Randomized phase II trial of MIBG versus MIBG/vincristine/irinotecan versus MIBG/vorinostat for relapsed/refractory neuroblastoma: A report from the New Approaches to Neuroblastoma Therapy Consortium.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10500-10500
Author(s):  
Steven G. DuBois ◽  
Meaghan Granger ◽  
Susan G. Groshen ◽  
Denice Tsao-Wei ◽  
Anasheh Shamirian ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Response Rates ◽  
Response Criteria ◽  
Current Response ◽  
Minor Response ◽  
Randomized Phase Ii ◽  
Grade 3

10500 Background: 131I-metaiodobenzylguanidine (MIBG) remains one of the most active agents for neuroblastoma. It is not clear if putative radiation sensitizers improve upon this activity. The primary aim of this trial was to identify the MIBG treatment regimen with highest response rate among: MIBG monotherapy (Arm A); MIBG/Vincristine/Irinotecan (Arm B); MIBG/Vorinostat (Arm C). The secondary aim was to compare toxicity across arms. Methods: We conducted a multicenter, randomized phase II trial. Patients 1-30 years with relapsed/refractory high-risk neuroblastoma were eligible with at least one MIBG-avid site and adequate autologous stem cells (ASCs). All patients received MIBG 18 mCi/kg on Day 1 and ASC on day 15. Patients on Arm A received only MIBG; patients on Arm B also received vincristine (2 mg/m2) IV on Day 0 and irinotecan (50 mg/m2) IV daily on Days 0-4; patients on Arm C also received vorinostat (180 mg/m2) orally once daily on days -1 to 12. The primary endpoint was response after one course according to NANT response criteria. The trial was designed as a pick-the-winner study with a maximum of 105 eligible and evaluable patients to ensure an 80% chance that the arm with highest response rate is selected, if that response rate is at least 15% higher than the other arms. Results: 114 patients enrolled. Three patients were ineligible and 6 eligible patients never received MIBG, leaving 105 eligible and evaluable patients (36 Arm A; 35 Arm B; and 34 Arm C; 55 boys; median age 6.5 years). 9 patients had received prior MIBG monotherapy, 65 prior irinotecan, and 7 prior vorinostat. After one course, the response rates (Partial Response or better) on Arms A, B, and C were 17% (95% CI 7-33%), 14% (5-31%), and 32% (18-51%). An additional 4, 4, and 7 patients met NANT Minor Response criteria [partial response in one disease category (e.g., bone marrow) and stable disease in other categories] on Arms A, B, and C, respectively. On Arms A, B, and C, rates of any grade 3+ non-hematologic toxicity were 19%, 49% and 32%; rates of grade 3+ diarrhea were 0%, 11%, 0%; and rates of grade 3+ febrile neutropenia were 6%, 11%, and 0%. Conclusions: The combination of vorinostat/MIBG had the highest response rate, with manageable toxicity. Vincristine and irinotecan do not improve the response rate to MIBG and are associated with increased toxicity. These data provide response rates for MIBG monotherapy in a contemporary patient population assessed with current response criteria. Clinical trial information: NCT02035137.

A Prospective Multicenter Phase II Trial of Pentostatin in Adult Patients with Steroid-Refractory Chronic Graft-Versus-Host Disease (cGvHD): A Cancer and Leukemia Group B/Eastern Cooperative Oncology Group Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2238-2238
Author(s):  
Sherif Farag ◽  
Kouros Owzar ◽  
Vera Hars ◽  
Hillard M. Lazarus ◽  
Edward A. Stadtmauer ◽  
...  
Keyword(s):  
Partial Response ◽  
Corticosteroid Therapy ◽  
Phase Ii ◽  
Graft Versus Host Disease ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Hematological Toxicity ◽  
Graft Versus Host ◽  
Grade 3 ◽  
Steroid Refractory

