scholarly journals Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Musa Yilmaz ◽  
Mansour Alfayez ◽  
Courtney D. DiNardo ◽  
Gautam Borthakur ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Median Overall Survival ◽  
Second Generation ◽  
Single Agent ◽  
Response Rates ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
First Time

Abstract Background Second-generation FLT3-inhibitors (FLT3i) demonstrated single-agent composite CR rates (CRc) of 45–55% in patients with relapsed/refractory (R/R) FLT3-mutated AML in phase II/III trials. However, > 85% of patients treated were prior FLT3i naïve. The response rates to sequential FLT3i exposure remain poorly defined. Methods We retrospectively reviewed patients with FLT3-mutated AML between November 2006 and December 2019. Results In frontline patients treated with a FLT3i (cohort 1), the CRc rates and median overall survival (OS) with the first (n = 56), second (n = 32), and third FLT3i-based (n = 8) therapy were 77%, 31%, and 25%, and 16.7 months, 6.0 months, and 1.4 months, respectively. In patients receiving a FLT3i-based therapy for the first time in a R/R AML setting (cohort 2), the CRc rates and median OS were 45%, 21%, and 10%, and 7.9 months, 4.0 months, and 4.1 months with the first (n = 183), second (n = 89), and third/fourth (n = 29) FLT3i-based therapy, respectively. In cohort 1, CRc rates with single-agent FLT3i (n = 21) versus FLT3i-based combinations (n = 19) in second/third sequential FLT3i exposures were 19% versus 42%, respectively. In cohort 2, the CRc rates with single-agent FLT3i (n = 82) versus FLT3i-based combinations (n = 101) in first FLT3i exposure were 34% versus 53%, respectively, and those with single-agent FLT3i (n = 63) versus FLT3i-based combinations (n = 55) in second/third/fourth sequential FLT3i exposures were 13% versus 25%, respectively. Conclusion CRc rates drop progressively with sequential exposure to FLT3i’s in FLT3-mutated AML. In all settings, CRc rates were higher with FLT3i-based combinations compared with single-agent FLT3i therapy in similar FLT3i exposure settings.

scholarly journals Improvement in Clinical Outcome of FLT3 Mutated AML Patients over the Last One and a Half Decade

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 949-949
Author(s):  
Talha Badar ◽  
Hagop M. Kantarjian ◽  
Gautam Borthakur ◽  
Guillermo Garcia Manero ◽  
Michael Andreeff ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Clinical Outcome ◽  
Induction Therapy ◽  
Research Funding ◽  
Median Overall Survival ◽  
Treatment Strategies ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Time To Relapse

