrogens (100%); ketaconazole (14%); docetaxel alone or in combination (27%); anthracyclines (27%); and vaccine (5%). Median PSA at baseline was 88 ng/ml (range 2.2–3559.4). 62% of patients received all six cycles. PSA declines of ≥50% were noted in 11 of 21 patients: 3 of 8 responders being chemo-naïve; and 8 of 13 with prior chemotherapy exposure. In addition, 4 of 11 patients with measurable disease at baseline, had a partial response. Treatment was well tolerated with no treatment-related deaths. The most significant grade 3/4 adverse event (AE) was neutropenia (43%). Grade 2 or less fatigue (66%), neuropathy (53%) diarrhea (47%), nausea (41%), anorexia (29%), thrombocytopenia (12%) and anemia (6%). Conclusions: The combination of oxaliplatin and docetaxel has promising activity in both chemo-naïve and previously treated AIPC. This 2-stage study will accrue a total of 37 patients. Final analysis will include time to progression, duration of response, and median survival. [Table: see text]

Phase II Trial of Bortezomib Combined with Weekly Doxorubicin and Oral Dexamethasone for Relapsed or Refractory Multiple Myeloma (MM): Effect of NF-κB Activation on Response.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3545-3545
Author(s):  
Natalie S. Callander ◽  
Shigeki Miyamoto ◽  
Brad Kahl ◽  
Stephanie Markovina ◽  
Martha Raschko ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stromal Cells ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Mobility Shift ◽  
Salvage Regimen ◽  
Cell Extracts ◽  
Grade 3 ◽  
Rpmi 8226

Abstract Despite new therapies, patients with MM continue to relapse. Resistant MM cells are known to possess enhanced NF-κB activity which can be partially overcome in vitro by the proteosome inhibitor bortezomib. Bortezomib can also ameliorate topoisomerase IIαinhibition and restore sensitivity to agents such as doxorubicin. We designed a phase II trial of bortezomib combined with doxorubicin and dexamethasone to exploit this interaction. We also studied NF-κB activation induced by stromal cells and in primary MM cells derived from subjects. Eligibility: Progressive or refractory secretory MM, ≥ 1 previous treatments, total previous doxorubicin ≤ 220 mg/m2; previous bortezomib, transplantation, renal insufficiency with creatinine <5 mg/dl, were allowed. Methods: Patients received bortezomib 1.3 mg/m2 IV days 1,4,8, 11; doxorubicin 15 mg/m2 IV d 1,8 and dexamethasone 20 mg orally on d 1,4,8,11. Cycles were repeated every 21 days up to a maximum of 8 cycles. NF-κB activity was assayed by electrophoretic mobility shift assay using a P32labelled DNA probe on whole cell extracts derived from CD-138 positive cells isolated from pretreatment bone marrow aspirates. For stromal cell studies, CD-138 negative cells were plated, incubated for 14 days and washed. Residual adherent fibroblast like cells were then cocultured with RPMI 8226 MM cells for 24 hours and NF-κB activation in these cells analyzed as described above. Results: 9 patients have been enrolled; 7 patients are assessable for response. Previous treatments included 2 lenalidomide failures, 2 bortezomib failures, 2 transplant failures 1 subject with plasma cell leukemia. Median number of previous regimens: two (range 1–5), age range 40–88. Six of seven (85%) responded with 1 CR, 2 near CR, and 3 partial responses, including both lenalidomide failures. One patient, who had failed all previous therapy, rapidly progressed after one cycle. Of note, MM cells isolated from this resistant patient showed the highest levels of constitutive NF-κB activity whereas MM cells from responding patients showed far less constitutive activity. Stromal cells isolated from other patients demonstrated the ability to induce NF-κB activation in RPMI 8226 cells. Toxicities: no grade 3 hematologic toxicity was observed; 1 patient experienced grade 3 neuropathy, 2 patients grade 2 neuropathy after 6 cycles requiring dose reductions of bortezomib. Cost of doxorubicin $184/cycle (versus $8884/cycle if liposomal doxorubicin substituted). Conclusions: Bortezomib/doxorubicin/dexamethasone is an active, cost effective salvage regimen even in patients failing lenalidomide and single agent bortezomib. Neuropathy was the dose limiting toxicity of this regimen. High levels of constitutive NF-κB may predict for resistance to this regimen and may imply a proteosome independent pathway for NF-κB activation. Further analysis of constitutive NF-κB activity of primary MM and stromal cells in comparison to response is planned.

