Pilot study of paclitaxel and carboplatin (P/C) with concurrent radiation therapy (RT) in high risk salivary gland carcinomas (SGC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15538-15538
Author(s):  
M. Langston ◽  
D. Farray ◽  
J. C. Ruzich ◽  
B. Emami ◽  
G. Petruzzelli ◽  
...  
Keyword(s):  
Pilot Study ◽  
High Risk ◽  
Surgical Resection ◽  
Phase Ii ◽  
Combined Modality Therapy ◽  
Performance Status ◽  
Cooperative Group ◽  
Salivary Gland Carcinomas ◽  
Grade Iii

15538 Background: Standard therapy for high risk SGC includes surgical resection with adjuvant RT, but a high risk of recurrence exists. The role of chemotherapy in this setting has not been fully defined. Methods: This limited institution pilot study evaluated the use of P/C with concurrent RT as adjuvant treatment of high risk SGC. The primary objective was to assess toxicity of this treatment in anticipation of a larger cooperative group phase II study. Eligible patients (pts.) had a Southwest Oncology Group (SWOG) performance status (PS) of 0–2 who after surgical resection of their SGC had high risk features including positive surgical margins, perineural invasion, multiple lymph node (LN) metastases, or extracapsular extension. Treatment included P = 40 mg/m2 intravenously followed by C = AUC of 2 concurrently on days 1, 8, 15, 22, 29, 36 of RT. RT consisted of a total dose of 60 Gy in 30 fractions to the primary and regional LN sites of disease. Results: Five pts. were enrolled 4 with adenoid cystic CA and 1 with high grade mucoepidermoid CA. Median age was 59 years (32–69), all with SWOG PS = 0. Four pts. completed the full 6 cycle P/C chemotherapy; all completed RT per protocol. Grade III/IV mucositis, the most common toxicity, occurred in 6 of 30 (20%) P/C cycles, leading to alteration of therapy in 1 pt. There was no reported neuropathy or significant laboratory abnormalities. Median follow up was 17.5 months (mos.); most were disease free at last follow up (13 to 37 mos.); 1 recurred at 14 mos.; this pt. accounts for the only death observed. One year survival was 100%. Conclusions: The regimen of P/C with concurrent RT, as defined, was tolerated well. Grade III/IV mucositis was the main toxicity. Based on the overall tolerability of this regimen, we believe that this postoperative combined modality therapy deserves further study in a larger cooperative group phase II trial to further define its toxicity and efficacy in high risk SGC. We thank Bristol Myers Squibb for support of this study. No significant financial relationships to disclose.

Analysis of the GeneXpert System on the International Multicentre ICORG 08–02 Phase II Study of Nilotinib 300mg BID as Frontline Treatment in Patients with Early Chronic Phase Chronic Myeloid Leukemia (ECPCML),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3774-3774 ◽  
Author(s):  
Michael E O'Dwyer ◽  
Ronan Swords ◽  
Francis Giles ◽  
Mary Frances McMullin ◽  
Philipp D. le Coutre ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Low Risk ◽  
Phase Iii ◽  
Additional Patient ◽  
Molecular Response ◽  
Grade Iii