Abstract Background: FMS-like tyrosine kinase 3 gene (FLT3) mutations occur in approximately 30% of all AML patients. The overall prognosis of FLT3 mutated AML patients (pts) remains poor. As we have learned more about the aggressive nature of this disease our treatment strategies have changed. Incorporating FLT3 inhibitors with chemotherapy and allogeneic stem cell transplant in first remission are routinely pursued in these pts. In this context we reviewed data to evaluate clinical outcome of FLT3-ITD mutated AML pts since 2000 in a single institution. Methods: We retrospectively analyzed 1441 pts referred to our institution between 2000 and 2014. FLT3 internal tandem duplications (FLT3-ITD) were found in 334 pts with AML. After excluding pts with core binding factor leukemia and acute promyelocytic leukemia, 224 pts were included in this analysis. Among these 224 pts, 21 (9%) pts also had tyrosine kinase domain D835 (TKDs) mutated. Patients are evaluated for response to therapy, treatment related mortality and overall survival. Results: Patients were divided into 5 cohorts by era: 2000-02 (Era 1, n=19), 2003-05 (Era 2, n=41), 2006-08 (Era 3, n=53), 2009-11 (Era 4, n=55), 2012-14 (Era 5, n=56). The median age from Era 1-5; 57, 61, 59, 61, and 65 yrs respectively, p= 0.55. None of the pts in Era 1 received FLT3 inhibitor (inh.) therapy, 4 (10%) in Era 2, 17 (32%) in Era 3, 34 (49%) in Era 4, and 34 (61%) in Era 5 received FLT3 inh. Among these 2 (5%) pts in Era 2, 11 (27%) in Era 3, 9 (16%) in Era 4 and 30 (54%) pts in Era 5 received FLT3 inh. with their frontline therapy. SCT in 1st remission occurred in 4 (21%) pts in Era 1, one in Era 2, 10 (19%) in Era 3, 18 (33%) in Era 4, and 14 (25%) in Era 5. Two (5%) pts in Era 2, 5 (9%) pts in Era 3, 3 (5%) pts in Era 4, and 2 (4%) pts in Era 5, had SCT in 2nd remission. The overall response rate (ORR) to induction chemotherapy in the 5 Eras were 74%, 51%, 77%, 84% and 82%, respectively. The rate of complete remission (CR) from Era 1-5 were 63%, 46%, 70%, 65%, and 57% respectively. Complete remission without platelet recovery (CRp) from Era 1-5 was 5%, 2%, 2%, 7% and 18% respectively. The ORR from Era 1-5 in pts who received FLT3 inhibitor combinations induction therapy was 85%; CR 60%, CRp 17%, HI 6% and PR 2%. Whereas ORR to non-FLT3 inhibitor induction therapy from Era 1-5 was 72%; CR 62%, CRp 6%, PR 2% and HI 2%. Among 21 (10%) pts who were FLT3-ITD and TKDs mutated, CR/CRp was achieved in 14 (67%) pts, compare to 139 (69%) pts with only FLT3-ITD mutated, p= 0.84. At 1 year (yr) from diagnosis through Era 1-5 42%, 29%, 58%, 72% and 61% were alive respectively. Four (10%) pts in Era 2, one pt each in Era 4-5 and none in Era 1 and 3 died ≤4 weeks from start of induction therapy. The median time to relapse was 10.6 months (mo) in Era 1, 6.1 mo in Era 2, 9.5 mo in Era 3, and 8.5 mo in Era 4. The median time to relapse was not reached in Era 5 with 63% of patient in CR/CRp at 1 yr, p= 0.45 (Fig.1). The median overall survival (OS) have improved over time, 9.6 mo in Era 1, 7.6 mo in Era 2, 14.4 mo in Era 3, 15.7 mo in Era 4 and 17.8 mo in Era 5, p= 0.0001 (Fig.2). The median OS in all pts who received FLT3 inhibitors in induction chemotherapy from Era 1-5 was 14 mo, compare to 13 mo in pts who had non FLT3 inhibitor induction therapy (p= 0.25). Patients who received FLT3 inhibitors any time in the course of their treatment, the OS was 14.2 mo, compare to 13 mo in pts who never had FLT3 inhibitor therapy (p= 0.941). In the subset analysis, excluding pts who received SCT in 1st CR, the median overall survival from Era 1-5 was 9.2, 6, 11, 13.4 and 17 mo respectively, p= 0.05. Conclusion: Our data suggested some improvement in outcome of FLT3- ITD mutated AML pts over the last decade and a half. This is probably due to more aggressive treatment strategies including integration of FLT3 inhibitors in chemotherapy regimens and increase use of SCT. Efforts are still needed to continue to improve outcome for these subset of poor prognostic AML patients. Figure 1 Figure 1. Disclosures Cortes: Ambit: Research Funding; Astellas: Research Funding; Ariad: Research Funding; Arog: Research Funding; Novartis: Research Funding; Astellas: Consultancy; Ariad: Consultancy; Novartis: Consultancy.

Phase II Study of Pemetrexed With and Without Folic Acid and Vitamin B12 as Front-Line Therapy in Malignant Pleural Mesothelioma

2003 ◽  
Vol 21 (8) ◽  
pp. 1556-1561 ◽  
Author(s):  
Giorgio V. Scagliotti ◽  
Dong-M. Shin ◽  
Hedy L. Kindler ◽  
Michael J. Vasconcelles ◽  
Uwe Keppler ◽  
...  
Keyword(s):  
Overall Survival ◽  
Folic Acid ◽  
Phase Ii ◽  
Malignant Pleural Mesothelioma ◽  
Median Overall Survival ◽  
Single Agent ◽  
Vitamin Supplementation ◽  
Vitamin B ◽  
Pleural Mesothelioma ◽  
Grade 3