Abstract Abstract 2238 Poster Board II-215 Chronic graft-versus-host disease is the most common late complication occurring following allogeneic transplantation, and is the principal cause of late morbidity and non-relapse mortality. Corticosteroids remain the cornerstone of primary treatment for cGvHD with about half of patients responding. Patients who fail to respond to initial corticosteroid therapy, however, have a poor outcome with no standard approach uniformly accepted. Pentostatin is a purine nucleoside analogue that irreversibly inhibits adenosine deaminase, with accumulation of dATP, causing apoptosis of lymphocytes, and holds promise for the management of acute and cGvHD. We conducted a multi-institutional, prospective phase II trial to evaluate the response rate (RR) of pentostatin in patients with steroid-refractory cGvHD. In a two-stage design with both types I and II errors set at 0.1, we hypothesized that pentostatin would produce a response rate (complete response + partial response) of 40% or more, with less than 20% being unaccpetable. Patients were eligible if they were >18 years old, had a Karnofsky performance status (KPS) of >30%, histologically-proven extensive stage cGvHD that was refractory to corticosteroids defined as progression of disease despite at least 2 weeks of treatment with 1 mg/kg/day of prednisone or equivalent, no response or minor response to at least 4 weeks of 1 mg/kg/day prednisone (or equivalent), or who achieved only a partial response after 8 weeks of corticosteroid therapy. Response was assessed using the Hopkins scoring system as previously reported (Jacobsohn et al. J Clin Oncol, 25:4255-61, 2007). Pentostatin was administered at a dose of 4 mg/m2 IV every 2 weeks for a maximum of 12 doses. From March 2004 to March 2007, 38 patients with median age 46.5 (27-66) years and median KPS 70% (40%-90%) were treated with pentostatin. cGvHD followed transplantation from matched related donors in 29 and unrelated donors in 9 patients. Thirty-three patients had progressive onset cGvHD, while onset was quiescent in 2, and de novo in 3 patients. The median time from onset of cGvHD to start of study treatment was 416 (26-2,813) days, and the median number of prior lines of therapy for cGvHD was 3 (range, 1-6). cGvHD involved skin (n=35) with scleroderma present in 21 patients, oral mucosa (n=24), liver (n=9), gut (n=4), and lung (n=2). Thirty-five patients were evaluable for response; 2 patients died after 6 and 7 days of treatment, respectively, due to sepsis, and data was incomplete in 1 patient who committed suicide after 3 cycles. Of 35 patients evaluable for response, there were 2 complete responses (CR), 5 partial responses (PR) for a total response rate of 20%. If minor responses (in 7 patients) are also considered, then 14 of 35 (40%) had an objective improvement in cGvHD. Six patients had stable disease, 1 a mixed response, and 14 patients progressed on therapy. Of 34 patients evaluable for toxicity, grade 3-4 hematological toxicity included neutropenia (n=4), thrombocytopenia (n=3), and anemia (n=1). Grade 3-4 clinically significant non-hematological toxicity that was at least possibly related to pentostatin included fatigue (n=3), renal failure (n=3), anorexia (n=2), infection (n=9), CNS hemorrhage (n=1), and rash (n=1). Thirteen patients died on study; causes of death were infection (n=6), cGvHD progression (n=3), and unrelated causes (n=3). The 1-year and 2-year progression-free survival (for GvHD) for all patients treated on study were 32% (95% CI: 18%-46%) and 24% (95% CI: 12%-38%), respectively. The 1-year and 2-year overall survival was 53% (95% CI: 38%-60%) and 50% (95% CI: 33%-65%), respectively. We conclude that pentostatin is an active agent in patients with steroid-refractory chronic GvHD but should be investigated further in cGvHD patients in an earlier course of their disease where a greater impact on long-term outcome may be observed. Disclosures: No relevant conflicts of interest to declare.

Randomized phase II trial of the nucleolin targeting aptamer AS1411 combined with high-dose cytarabine in relapsed/refractory acute myeloid leukemia (AML)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7019-7019 ◽  
Author(s):  
R. K. Stuart ◽  
K. Stockerl-Goldstein ◽  
M. Cooper ◽  
M. Devetten ◽  
R. Herzig ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Synergistic Effects ◽  
Response Rates ◽  
High Dose ◽  
Open Label ◽  
Randomized Phase Ii ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
And Control