Abstract Abstract 3774 BACKGROUND/METHODS: Data from the ENESTnd phase III trial showed superiority of nilotinib over imatinib leading to accelerated approval of nilotinib as initial treatment of ECPCML at a dose of 300mg BID. ICORG, the All-Ireland Cooperative Oncology Research Group, has been coordinating an international open-label, single stage, multicenter, investigator-initiated phase II study (ClinicalTrials.gov NCT00809211) of the safety and efficacy of nilotinib 300 mg BID in previously untreated patients with ECPCML. The primary study endpoint is the complete cytogenetic response (CCyR) rate at 6 months; secondary endpoints include the kinetics of molecular response, determined by RQ-PCR at baseline and 3 monthly from start of treatment as well as an evaluation of a novel rapid turnaround PCR system “GeneXpert” with IS BCR-ABL1/ABL1 RQ-PCR. The study closed to accrual with 61 patients (median age 54 years [range 20 –77]) enrolled; 53% have low risk Sokal score, 25% intermediate and 22% high risk. Median follow up is currently 12 months (range 1–30) and by November 2011 all patients will have had at least 6 months follow up. RESULTS: At the time of this analysis, 6 and 12 month follow up data were available in 43 and 31 patients, respectively. By intention to treat analysis, 41/43 (95%) have achieved CCyR within 6 months with all patients still on treatment at 12 months achieving CCyR. 26/43 (60%) and 25/31 (81%) of patients have achieved a major molecular response (MMR) (BCR-ABL1/ABL1 IS ≤ 0.1%) within 6 and 12 months, respectively, with 16/31 (52%) and 11/31 (35%) patients on treatment at least 12 months achieving BCR-ABL1/ABL1 IS ≤ 0.01% and ≤ 0.0032%, respectively. Sokal risk had no apparent effect on response with 12/16 (75%) low risk and 13/15 (87%) intermediate/high risk patients achieving MMR within 12 months, p=0.65. Thus far 4/6 (67%) high risk Sokal patients achieved BCR-ABL1/ABL1 IS ≤ 0.0032% within 12 months. No patients have suffered CML progression to date. 53 patients remain on study. Six patients have been removed from study due to adverse events: 4 patients due to persistent drug-related toxicity; 2 patients non drug-related events (death due to progressive multiple system atrophy and colorectal carcinoma, respectively). In addition, one patient was enrolled but never received study drug and an additional patient was lost to follow up. Treatment was generally well tolerated and toxicities easily managed. Haematologic toxicity was minimal with grade III/IV thrombocytopenia seen in 3 (5%) patients and only a single patient (2%) each with grade III/IV neutropenia and anemia, respectively. The most common grade III/IV non-haematologic toxicity was lipase elevation, seen in 14/61 (23%). No cases of acute pancreatitis were seen. Other grade III/IV non-hematologic toxicities were uncommon (< 5% patients). While treatment was interrupted at least once in 36/59 (61%) patients, the median duration of interruptions was short (5 days). At last follow up 49/59 (83%) of patients were taking ≥ 300mg BID. The study evaluation of the “GeneXpert” PCR system consisted of paired BCR-ABL1/ABL1 measurements performed by RQ-PCR methodologies aligned to International Standard (IS) and by the Xpert BCR-ABL Monitor system on 36 evaluable patients at diagnosis and at 128 subsequent three-monthly time-points. In patients expressing e13a2 or e14a2 BCR-ABL1 transcripts, both techniques had comparable results at diagnosis: IS median BCR-ABL1/ABL1 41.0% vs 44.0% median BCR-ABL1/ABL1 on the Xpert BCR-ABL Monitor. In the 122 paired analyses, correlation between methodologies, without automated system IS conversion, over a five log range (IS BCR-ABL1/ABL1 100–0.001%) was favourable (r2=0.845), however a progressive decline in correlation was noted with each decreasing log IS BCR-ABL1/ABL1 level. No significant difference was observed between the Xpert BCR-ABL Monitor and IS RQ-PCR in identifying MMR (44.3% vs 41.8%). CONCLUSION: In ECPCML, nilotinib 300mg BID induces high rates of CCyR and MMR with a substantial fraction of patients achieving responses in the range of complete molecular response (CMR). This regimen's toxicity is modest. The GeneXpert system provides a reliable and rapid means of assessing CML patients' response to tyrosine kinase inhibitor (TKI) therapy. Development of a reagent lot-specific conversion factor to the IS would enhance GeneXpert's applicability in monitoring TKI therapy in patients with CML. Disclosures: O'Dwyer: Novartis: Honoraria, Research Funding. Giles:Novartis: Consultancy, Honoraria, Research Funding. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau. Nagler:Novartis: Honoraria, Research Funding. Egan:Novartis: Employment. Conneally:Novartis: Honoraria.

scholarly journals Primary mFOLFOX6 Plus Bevacizumab Without Resection of the Primary Tumor for Patients Presenting With Surgically Unresectable Metastatic Colon Cancer and an Intact Asymptomatic Colon Cancer: Definitive Analysis of NSABP Trial C-10

2012 ◽  
Vol 30 (26) ◽  
pp. 3223-3228 ◽  
Author(s):  
Laurence E. McCahill ◽  
Greg Yothers ◽  
Saima Sharif ◽  
Nicholas J. Petrelli ◽  
Lily Lau Lai ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Surgical Resection ◽  
Primary Tumor ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Morbidity Rate ◽  
Metastatic Colon Cancer ◽  
Major Morbidity ◽  
End Point