Purpose: This phase II clinical study evaluated the efficacy of pemetrexed for the treatment of malignant pleural mesothelioma (MPM). Patients and Methods: Patients with a histologically proven diagnosis of MPM, chemotherapy-naive measurable lesions, and adequate organ function received pemetrexed (500 mg/m2) intravenously over 10 minutes every 3 weeks. After a protocol change, most patients also received folic acid and vitamin B12 supplementation to improve safety. Results: A total of 64 patients were enrolled. Nine (14.1%) of the 64 patients had a partial response. The Kaplan-Meier estimate for median overall survival was 10.7 months. Forty-three patients received vitamin supplementation for all courses of therapy, and 21 patients did not. Seven of the nine responders were vitamin supplemented. The median overall survival was 13.0 months for supplemented patients and 8.0 months for nonsupplemented patients. Vitamin-supplemented patients completed more cycles of therapy than nonsupplemented patients (median, six v two cycles, respectively). Grade 3/4 neutropenia (23.4%) and grade 3/4 leukopenia (18.8%) were the most common laboratory toxicities. Fatigue and febrile neutropenia were the most commonly reported nonlaboratory events (grade 3, 6.3%; grade 4, 0.0% each). The incidence of these toxicities was generally lower in the supplemented patients. Conclusion: Single-agent pemetrexed for MPM resulted in a moderate response rate (14.1%) and median overall survival of 10.7 months. Patients supplemented with folic acid and vitamin B12 tolerated treatment better (less toxicity and more cycles of treatment) and had a 5-month greater median overall survival than nonsupplemented patients. These results indicate that patients with MPM could benefit from single-agent pemetrexed treatment combined with vitamin supplementation.

scholarly journals Phase II Evaluation of Sorafenib in Advanced and Metastatic Squamous Cell Carcinoma of the Head and Neck: Southwest Oncology Group Study S0420

2010 ◽  
Vol 28 (20) ◽  
pp. 3330-3335 ◽  
Author(s):  
Stephen K. Williamson ◽  
James Moon ◽  
Chao H. Huang ◽  
Perry P. Guaglianone ◽  
Michael LeBlanc ◽  
...  
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Phase Ii ◽  
Single Agent ◽  
Response Probability ◽  
Oncology Group ◽  
Southwest Oncology Group

Purpose We conducted a phase II trial to evaluate the efficacy and safety of single-agent sorafenib in chemotherapy-naïve patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN). The primary end point was response probability (ie, confirmed complete and partial response [PR]). Patients and Methods Chemotherapy-naïve patients with metastatic, persistent, or recurrent SCCHN who received one induction or fewer or received an adjuvant chemotherapy regimen, who had adequate organ function, and who had a performance status ≤ 1 were eligible. Sorafenib was administered orally at 400 mg twice daily on a continuous basis in 28-day cycles. Responses were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors). Results Sorafenib was generally well tolerated. Of the 41 eligible patients assessed for adverse events, one experienced a grade 4 adverse event as a result of an asymptomatic pulmonary embolus. The most common grades 2 to 3 adverse events were fatigue, anorexia, stomatitis/oral pain, abdominal pain, hand-foot syndrome, weight loss, and hypertension. There was one confirmed PR and two unconfirmed PRs. The estimated confirmed response probability was 2% (95% CI, 0% to 13%). The estimated median progression-free survival was 4 months (95% CI, 2 to 4 months), and the estimated median overall survival was 9 months (95% CI, 7 to 14 months). Conclusion Sorafenib was well tolerated. Although response was poor, progression-free and overall survival times compare favorably with previous Southwest Oncology Group, phase II, single-agent trials.

Safety and Efficacy of Using a Single Agent or a Phase II Agent Before Instituting Standard Combination Chemotherapy in Previously Untreated Metastatic Breast Cancer Patients: Report of a Randomized Study—Cancer and Leukemia Group B 8642

1999 ◽  
Vol 17 (5) ◽  
pp. 1397-1397 ◽  
Author(s):  
Mary E. Costanza ◽  
Raymond B. Weiss ◽  
I. Craig Henderson ◽  
Larry Norton ◽  
Donald A. Berry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Combination Chemotherapy ◽  
Single Agent ◽  
Metastatic Breast ◽  
Response Rates ◽  
Breast Cancer Patients ◽  
Safety And Efficacy