7019 Background: Aptamers are small synthetic oligonucleotides that form stable nuclease-resistant 3D structures and bind target proteins with specificity and affinity similar to antibodies. These “chemical antibodies” represent a new class of therapeutics. The AS1411 aptamer binds nucleolin on the surface of cancer cells and induces apoptosis. AS1411 has synergistic effects in combination with cytarabine on AML cell lines in vitro and in vivo. A phase I trial of AS1411 monotherapy in 30 patients with advanced cancer showed objective responses without serious toxicities. Methods: This open-label randomized phase II trial compared AS1411 plus high-dose cytarabine (HiDAC) with HiDAC alone in patients with primary refractory or relapsed AML who had received up to 3 previous lines of chemotherapy. Patients in cohort I were randomized 2:1 to receive AS1411 10 mg/kg/day as continuous IVI on days 1–7 + HiDAC 1.5 g/m2/ twice daily on days 4–7 or HiDAC alone for 4 days. Following safety assessment, a second cohort was randomized in a similar manner, with AS1411 escalated to 40 mg/kg/day. Objectives were comparison of response rates (CR+CRp), safety and tolerability between treatment groups. Results: Accrual has been completed, with 71 patients randomized: 22 to AS1411 10 mg/kg/day + HiDAC (AS1411–10), 26 to AS1411 40 mg/kg/day + HiDAC (AS1411–40) and 23 to HiDAC alone (control). Safety findings are currently available for 44 patients (AS1411–10, 21; AS1411–40, 9; control, 14). The main grade 3/4 toxicities were hematologic, notably febrile neutropenia, neutropenia, and thrombocytopenia; and infections. Safety findings were similar across groups, except that grade 3 hypokalemia was more frequent with AS1411–40. Deaths within 28 days of treatment were: AS1411–10, 1/21; AS1411–40, 1/9; and control, 2/14. Response data are currently available for 39 patients; response rates were: AS1411–10, 16% (3/19); AS1411–40, 14% (1/7); and control, 0% (0/13). Conclusions: Data from this first phase II trial of an aptamer in oncology are encouraging. The combination of AS1411 at 10 or 40 mg/kg/day with HiDAC appears well tolerated and shows promising signs of activity in patients with relapsed/refractory AML. [Table: see text]

Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium

2021 ◽  
pp. JCO.21.00703
Author(s):  
Steven G. DuBois ◽  
M. Meaghan Granger ◽  
Susan Groshen ◽  
Denice Tsao-Wei ◽  
Lingyun Ji ◽  
...  
Keyword(s):  
Stem Cells ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Minor Response ◽  
Once Daily ◽  
True Response ◽  
New Approaches ◽  
Randomized Phase Ii ◽  
Nonhematologic Toxicity ◽  
Grade 3

PURPOSE 131I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate. PATIENTS AND METHODS Patients 1-30 years were eligible if they had relapsed or refractory neuroblastoma, at least one MIBG-avid site, and adequate autologous stem cells. Patients received MIBG 18 mCi/kg on day 1 and autologous stem cell on day 15. Patients randomly assigned to arm A received only MIBG; patients randomly assigned to arm B received intravenous vincristine on day 0 and irinotecan daily on days 0-4; patients randomly assigned to arm C received vorinostat (180 mg/m2/dose) orally once daily on days 1 to 12. The primary end point was response after one course by New Approaches to Neuroblastoma Therapy criteria. The trial was designed with 105 patients to ensure an 80% chance that the arm with highest response rate was selected. RESULTS One hundred fourteen patients were enrolled, with three ineligible and six unevaluable, leaving 105 eligible and evaluable patients (36 in arm A, 35 in arm B, and 34 in arm C; 55 boys; and median age 6.5 years). After one course, the response rates (partial response or better) on arms A, B, and C were 14% (95% CI, 5 to 30), 14% (5 to 31), and 32% (18 to 51). An additional five, five, and four patients met New Approaches to Neuroblastoma Therapy Minor Response criteria on arms A, B, and C, respectively. On arms A, B, and C, rates of any grade 3+ nonhematologic toxicity after first course were 19%, 49%, and 35%. CONCLUSION Vorinostat and MIBG is likely the arm with the highest true response rate, with manageable toxicity. Vincristine and irinotecan do not appear to improve the response rate to MIBG and are associated with increased toxicity.

Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers.