Purpose Major concerns surround combining chemotherapy with bevacizumab in patients with colon cancer presenting with an asymptomatic intact primary tumor (IPT) and synchronous yet unresectable metastatic disease. Surgical resection of asymptomatic IPT is controversial. Patients and Methods Eligibility for this prospective, multicenter phase II trial included Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1, asymptomatic IPT, and unresectable metastases. All received infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) combined with bevacizumab. The primary end point was major morbidity events, defined as surgical resection because of symptoms at or death related to the IPT. A 25% major morbidity rate was considered acceptable. Secondary end points included overall survival (OS) and minor morbidity related to IPT requiring hospitalization, transfusion, or nonsurgical intervention. Results Ninety patients registered between March 2006 and June 2009: 86 were eligible with follow-up, median age was 58 years, and 52% were female. Median follow-up was 20.7 months. There were 12 patients (14%) with major morbidity related to IPT: 10 required surgery (eight, obstruction; one, perforation; and one, abdominal pain), and two patients died. The 24-month cumulative incidence of major morbidity was 16.3% (95% CI, 7.6% to 25.1%). Eleven IPTs were resected without a morbidity event: eight for attempted cure and three for other reasons. Two patients had minor morbidity events only: one hospitalization and one nonsurgical intervention. Median OS was 19.9 months (95% CI, 15.0 to 27.2 months). Conclusion This trial met its primary end point. Combining mFOLFOX6 with bevacizumab did not result in an unacceptable rate of obstruction, perforation, bleeding, or death related to IPT. Survival was not compromised. These patients can be spared initial noncurative resection of their asymptomatic IPT.

Sphingosomal Vincristine in CHOP +/− Rituximab Is a Promising New Treatment for Patients with High Risk Untreated Aggressive Non-Hodgkin’s Lymphoma (NHL): Follow-Up Results of a Phase II Study Sphingosomal Vincristine in CHOP +/− Rituximab Is a Promising New Treatment for Patients with High Risk Untreated Aggressive Non-Hodgkin’s Lymphoma (NHL): Follow-Up Results of a Phase II Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4602-4602
Author(s):  
Maria Alma Rodriguez ◽  
Andreas Sarris ◽  
Nam H. Dang ◽  
Luis Fayad ◽  
Andre Goy ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Hodgkin’S Lymphoma ◽  
Phase Ii Study ◽  
Hodgkin's Lymphoma ◽  
Total N ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
New Treatment

Abstract Sphingosomal vincristine (SV) is a novel formulation of vincristine encapsulated in sphingomyelin liposomes or ‘sphingosomes’. SV was well tolerated with 45% ORR in multiply relapsed aggressive NHL (ASH Abst.412, 1999). The addition of rituximab to CHOP improves response in aggressive B-cell lymphomas in the elderly (Coiffier et al., NEJM2002:346; 235–42). Based on these data, a phase II study of RCHOP, substituting SV for free vincristine, was undertaken in patients with previously untreated aggressive NHL (excluding rituximab if T-cell lymphoma). Methods: Patients were treated with standard dose CHOP that included SV 2.0 mg/m2 without dose capping ± rituximab 375 mg/m2, given every 21 days for 6 to 8 courses (ASH Abst.338, 2002). Results: Of 73 patients enrolled in the study, 68 were evaluable for response. Median age was 63 (range 22–80). IPI score was 0–2 in 44 pts and ≥ 3 in 24 pts. Patients received a median of 6 study treatments (range 1–8). ORR was 93% (63/68 pts) with 62 pts achieving CR and Cru (91%), and 1 PR (2%). 3 pts had PD (4%) and 2 were not assessed for response (3%). The median PFS and OS have not been reached at a median follow up of 29.5 months. Responses according to IPI score were as follows: Results IPI 0–2 (n=44) IPI ≥3 (n=24) Total (n=68) ORR 93% (41) 92% (22) 93% (63) −CR 77% (34) 88% (21) 81% (55) −Cru 14% (6) 4% (1) 10 (7) −PR 2% (1) 0% (0) 2% (1) PD 5% (2) 4% (1) 4% (3) Not Assessed 2% (1) 4% (1) 3% (2) The probability of being progression free at 25 months was 86% (5 relapses and 1 death, reason unknown) for pts with IPI 0–2 and 77% (6 relapses) for pts with IPI ≥3. Overall survival probability was 94% at 28 months (1 death in the group with IPI 0–2 and 2 deaths in the group with IPI ≥3). Neuropathy was generally mild (Gr.1–2). Hematological toxicities were as follows: 64% Gr.3–4 neutropenia, 6% Gr.3 anemia, and 14% Gr.3–4 thrombocytopenia. Conclusions: CHOP plus rituximab regimen with sphingosomal vincristine substituted for free vincristine demonstrated promising activity with durable responses similar in both groups of patients with IPI score 0–2 and IPI ≥ 3. The treatment was well tolerated with only mild neurotoxicity.