PURPOSE: We undertook a prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients. PATIENTS AND METHODS: A total of 365 women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide, carboplatin, or elsamitrucin, followed by CAF. RESULTS: The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates for the single agent followed by CAF were not statistically different from those of CAF alone (44% v 52%; P = .24). However, in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the phase II agent plus CAF arm (P = .078). Although survival and response duration also were not statistically significantly different between the two study arms (P = .074 and P = .069, respectively), there was a suggestion of benefit for the CAF-only arm. CONCLUSION: The brief use of a phase II agent, regardless of its efficacy, followed by CAF resulted in response rates, toxicities, durations of response, and survival statistically equivalent to those seen with the use of CAF alone. These findings support the use of a new paradigm for the evaluation of phase II agents in the treatment of patients with metastatic breast cancer.

AC220 Is a Uniquely Potent and Selective Second-Generation FLT3 Inhibitor

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 859-859 ◽  
Author(s):  
Patrick P Zarrinkar ◽  
Robert C Armstrong ◽  
Ruwanthi N Gunawardane ◽  
Joyce James ◽  
Mazen W Karaman ◽  
...  
Keyword(s):  
Cell Line ◽  
Tyrosine Kinases ◽  
Second Generation ◽  
Receptor Tyrosine Kinases ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
Inhibition Of Proliferation ◽  
Flt3 Inhibitor ◽  
Pharmacokinetic Properties ◽  
Flt3 Inhibitors

Abstract Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30 % of acute myeloid leukemia (AML) patients, implicating FLT3 as a potential target for kinase inhibitor therapy. While several compounds have been evaluated in the clinic as FLT3 inhibitors, including CEP-701 (lestaurtinib), PKC-412 (midostaurin), MLN-518 (tandutinib) and most recently sorafenib, none of these was originally developed as a FLT3 inhibitor. We report here the characterization of AC220, a novel compound that has been expressly optimized as a selective FLT3 inhibitor. We demonstrate that this second generation FLT3 inhibitor has a unique combination of high potency, exceptional selectivity, bioavailability, and pharmacokinetic properties compatible with once a day oral dosing. In an in vitro binding assay AC220 interacted with FLT3 with high affinity (Kd = 1.6 nM). In the FLT3 dependent human leukemia cell line MV4-11, which harbors a homozygous activating FLT3 internal tandem duplication (ITD) mutation, AC220 inhibited FLT3 autophosphorylation and cellular proliferation with subnanomolar potency. Inhibition of proliferation of a FLT3 independent cell line was several hundred-fold less potent, demonstrating cellular selectivity for FLT3. A biochemical screen against a panel of 402 kinase assays representing almost 80 % of human protein kinases revealed a highly focused and selective interaction pattern. The only targets with affinity for AC220 within 10-fold that for FLT3 were closely related class III receptor tyrosine kinases (KIT, PDGFR, RET, CSF1R), and the only targets with affinity within 100-fold that for FLT3 were four additional receptor tyrosine kinases (FLT1, FLT4, DDR1, VEGFR2). When orally administered to mice at a dose of 10 mg/kg, AC220 achieved a peak plasma concentration (Cmax) of 3.8 μM (2,100 ng/mL) within two hours of dosing. When corrected for plasma protein binding, the concentration of AC220 in plasma remained above the cellular IC50 for FLT3 inhibition 24 hours after dosing. Total exposure (AUC0-24 h) as well as Cmax increased proportionally with the administered dose from 0.1 to approximately 30 mg/kg. At higher doses, both Cmax and AUC0-24 h continued to increase, approaching a plateau above 100 mg/kg. In a FLT3-ITD-dependent MV4-11 tumor xenograft model, AC220 showed substantial, dose dependent efficacy when dosed at 1, 3 and 10 mg/kg orally once a day for 28 days. Tumors regressed at 3 and 10 mg/kg, and remained static at 1 mg/kg. In a follow-on study at the 10 mg/kg oral dose, tumor size was monitored for an additional 60 days after dosing was discontinued. By the end of the study eight complete responses and two partial responses were observed in the ten animals treated with AC220. AC220 also had activity in a leukemia tumor model at doses as low as 1 mg/kg given orally once a day. A direct comparison of AC220 with the first generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib and sunitinib revealed that the combination of potency, selectivity and pharmacokinetic properties is unique to AC220. AC220 is a second generation FLT3 inhibitor that has been explicitly optimized for the combination of properties believed to be required for the successful treatment of FLT3-dependent AML, and specifically to test the hypothesis that selective FLT3 inhibition will result in clinical benefit. AC220 is currently being evaluated in a phase I clinical trial in relapsed or refractory AML patients.