A Phase II Trial of Dexamethasone, High-Dose Cytarabine, and Cisplatin (DHAP) in Combination with Rituximab as Salvage Treatment for Patients with Refractory or Relapsed Aggressive Non-Hodgkin’s Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4618-4618
Author(s):  
Ulrich J.M. Mey ◽  
John W. Strehl ◽  
Katjana S. Orlopp ◽  
Dimitri Flieger ◽  
J. Birkmann ◽  
...  
Keyword(s):  
Phase Ii ◽  
Survival Data ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Aggressive Lymphoma ◽  
High Dose ◽  
Refractory Disease ◽  
Overall Response ◽  
First Relapse ◽  
Grade 3

Abstract Purpose: With commonly used salvage chemotherapy regimens like DHAP, response and overall survival rates are unsatisfactory. We designed a multicenter phase II trial to evaluate the safety and efficacy of the combination of rituximab with the DHAP regimen in patients who relapsed after or were resistant to a CHOP-like regimen. Methods: 61 patients with relapsed or resistant aggressive B-cell NHL were included in this trial so far. The median age was 61,5 years. 39 patients were in first relapse; 21 had recurrence during the first 12 months after treatment. 5 patients had second or subsequent relapse, 17 had primary refractory disease. Treatment consisted of rituximab infusions (375 mg/m2 per dose) on day 1 followed by dexamethasone 40 mg d3–6 (d 3–5 in first cycle), cytarabine 2 x 2000 mg/m2 d 4 (2 x 1000 mg/m2 in first cycle), 2 x 1000 mg/m2 for patients &gt; 60 years of age (2 x 500 mg/m2 in first cycle), and cisplatin 25 mg/m2 d 3–6 (d3–5 in first cycle) for a maximum of 4 cycles. When hematological toxicity did not allow continuation of chemotherapy on day 22, rituximab was given as single agent on day 22 and the next cycle was postponed until day 29. Results: The overall response rate in evaluable patients was 54.0%. 29.0% of patients achieved a complete response, 25% of patients had a partial response, 15.0% of patients had stable disease. 31.0% of patients showed progressive disease. Patients in first relapse achieved an overall response of 67.0 % as opposed to only 27.0% in patients with refractory disease. Grade 3/ 4 nausea and vomiting were the only severe toxicities attributed to rituximab in one patient. Main toxicities were neutropenia and thrombocytopenia. Grade 3/ 4 nephrotoxicity occured in 2 patients. Survival data will be presented at the meeting. Conclusions: Interim analysis of the data suggests that the combination of rituximab with the DHAP regimen in the treatment of relapsed or refractory aggressive lymphoma is feasible and effective. In view of the unfavorable prognostic factors in our patient population, response rates (ORR = 54%) are encouraging and warrant further investigation.

scholarly journals Phase II Trial of Cetuximab With or Without Paclitaxel in Patients With Advanced Urothelial Tract Carcinoma

2012 ◽  
Vol 30 (28) ◽  
pp. 3545-3551 ◽  
Author(s):  
Yu-Ning Wong ◽  
Samuel Litwin ◽  
David Vaughn ◽  
Seth Cohen ◽  
Elizabeth R. Plimack ◽  
...  
Keyword(s):  
Phase Ii ◽  
Urothelial Cancer ◽  
Single Agent ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
Free Survival ◽  
Metastatic Urothelial Cancer ◽  
Metastatic Setting ◽  
Previously Treated ◽  
Grade 3

Purpose The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. Patients and Methods Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m2 with or without paclitaxel 80 mg/m2 per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. Results We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). Conclusion Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers.

Sign in / Sign up

Export Citation Format

Share Document