Age-Stratified Treatment-Modalities for Patients with Primary CNS Lymphoma: Results of a Phase II Study and Two Pilot-Studies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4683-4683
Author(s):  
Gerald Illerhaus ◽  
Reinhard Marks ◽  
Fabian Mueller ◽  
Friedrich Feuerhake ◽  
Christoph Ostertag ◽  
...  
Keyword(s):  
Overall Survival ◽  
Pilot Study ◽  
Phase Ii ◽  
Phase Ii Study ◽  
High Dose ◽  
Single Center ◽  
Pilot Phase ◽  
Multicenter Phase ◽  
New Treatment

Abstract Background: Primary NHL of the CNS (PCNSL) are associated with a dismal prognosis despite initial response to steroids and radiotherapy (RT). Addition of high-dose methotrexate (HD-MTX) to RT has improved the prognosis of patients (pts) with PCNSL. However, the majority of pts eventually relapse. To improve survival we performed a multicenter phase II study with early high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) followed by hyperfractionated whole-brain radiation (WBRT) for 30 pts under 65yrs. Five-year overall survival rates of 69% for all pts and 87% for 23 pts receiving HDT and ASCT could be reported (Illerhaus et al., J Clin Oncol. 2006). Purpose: Here we present the results of 1) a pilot study for HDT and ASCT with WBRT restricted to residual disease in pts ≤65 years; 2) a multicenter phase II study for MTX-based CT and 3) a pilot-study for chemo-immunotherapy in pts &gt; 65 years. Methods and Results: New treatment regimen for pts ≤65 years: CT consists of 4 cycles HD-MTX (8g/m2), 2 cycles AraC (2×3g/m2) and thiotepa (40mg/m2) followed by HDT with BCNU (400mg/m2) and thiotepa (4×5mg/kg) before ASCT. To date, 12 pts have been treated in this single center pilot-study. After HDT and ASCT 7/10 pts (70%) responded with complete remission (CR), 2/10 pts with partial remission (PR), 1 pt showed progressive disease (PD) and died after refusing RT. The 2 pts with PR have been irradiated resulting in continuous CR. Two pts were off study due to refractory disease. After a median follow-up of 17 months (mo) (range 4–41) 9/12 pts are alive in continuous CR. One pt developed a systemic relapse and died 8 months after ASCT. Overall, the treatment was well tolerated without grade IV toxicity. Patients &gt;65 yrs, MCP-protocol: Thirty-two pts (17 female, 15 male, median age 71 yrs, range 57–79y) were treated in a phase II trial with 3 repetitive cycles of HD-MTX (3g/m2, d1, 15, 30) combined with procarbazine (60 mg/m2 p.o., d1-10) and CCNU (110 mg/m2 p.o., d 1). There was no lower limit of Karnofsky Performance Status. Thirty-two pts received 1 cycle, 17 pts received 2 cycles and 10 pts received 3 cycles. Best documented response in 25 evaluable pts were CR in 13/32 (41%), PR in 7/32 (22%) and PD 5/32 (16%) pts. Five of 32 pts developed severe renal impairment after MTX and were treated off-study. One patient died due to neutropenic fever. With a median follow-up of 64 mo (range 0–82 mo), the 5-year overall survival probability currently is 30.5%, the median survival is 15 mo. As of July 2006 9/32 (28%) pts are alive, 8 without evidence for leukoencephalopathy. New treatment regimen for pts &gt;65 years, R-MCP-Protocol: In a subsequent pilot-phase rituximab has been added before each MTX-application. In a single center pilot-phase, 9 pts were treated within the protocol. The response rates were CR in 4/7 (57%) evaluable pts, PR, SD and PD, each in one pt, respectively. One patient received only one dose of MTX due to liver toxicity and developed CR with rituximab as single agent. To date, after a median follow-up of 4 mo (range 0–11mo) 8 of 9 pts are alive. Conclusion: The protocols presented here are safe and show high efficacy in treating patients with PCNSL in both age-groups. The addition of rituximab to MTX-based chemotherapy is promising and warrants further investigation.

Phase II Pilot Study of Oral Dasatinib in Subjects with Higher Risk Myelodysplastic Syndrome (MDS) Who Failed Conventional Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1727-1727
Author(s):  
Vu H. Duong ◽  
Michael V. Jaglal ◽  
Ling Zhang ◽  
Vishakha Kale ◽  
Jeffrey E. Lancet ◽  
...  
Keyword(s):  
Pilot Study ◽  
High Risk ◽  
Disease Progression ◽  
Phase Ii ◽  
Stable Disease ◽  
Leukemic Cell ◽  
Cell Transplant ◽  
Time To Progression ◽  
Lyn Kinase ◽  
Dasatinib Treatment