1998 ◽  
Vol 16 (8) ◽  
pp. 2739-2744 ◽  
Author(s):  
Y Bécouarn ◽  
M Ychou ◽  
M Ducreux ◽  
C Borel ◽  
F Bertheault-Cvitkovic ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Sensory Neuropathy ◽  
Progression Free Survival ◽  
Free Survival ◽  
Duration Of Response ◽  
Grade 3 ◽  
Colorectal Cancer Patients ◽  
Peripheral Sensory

PURPOSE To evaluate the objective tumor response rate and safety profile of oxaliplatin when administered to patients with previously untreated metastatic colorectal adenocarcinoma. PATIENTS AND METHODS A total of 39 patients were entered onto this phase II trial. One patient was excluded for having had a second cancer, so the study was based on 38 patients. Patients were treated with oxaliplatin 130 mg/m2 as a 2-hour infusion on day 1, every 21 days. Patients were assessed for response every three courses. All clinical and radiologic data were reviewed by an external panel of experts, with their assessment being considered definitive. RESULTS Nine partial responses (PRs) were observed (response rate, 24.3%; 95% confidence interval, 11.8% to 41.2%). The median duration of response was 216+ days. Fifteen patients (40.5%) had stable disease and 13 (35.2%) had progressive disease. The median progression-free survival time for all patients was 126+ days (range, 21 to 447+). The main toxicity was peripheral sensory neuropathy. Grade 3 neurotoxicity (National Cancer Institute common toxicity criteria [NCI-CTC]) was reported in 13%. Hematologic and gastrointestinal toxicities were mild. The incidence of grade 3 neutropenia was 5.2%, while that of grade 3 or 4 thrombopenia was 7.9%. Vomiting (grade 3 or 4) occurred in 7.9% of patients and grade 3 diarrhea in 2.6%. CONCLUSION This phase II study provides clear evidence of the safety and efficacy of oxaliplatin monotherapy at this dose and schedule in patients with previously untreated metastatic colorectal carcinoma.

Efficacy and safety results from GEICO 1205, a randomized phase II trial of neoadjuvant chemotherapy with or without bevacizumab for advanced epithelial ovarian cancer

2019 ◽  
Vol 29 (6) ◽  
pp. 1050-1056 ◽  
Author(s):  
Yolanda Garcia Garcia ◽  
Ana de Juan Ferré ◽  
Cesar Mendiola ◽  
Maria-Pilar Barretina-Ginesta ◽  
Lydia Gaba Garcia ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Adverse Events ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Debulking Surgery ◽  
Randomized Phase Ii ◽  
Interval Debulking Surgery ◽  
Grade 3 ◽  
Macroscopic Response

BackgroundBevacizumab is an approved treatment after primary debulking surgery for ovarian cancer. However, there is limited information on bevacizumab added to neoadjuvant chemotherapy before interval debulking surgery.ObjectiveTo evaluate neoadjuvant bevacizumab in a randomized phase II trial.MethodsPatients with newly diagnosed stage III/IV high-grade serous/endometrioid ovarian cancer were randomized to receive four cycles of neoadjuvant chemotherapy with or without ≥3 cycles of bevacizumab 15 mg/kg every 3 weeks. After interval debulking surgery, all patients received post-operative chemotherapy (three cycles) and bevacizumab for 15 months. The primary end point was complete macroscopic response rate at interval debulking surgery.ResultsOf 68 patients randomized, 64 completed four neoadjuvant cycles; 22 of 33 (67%) in the chemotherapy-alone arm and 31 of 35 (89%) in the bevacizumab arm (p=0.029) underwent surgery. The complete macroscopic response rate did not differ between treatment arms in either the intention-to-treat population of 68 patients (6.1% vs 5.7%, respectively; p=0.25) or the 55 patients who underwent surgery (8.3% vs 6.5%; p=1.00). There was no difference in complete cytoreduction rate or progression-free survival between the treatment arms. During neoadjuvant therapy, grade ≥3 adverse events were more common with chemotherapy alone than with bevacizumab (61% vs 29%, respectively; p=0.008). Intestinal (sub)occlusion, fatigue/asthenia, abdominal infection, and thrombocytopenia were less frequent with bevacizumab. The incidence of grade ≥3 adverse events was 9% in the control arm versus 16% in the experimental arm in the month after surgery.ConclusionsAdding three to four pre-operative cycles of bevacizumab to neoadjuvant chemotherapy for unresectable disease did not improve the complete macroscopic response rate or surgical outcome, but improved surgical operability without increasing toxicity. These results support the early integration of bevacizumab in carefully selected high-risk patients requiring neoadjuvant chemotherapy for initially unresectable ovarian cancer.