Abstract Abstract 1727 Introduction: Src family kinases (SFKs), in particular Lyn kinase, play a critical role in mediating GM-CSF and G-CSF response in myeloid leukemic cell proliferation. Lyn kinase is constitutively active in AML blasts and MDS megakaryocyte progenitors, and inhibition of Lyn suppresses leukemic cell growth in vitro (Ozawa Y, et. al. Leuk Res 2008). Given dasatinib's broad spectrum of kinase inhibition, we hypothesized that dasatinib treatment could limit blast proliferation in patients with high risk MDS. Methods and Materials: This was a single-center, open-label, 2-stage phase II pilot study of dasatinib in patients with Int-2 or High risk MDS according to International Prognostic Scoring System (IPSS) score. All WHO subtypes of MDS, CMML, or MDS/MPD were allowed. Patients with AML with Multilineage Dysplasia (MDS/AML) with <30% blasts (RAEB-t) who either declined or were deemed unfit for induction chemotherapy were also eligible. Exclusion criteria were WBC >50,000 off hydroxyurea, another malignancy requiring radiation or chemotherapy within the past 3 years, or concurrent therapy for MDS or AML. The primary objectives were to estimate the response rates utilizing international working group criteria (IWG 2006). Secondary objectives were to assess time to progression, median duration of response, and to assess the relationship between response and target phosphorylation of src-Tyr416. All patients received a daily dose of oral dasatinib 100 mg daily. All patients were followed for 16 weeks from the first dose. Dose escalation to 150 mg per day was permitted for patients who did not achieve at least a partial response and who were tolerating treatment. Responding patients continued dasatinib treatment for up to 48 weeks in the absence of treatment failure, disease progression, limiting toxicity, or death. Results: Between March 7, 2008 and July 15, 2009, 18 patients were treated at the Moffitt Cancer Center. Median age was 73.5 years (range 60–84), 10 (55%) were male, median bone marrow blast percentage was 13.5%, and all patients had received prior therapy with hypomethylating agents (HMAs). By WHO classification, 2 patients (11%) had RAEB-1, 11 (61%) had RAEB-2, 2 had AML (11%), and 3 (17%) had CMML. There were 3 responses (17%), all of which were marrow CRs without hematologic improvement. Four patients (22%) had stable disease and 10 patients (59%) experienced disease progression. One patient stopped treatment after one week due to cholecystitis and elected for hospice. Fifteen of the 18 patients discontinued therapy due to lack of hematologic response or disease progression, 2 due to adverse events, and one patient received an allogeneic stem cell transplant. Eight of the 16 patients (50%) with MDS or CMML progressed to AML with a median time to progression of 4.4 months [95% CI 0.3–8.5 months]. Kaplan-Meier estimate of median overall survival was 7.6 months [95% CI 2.6–12.5 months] (Figure 1), with an estimated 1 year survival of 38%. The 7 patients that achieved at least stable disease had longer survival (28.5 months, 95% CI 0.0–60.9) than the 11 patients with disease progression or failure (4.0 months, 95% CI 1.8–6.3). The most common grade 3 or 4 toxicities were fatigue, infection, anemia, and thrombocytopenia. Laboratory studies evaluating src-Tyr416 phosphorylation are currently under review. Conclusions: Dasatinib was found to have limited activity in patient higher-risk myelodysplastic syndromes that failed HMAs, but with acceptable toxicity. Further studies should focus on development of predictive markers to guide selection of patients most likely to benefit. Disclosures: No relevant conflicts of interest to declare.

Prolonged Survival with Low Incidence of CNS Relapse and Late Toxicities in a Retrospective Series of 278 Young Patients with High-Risk (aa-IPI 2–3) Diffuse Large B-Cell Lymphoma Treated with Intensified Chemotherapy with or without Rituximab At Diagnosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1606-1606
Author(s):  
Annalisa Chiappella ◽  
Alessia Castellino ◽  
Maria Giuseppina Cabras ◽  
Anna Marina Liberati ◽  
Andrea Evangelista ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Secondary Malignancies ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Dose Dense

Abstract Abstract 1606 Introduction. Diffuse Large B-cell Lymphoma (DLBCL) patients at high-risk (age-adjusted International Prognostic Index (aa-IPI) 2–3), had a dismal prognosis if treated with conventional chemotherapy. The introduction of intensive regimens and the addition of monoclonal antibody anti-CD20, improved prognosis, but some issues remain unresolved such as: the risk of central nervous system (CNS) relapses and the incidence of late toxicities. We analyzed a series of young DLBCL patients at high-risk consecutively treated in four prospective trials by the Italian Lymphoma Foundation (FIL) with the aim to assess the risk of CNS relapses and late toxicities in this series of patients with a prolonged follow-up Methods. From 1986 to 2006, 278 patients with DLBCL with aa-IPI 2–3 at diagnosis, were enrolled in four consecutive trials previously reported. Thirty-two into a phase II study, treated with 12 weekly infusion of MACOP-B; 39 into a phase II trial with eight weekly MACOP-B infusions followed by high-dose cytarabine, mitoxantrone and dexamethasone (MAD) plus standard BEAM and autologous stem cell transplantation (ASCT); 95 in a phase III trial that randomized high-dose sequential (HDS) chemotherapy plus ASCT (45 patients) vs six courses of dose-dense intensified CHOP (iCHOP) (50 patients); 112 into a phase II trial with four courses of iCHOP in combination with Rituximab followed by Rituximab-MAD + BEAM and ASCT. CNS prophylaxis was not mandatory in the four protocols. Updated data regarding of survival, CNS relapses and late toxicities were recorded on June 2011. Results. Clinical characteristics were: aa-IPI 2 in 55%, aa-IPI 3 in 45%, PS > 2 in 66%, LDH upper normal value in 89%, number of extranodal sites > 2 in 35%, bone marrow involvement in 27% of patients, with no statistical differences between the four trials. With a median follow-up of five years, 5-year Overall Survival (OS) was 63% (95% CI: 57–69%) in the whole series; 5-year OS by treatment was 41% (95%CI: 24–74%) in MACOPB, 54% (95%CI: 37–68%) in MACOPB+MAD+BEAM and ASCT; 53% (95%CI: 38–67%) in HDS+ASCT; 58% (95%CI: 43–70%) in iCHOP; 79% (95%CI: 70–86%) in R-iCHOP+R-MAD+BEAM and ASCT. In a multivariate analysis, the risk of death was significantly reduced in R-iCHOP+R-MAD+BEAM and ASCT (p<.001) and was adversely influenced by age with a progressive increase of five years at diagnosis (p.008) or aa-IPI3 (p.001). Four patients experienced CNS relapses, three of them in R-iCHOP+R-MAD+BEAM and ASCT and one in MACOPB. Only one of the four patients received CNS prophylaxis with intrathecal Methotrexate, even if all of them were at risk for CNS relapse according to Italian Society of Hematology guidelines (Barosi, Hematol 2006). Cumulative incidence of CNS recurrence at 10 years for R-iCHOP+R-MAD+BEAM and ASCT regimen was 3.6% (0 to 7.8). Most frequent late toxicities were dyslipidemia and secondary amenorrhea. Regarding to secondary malignancies, myelodisplasia or acute myeloid leukemia were recorded in three patients, two of them treated with R-iCHOP+R-MAD+BEAM and ASCT, at a median time of seven years off therapy. The actuarial risk of secondary malignancies at 10 years for R-iCHOP+R-MAD+BEAM and ASCT was 4.2% (0 to 10). Conclusions. The addition of Rituximab to dose-dense iCHOP plus high-dose chemotherapy plus BEAM and ASCT improved the outcome in young untreated DLBCL patients at poor prognosis, with an acceptable risk of secondary malignancies and late toxicities. A careful identification of patients at risk could avoid the risk of CNS relapse. Disclosures: Vitolo: Roche Italy: Speakers Bureau; Celgene: Speakers Bureau; Jannsen-Cilag: Speakers Bureau.

Car-Bird [Carfilzomib, Clarithromycin(Biaxin®), Lenalidomide/(Revlimid®), Dexamethasone) for Newly-Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4761-4761 ◽  
Author(s):  
Tomer M Mark ◽  
Abbe Schickner ◽  
John N. Allan ◽  
Adriana C Rossi ◽  
Roger Pearse ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Maximum Response ◽  
First Line ◽  
Advisory Committees ◽  
Cell Harvest ◽  
Grade Iii