A Phase II Trial of Doxil, Vincristine and Reduced Schedule Dexamethasone (DVd) for Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2415-2415 ◽  
Author(s):  
Paul Masci ◽  
Mary A. Karam ◽  
Luba Platt ◽  
Steven Andresen ◽  
Alan Lichtin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Liposomal Doxorubicin ◽  
Phase Ii Trial ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Response Rates ◽  
Free Survival ◽  
Median Progression Free Survival ◽  
Grade 3

Abstract Patients with newly diagnosed multiple myeloma (MM) typically have responses to initial cytotoxic or steroid based therapy. Disease relapse occurs in all patients. As high as 90% of patients with relapsed or refractory disease will have over-expression of the multi-drug resistance (MDR) gene. Pharmacokinetic data suggest that prolonged exposure to high concentrations of doxorubicin can overcome MDR. Pegylated liposomal doxorubicin can theoretically achieve this goal as the angiogenic activity of the MM bone marrow is significantly increased. We proceeded with a phase II trial to evaluate the response rate of patients with relapsed or refractory MM (R/R-MM) to the DVd regimen. Eligible patients had clinically active R/R-MM following at least one prior cytotoxic based treatment regimen. Patients received intravenous (IV) pegylated liposomal doxorubicin 40 mg/m2 day 1, vincristine 2 mg day 1 and oral or IV dexamethasone 40 mg daily days 1–4. Cycles were repeated every 28 days for a minimum of 6 cycles and 2 cycles after best response. Myeloma parameters were measured at the start of each cycle. SWOG criteria were used to determine response. Thirty-five patients (21 male and 14 female) with R/R-MM clinically active disease were enrolled. Median age was 59 years (range 43–87). Patients received a median of 2 (range 1–4) prior cytotoxic based treatments. All patients received at least one cycle of treatment (median=5; range 1–12) and were evaluable for response. Ten (29%) patients responded to therapy; 5 partial responses (PR > 50%) and 5 responses (R > 75%) were observed after a median of 2 cycles (range 1–9). Median progression free survival of responding patients (PR + R) was 4.5 mos. (range 0.67–44.8). Patients achieving R had a median progression free survival of 32.5 mos. (3.0–44.8). Thirteen (37%) patients had stable disease (SD) for a median of 1.4 mos. (range 0.8–9.9). Twelve (34%) patients had progressive disease after a median of 1 cycle (range 1–5). The most common toxicities were hematologic; there were four occurrences of febrile neutropenia. Three patients experienced grade 3 constipation and one grade 3 palmar-plantar erythrodysethesia was observed. This study suggests that in patients with R/R-MM, DVd alone yields response rates similar to bortezomib with patients achieving an R experiencing a durable plateau phase. Ongoing studies of DVd in combination with thalidomide or CC-5013 in patients with R/R-MM have resulted in higher and better quality response rates (comparable to autologous SCT) translating to a durable progression free survival. We would not recommend the DVd regimen in patients with R/R-MM without the addition of an immune modulator such as thalidomide.

Phase II Trial of the Tyrosine Kinase Inhibitor PKC412 in Advanced Systemic Mastocytosis: Preliminary Results.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3609-3609 ◽  
Author(s):  
Jason Gotlib ◽  
Tracy I. George ◽  
Andrea Linder ◽  
Alisa Ruddell ◽  
Sylvia Quesada ◽  
...  
Keyword(s):  
Mast Cell ◽  
Partial Response ◽  
Tyrosine Kinase ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Systemic Mastocytosis ◽  
High Rate ◽  
Minor Response ◽  
Kit Mutation ◽  
Grade 3