Abstract Background: Carfilzomib (Cfz), lenalidomide, and dexamethasone synergize to provide an impressive overall response rate (ORR) in upfront treatment of multiple myeloma (MM) (Jakubowiak et al 2012). The ORR to Cfz+dexamethasone (Cfz-Dex) as first-line therapy is unknown. We hypothesized that sequential treatment with Cfz-dex and BiRD would improve provide similar ORR and improve tolerability. A protocol of Cfz-Dex, consolidation with BiRd (Clarithromycin(Biaxin¨), Lenalidomide/(Revlimid¨), dexamethasone), and lenalidomide maintenance (Len) was conducted to evaluate ORR and safety as induction therapy for MM. Methods: Forty patients (pts) with symptomatic untreated MM were enrolled in a phase 2 study of Car-BiRd. Car-BiRd therapy is: Cfz IV over 30 min on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of the 1st cycle only and 45mg/m2 for each dose thereafter and dex 40mg on D1, 8, 15, 22. After the first 26 pts were enrolled, the protocol was amended to increase the Cfz from 45 to 56mg/m2. Echocardiography and spirometry were performed prior to study entry and serum brain natriuretic peptide (BNP) was followed monthly to evaluate for heart or lung toxicity. Cfz-dex was continued until plateau in disease response, defined as unchanged M-protein for 2 cycles. Elective stem cell collection was then performed in transplant eligible pts and consolidation with BiRd initiated. Transplant ineligible pts proceeded directly to BiRd. BiRd is: Clarithromycin 500mg BID, lenalidomide 25mg daily on D1-21, and dex 40mg on D1, 8, 15, 22 of 28-day cycle. BiRd was continued until a 2nd response plateau after which lenalidomide maintenance (Len) at 10mg daily D1-21 of 28 day cycle was continued until disease progression or intolerability. Results: 36 pts completed at least 1 cycle and were evaluable for response. 58% of pts were ISS II/III. High-risk cytogenetics and unfavorable MyPRS score were found in 62% and 21% of pts, respectively. Median study follow-up was 66.2 weeks (range 3.7-114.7). Maximum response to the Cfz-dex, BiRd, and Len is shown in Table 1. Median time to PR was 1 cycle. Median time to maximum response with Cfz-dex, BiRD, and Len was 2, 2, and 4 cycles respectively. At last audit, 8 (22%) pts remain on Cfz-Dex; 21 (58%) reached plateau and received BiRd. Of the pts that received BiRd, 9 (43%) improved categorical response and 19 (90.5%) received Len. Two (11%) pts deepened response to CR while on Len. 97.5% of pts are alive and 82.5% without progression at last follow-up. One pt died after coming off study (withdrew consent) from sepsis during elective autologous stem cell transplant. Pts with high risk cytogenetics had a trend towards a shorter progression free survival (PFS), with median 71.7 weeks vs not reached (NR) (P = 0.058). Similar results were seen with unfavorable MyPRS score with a shorter median PFS at 71.7 weeks vs NR (P = 0.094). 17 pts had stem cell harvest following Cfz-dex. All collected stem cells to support at least two transplants, with median 14.5 x 10^6 (range 7.06-27) CD34/kg in a median of 1 (range 1-2) apheresis session. 18 pts (46.2%) have come off study, 6 (15%) for disease progression (2 during CfzDex , 1 during BiRD, 3 during Len) and 5 pts (12.5%) due to toxicity: 3 pts for renal failure [2 Grade 2, I grade 3, all with renal recovery after discontinuation, all attributable to Cfz]; 1 pt due to Grade III CHF [attributable to Cfz with recovery]; 1 pt with Grade III Thromboembolic [attributable Len]. There was no correlation between pre-study cardiac and lung function, or serial BNP, with toxicities. Seven (17.9%) pts came off study for noncompliance, lost to follow up, investigator discretion, or withdrew consent (Cfz-dex: 4, BiRD: 1, Len: 2). Discussion: This is the first prospective study evaluating induction response to Cfz/Dex in MM. Cfz/Dex is safe and active, with ORR of 91.7% and rate of >=VGPR of 55.6%, despite the majority with a high-risk cytogenetics. Cfz-dex did not hinder stem cell harvest. ORR improved with lenalidomide-based consolidation and maintenance, with CR rate > 50%. Baseline heart/lung function or serial BNP change did not predict emerging toxicities. Table 1: Maximum Response For Car-BiRD Phase: Response Category Car-Dex BiRD Lenalidomide N = 36 N = 21 N = 19 PD 0 1 (4.8) 0 SD 3 (8.3) 0 0 PR 13 (36.1) 1 (4.8) 1 (5.3) VGPR 17 (47.2) 12 (57.1) 8 (42.1) CR 1 (2.8) 0 0 SCR 1 (2.8) 5 (23.8) 8 (42.1) ICR 1 (2.8) 2 (9.5) 2 (10.5) >=PR 91.7 95.2 100 >=VGPR 55.6 90.4 94.7 >=CR 8.4 33.3 52.6 Disclosures Mark: Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib is not approved for first-line treatment of myeloma. . Rossi:Celgene: Speakers Bureau. Pekle:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Onyx: Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesvizky:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Biweekly cetuximab and irinotecan as second-line therapy to patients with platinium-resistant gastroesophageal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15624-e15624 ◽  
Author(s):  
J. K. Bjerregaard ◽  
K. R. Schønnemann ◽  
H. A. Jensen ◽  
L. W. Vestermark ◽  
T. P. Hansen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Performance Status ◽  
Haematological Toxicity ◽  
Median Number ◽  
National Board ◽  
Line Therapy ◽  
Grade 3 ◽  
Number Of Cycles ◽  
The Cost