Abstract Background: Advanced forms of systemic mastocytosis (aggressive systemic mastocytosis [ASM] and mast cell leukemia [MCL]) are myeloproliferative disorders with few treatment options and a poor prognosis. In the majority of patients (pts), the pathogenesis of ASM/MCL is related to constitutive activation of the receptor tyrosine kinase (TK) KIT, due to an aspartate to valine mutation within protein codon 816 (D816V). D816V KIT is imatinib resistant both in vitro and in vivo. We demonstrated that PKC412 (N-benzoyl-staurosporine), a structurally different KIT TK inhibitor, can block the growth of D816V KIT-transformed cells at a low 50% inhibitory concentration of 30-40 nM (vs. imatinib > 1 uM). In addition, we treated a MCL pt with PKC412 on a compassionate basis, resulting in a good partial response (Gotlib et al, Blood. 2005; 106:2865-70). Therefore, we initiated a phase II study designed to assess PKC412 efficacy and safety in ASM/MCL pts. Methods: PKC412 100 mg bid was administered in 28-day cycles. Pts without a major response (MR) or partial response (PR) by Valent criteria after 2 cycles were discontinued. Results: To date, 11 ASM pts (n=6 male) have been enrolled, 7 with an associated CMML or mixed MDS/MPD. Median age at entry was 62 yrs (range 30–72); the median # of prior therapies was 1 (range 0–3). Efficacy: Currently, 9 pts are evaluable for efficacy. Responses were observed in 6/9 (67%) pts, including 2 pts with a MR (both incomplete remission), and 4 pts with a PR (3 good PR, 1 minor response). Three pts were discontinued after 2 cycles (2 progressive disease, 1 stable disease). The 2 MRs consisted of resolution of hypoalbuminemia and correction of the platelet count to >100,000/mm3 in one pt, and normalization of splenomegaly with a 69% decrease in serum tryptase in the second pt. The 3 good PRs includedalmost complete resolution of large-volume ascites,> 50% reduction in palpable hepatosplenomegaly, and>50% reduction in direct hyperbilirubinemia.Serum tryptase decreased by 60–70% in 2 of these pts. All MRs and good PRs were accompanied by a marked improvement in performance status. Median duration of treatment in responders is 4.5 cycles (2+ - 11+). Bone marrow (BM) mast cell (MC) burden was stable to slightly decreased in responders; in 1 PR pt, the BM MC burden decreased from 50% to 20% with loss of expression of the neoplastic mast cell surface marker CD25. Safety: PKC412 was generally well tolerated. Non-hematologic AEs included grade 1–2 nausea and/or vomiting (N/V), and less commonly diarrhea, fatigue, and headache (HA). Worsening of pre-existing anemia developed in 2 pts (grade 2 and 3, n=1 each). Dose reduction to 50 mg bid was undertaken in 3 pts for grade 3 thrombocytopenia, grade 2 N/V, and grade 2 HA. Two pts discontinued therapy after 4 cycles (1 for grade 3 fatigue and 1 for grade 2 N/V). Conclusion: PKC412 demonstrates a high rate of MRs and PRs in this initial cohort of advanced SM pts, supporting further accrual in this Simon two-stage trial. Ongoing biologic investigations include pharmacokinetics, KIT mutation and phosphorylation status, serum KIT/KIT ligand levels, and ex vivo effects of PKC412 with BM MC.

Phase II Pilot Study of Rituximab + CHOP in Patients with Newly Diagnosed Waldenström’s Macroglobulinemia, an Eastren Cooperative Oncology Group Trial (Study E1A02).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3616-3616 ◽  
Author(s):  
Rafat Abonour ◽  
Lijun A. Zhang ◽  
Vincent Rajkumar ◽  
Gordan Srkalovic ◽  
Philip R. Greipp ◽  
...  
Keyword(s):  
Median Time ◽  
Phase Ii ◽  
Response Rate ◽  
Objective Response ◽  
Visual Disturbance ◽  
Low Grade ◽  
Minor Response ◽  
Duration Of Response ◽  
Grade 3 ◽  
A Minor