e15624 Background: There is no established 2nd line therapy for patients (pts) with advanced gastroesophageal (GE) cancer. In 2004, the Danish government initiated a national health programme for pts with advanced cancer. Non- proven therapy may be offered after approval by an expert panel appointed by the National Board of Health that subsequently finances the cost of treatment. This programme has had a major impact on the management of cancer pts in Denmark and has accelerated the introduction and implementation of new therapies. Inspired by the excellent results in colorectal cancer a combination of cetuximab and irinotecan (CetIri) was chosen for platinum-resistant GE cancer. While awaiting approval of a phase II protocol CetIri was offered at a single institution. We report our preliminary experience with biweekly CetIri as 2nd line therapy in pts with GE cancer. Methods: All pts had histologically confirmed GE cancer (adeno- or squamous cell carcinoma) and all pts had previously received first line platinum based therapy. Pts received CetIri (cetuximab 500 mg/m2and irinotecan 180 mg/m2day 1) every 2nd week until progression or unacceptable toxicity. Response rate was evaluated by the investigator according to RECIST every 8th week. Toxicity was prospectively evaluated according to NCIC-CTC 3.0. Results: From December 2007 to August 2008, 31 consecutive pts was treated with CetIri. Median age was 62 years (33–76). Median performance status was 1 (0–2). Localisation of primary was: Esophagus 10%, GE junction 64%, gastric 26%. Twenty-seven pts (87%) had adenocarcimona. Median number of cycles were 6 (1–21). Most important grade 2–4 toxicities were non-haematological toxicity as diarrhea (25%), nausea (21%) and vomiting (11%). Three pts (11%) had grade 3 leukopenia, 1 had febrile neutropenia. Two pts had PR. Median PFS was 3.2 months. Fourteen pts (45%) received at least 6 courses (3 month of therapy). After a median follow-up of 6 month 5 pts continue CetIri without sign of PD. Conclusions: Biweekly CetIri is a convenient and well-tolerated 2nd line regimen in pts with GE cancer. Predictive factors are needed to select which pts will benefit from therapy. A confirmatory phase II study is ongoing. [Table: see text]

Phase II study of the frontline combination of ipilimumab and temozolomide in patients with metastatic melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8514-8514 ◽  
Author(s):  
Sapna Pradyuman Patel ◽  
Wen-Jen Hwu ◽  
Kevin B. Kim ◽  
Nicholas E. Papadopoulos ◽  
Patrick Hwu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Cell Function ◽  
Performance Status ◽  
Phase Iii ◽  
Induction Phase ◽  
Ecog Performance Status ◽  
Two Phase

8514 Background: Ipilimumab (Ipi) alters the immune system balance by inhibiting the suppression of T-cell function. In two phase III trials, Ipi has shown an overall survival benefit alone and in combination with dacarbazine in previously treated and treatment-naïve patients (pts) with metastatic melanoma (MM), respectively. We performed a single-institution, phase II clinical trial of Ipi plus temozolomide (Tem) in pts with MM. Methods: Pts between the ages of 18 and 75 with previously untreated unresectable stage III or stage IV MM and an ECOG Performance Status of 0 to 1 were enrolled in a phase II trial of Ipi plus Tem. Induction phase consisted of Ipi 10mg/kg intravenous on Day 1 and oral Tem 200 mg/m2 on Days 1 – 4 every 3 weeks for 4 doses. Maintenance consisted of Ipi 10 mg/kg intravenous on Day 1 starting week 12 and repeated every 12 weeks and oral Tem 200 mg/m2 on Days 1 – 5 starting week 12 and repeated every 4 weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS) rate at 6 months. Responses were evaluated using immune-related response criteria. Results: Sixty-four pts were enrolled and received at least one dose of study drug. All pts were included in the analysis. With a median follow-up of 8.5 months, the PFS rate at 6 months was 43%, exceeding the proposed rate of 30%, and the median PFS was 5.1 months. There were 10 (15.6%) confirmed complete responses and 8 (12.5%) confirmed partial responses. At the time of this analysis, median overall survival has not been reached. Immune-related adverse events (irAEs) were experienced by 88% of pts, most commonly pruritus (88%), rash (83%), diarrhea (56%), transaminitis (45%), and colitis (11%). Grade 3/4 irAEs seen in more than one patient were skin rash (11%), diarrhea (9%), pruritus (6%), and transaminitis (5%). Constipation occurred in 70% of pts and was the most common gastrointestinal (GI) toxicity. There were no GI perforations or deaths on study due to treatment. Conclusions: At a median follow-up of 8.5 months, the best overall response rate in this study is 28%. Ipi at 10 mg/kg in combination with Tem given in an induction followed by maintenance fashion is safe, well-tolerated, and efficacious in MM.

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