Abstract Waldenström’s Macroglobulinemia (WM) is a low-grade lymphoplasmacytic disorder associated with an IgM monoclonal protein that may present with anemia, lymphadenopathy, and hepatosplenomegaly. Since combination chemotherapy and Rituximab are both active in this disease, it is possible the response rate can be enhanced by using a combined modality of Rituximab and CHOP. This approach has been used in indolent lymphoma with remarkable results and limited toxicity. Objective: To determine the response rate in previously untreated patients with Waldenström’s Macroglobulinemia receiving rituximab and CHOP. Methods: This was a phase II study of standard R-CHOP in symptomatic WM patients. The study was activated on June 15, 2004 and closed on April 26, 2007 due to poor accrual. The median age of the sixteen patients enrolled was 60 (44–79 years), β2M 3 ug/ml (2.1–7.6), median hemoglobulin was 9 g/dl (7.7–10.9), Viscosity 3.4(1.6–10), and IgM 6389 (3229–13300 mg/dl). The most common symptoms were Fatigue (13/16), visual disturbance (7/16) and parasthesias or painful/numb feet (6/16). Only one patient had bulky adenopathy (6.3%). Results: Of 16 patients treated, 5 patients have no response data available (it will be presented at the meeting). Objective response was 91% (90% CI: 63.5% ∼ 99.5%) and 1 patient had a minor response with an overall response rate of 100%. Median time to response was 1.6 months from registration and median time to maximum response was 2.1 months. Median duration of response has not been reached. The median follow up time of the 16 patients was 18.3 months with a range of 3.6–24.8 months. Among the 16 treated patients, there were 8 (50%, 90% exact binomial CI: 27.9%∼72.1%) grade 4 neutropenia. 8 patients experienced grade 3 lymphopenia (50%, 90% exact binomial CI: 27.9%∼72.1%). Only 2 grade 3 febrile neutropenia were noted. As of August 4, 2007, none of the 16 patients has died. R-CHOP is a promising regimen in the treatment of patients with Waldenström’s Macroglobulinemia. To succeed in completing clinical trials in this rare disease better international collaboration and involvement in advocacy groups are required.

NCRI CLL201 Trial: A Randomized Phase II Trial of Fludarabine, Cyclophosphamide and Mitoxantrone (FCM) with or without Rituximab in Previously Treated CLL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 752-752 ◽  
Author(s):  
Peter Hillmen ◽  
Christopher Pocock ◽  
Dena Cohen ◽  
Kim Cocks ◽  
Hazem A. Sayala ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Residual Disease ◽  
Early Death ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Color Flow ◽  
Randomized Phase Ii ◽  
Number Of Patients

Abstract Standard front-line therapy for chronic lymphocytic leukemia (CLL) is fludarabine plus cyclophosphamide. Adding mitoxantrone (FCM) or rituximab (FCR) appears to improve responses although no large randomized trials have been reported. We report a randomized Phase II trial of FCM and FCM-R in relapsed CLL. FCM was oral fludarabine (24mg/m2 for 5 days) and cyclophosphamide (150mg/m2 for 5 days) plus i.v. mitoxantrone (6mg/m2) on Day 1 of each cycle. FCM-R was identical with rituximab on Day 1 of each cycle (375mg/m2 cycle 1; 500mg/m2 cycles 2 to 6). Prophylaxis with aciclovir and co-trimoxazole was given. The primary end-point was response by NCI Criteria 2 months after therapy. Complete remission with incomplete marrow recovery (CR(i)) was defined according to the 2007 CLL Guidelines - clinical CR with a morphologically normal marrow but persistent cytopenias (i.e. platelets <100x109/l and/or neutrophils <1.5x109/l). In addition, minimal residual disease in the marrow was studied 2 months after therapy by four-color flow cytometry with MRD negativity defined as <0.01% CLL cells. 52 patients were entered into the trial with 26 in each arm. The median age was 65 (32–79) with 79% men. 42% had a β2m >4. The median number of prior therapies was 2 (1–6), 31 had prior fludarabine and 6 (12%) were refractory to or relapsed <6 months after fludarabine. 26/44 (59%) had unmutated VH genes (15/22 FCM-R; 11/22 FCM). 11 patients had deletion of 11q (FCM-R 5, FCM 6) and 1 patient had >20% 17p deleted cells (FCM-R). 36/52 (69%) received 4 or more cycles of therapy with no difference between FCM and FCM-R (18/26). Responses are shown in the Table. 35 SAE’s were reported in 23 patients. There was no difference in the number of patients with SAE’s between the arms (FCM 11, FCM-R 12). 6/7 patients (86%) who had 4 or more prior therapies reported an SAE, compared to 17/45 patients (38%) who had less than 4. 16 SAE’s were suspected to be related to FCM-R and 10 related to FCM. In summary, FCM-R is an effective therapy for relapsed CLL with over two-thirds of patients responding. The study design does not allow a statistical comparison between FCM and FCM-R but the results suggest that adding rituximab to FCM results in a higher complete response rate (CR + CR i = 43% for FCM-R and 13% for FCM) with more patients achieving MRD negativity (5 after FCM-R; 2 after FCM). The results of this randomised Phase II trial justify the study of FC with mitoxantrone and/or rituximab in larger randomized Phase III trials. Responses in 46 evaluable patients (remaining 6 not yet evaluable) All patients FCM FCM-R Number of patients 46 23 23 Overall response rate 29 (63%) 13 (57%) 16 (70%) CR 5 (11%) 1 (4%) 4 (17%) CR(i) 8 (17%) 2 (9%) 6 (26%) PR 16 (35%) 10 (43%) 6 (26%) SD/PD 12 (26%) 7 (30%) 5 (22%) Early Death (before assessment) 4 (9%) 2 (9%) 2 (9%) Withdrew consent (before assessment) 1 (2%) 1 (4%) 0 (0%) MRD negative 7 (15%) 2 (9%) 5 (22%)

Results From the Phase II Dose Expansion of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 445-445 ◽  
Author(s):  
Joseph R. Mikhael ◽  
Craig B. Reeder ◽  
Edward N. Libby ◽  
Luciano J. Costa ◽  
P. Leif Bergsagel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Phase Ii ◽  
Initial Phase ◽  
Stem Cell Transplant ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Abstract 445 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has a favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM), leading to recent FDA accelerated approval. To achieve rapid and deep response in patients eligible for stem cell transplant, we combined carfilzomib with the regimen of cyclophosphamide-thalidomide-dexamethasone (CTD). We recently reported the results of the Phase I component of the trial (in which no MTD was reached) followed by the initial Phase II trial; however, with increasing evidence for the safe and effective use of higher doses of carfilzomib, we now report results from dose escalation extension of the Phase II trial. Methods: Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with Carfilzomib IV Days 1,2,8,9,15,16 (see Table 1 below for dosing per cohort) along with Cyclophosphamide 300 mg/m2 PO Days 1,8,15, Thalidomide 100 mg PO Days 1–28 and Dexamethasone 40 mg PO Days 1,8,15,22. We initially conducted a Phase I run in trial of 6 patients with no DLT observed before expanding to the Phase II portion of the study. The initial phase II regimen is shown below – as no DLTs were observed, we have now fully accrued to the Phase II dose level +1. Treatment was for 4 cycles with expected SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: A total of 38 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II, and the remaining at dose escalated cohorts. We are reporting the 27 patients who have completed therapy and will update with the dose escalated cohorts. Median age was 65 (range 27–74) and 52% were female. ISS Stage was advanced (II-III) in 56%. Best overall response rate during 4 cycles of CYCLONE at dose level 0 is 96%: CR 29%, VGPR 46%, PR 21% (1 pt achieved MR). Adverse events of grade 3 or higher at least possibly related to CYCLONE occurred in 12 (44%). Most commonly reported non hematological toxicities (all grades) included fatigue (67%), constipation (56%), lethargy (41%) somnolence (37%), malaise (30%) depressed level of consciousness (22%); however, grade 3/4 toxicities occurring in >5% were uncommon: thromboembolic event 11%) and muscle weakness (7%). Two cases of pneumonia required hospitalization. Eight patients (30%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included neutropenia (15%) and lymphopenia (7%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. Conclusion: The 4 drug CYCLONE regimen is highly efficaceous with a response rate after only 4 cycles of 96% (75% ≥VGPR, 29% CR) at the current dosing level of carfilzomib IV 20/27 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. Increasing the dose of carfilzomib is feasible and updated results of dose escalated cohorts will be reported at 20/36 and 20/45 mg/m2. Disclosures: Bergsagel: onyx: Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

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