Frontline Therapy for Older Patients (pts) with Acute Myeloid Leukemia (AML): Clofarabine Plus Low-Dose Cytarabine Induction Followed by Prolonged Consolidation with Clofarabine Plus Low-Dose Cytarabine Alternating with Decitabine

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 336-336 ◽  
Author(s):  
Stefan Faderl ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Xuelin Huang ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Median Overall Survival ◽  
Low Dose ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
Prolonged Consolidation ◽  
Low Dose Cytarabine

Abstract Abstract 336 Standard therapy (e.g. “3+7”) of newly diagnosed older pts (≥ 60 yrs) with AML is characterized by low response rates, short response durations, and substantial toxicities. New approaches are therefore actively explored in clinical trials. Clofarabine is a second generation deoxyadenosine nucleoside analogue with activity in older pts with frontline AML and presence of unfavorable prognostic factors. In our experience, the combination of clofarabine with low-dose cytarabine achieved higher response rates at no increase of toxicity compared with clofarabine alone (Faderl S et al. Blood 2008). Based on the initial experience, we have designed a combination of lower-dose clofarabine plus low-dose cytarabine induction followed by a prolonged consolidation of these drugs alternating with decitabine to improve survival and maintain the high response rates from the earlier study. Pts were eligible if ≥ 60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, creatinine > 1.5 mg/dL, cardiac ejection fraction < 40%, and prior therapy with clofarabine or decitabine. Induction therapy consisted of clofarabine 20mg/m2 i.v daily × 5 days plus cytarabine 20mg s.c. twice daily × 10 days. Responding pts could receive up to 17 courses of consolidation therapy of clofarabine plus cytarabine (over 3 and 7 days, respectively) during courses 1–2, 6–8, 12–14 alternating with decitabine 20mg/m2 i.v. daily for 5 days during courses 3–5, 9–11, and 15–17. All pts received antibiotic prophylaxis with levofloxacin, valacyclovir and itraconazole (or equivalent). Fifty-nine pts have been accrued with a median age of 70 yrs (range 60–81), of whom 17 pts (29%) were ≥ 75 yrs. Eleven pts (19%) had a PS of 2. Seven pts (12%) had a WBC of > 20,000/mcl at diagnosis. Thirty pts (51%) had abnormal cytogenetics. Molecular profile: FLT3/ITD 5 pts (9%), FLT3/D835 2 (4), NPM1 6 (13), Ras 2 (4). Thirteen pts (22%) had prior MDS (4 pts prior azacitidine; 2 pts prior lenalidomide) and 17 pts (29%) had secondary AML (Hx of prior chemo and/or XRT). Of 57 pts evaluable for response, 35 (61%) achieved CR and 4 (7%) CRp for an ORR of 68%. Six pts (11%) required more than one course to response. The ORR for pts with diploid vs abnormal cytogenetics was 79% vs 57%; for pts with prior MDS 46% vs 82% for pts with neither MDS nor secondary AML. All 7 pts with a FLT3 mutation responded. With a median follow up of 11.6 months (1.1-20.2+), 16 pts relapsed. Responses (CR) are ongoing in 19 pts. Median CR duration is 14.1 mos (1.8-16.4). Six pts (10%) died on study. Only one pt suffered an early death ≤ 28 days from induction (C1D26). Deaths were due to myelosuppression-associated infectious complications. Median overall survival for all 59 pts was 18.1 mos (0.8-20.2+). Median overall survival for responding patients has not been reached. The median number of consolidation cycles received by pts in CR/CRp was 4 (0-14). Fifteen of these pts have so far received at least 6 consolidation cycles. Most toxicities were ≤ grade 2 and included rash (64%), nausea (61%), transaminase elevations (58%), bilirubinemia (51%), diarrhea (32%), mucositis, creatinine evelations, and headache (12% each). Among toxicities > grade 2, transaminase elevations (14%) and bilirubinemia (5%) were most frequent. One pt (65 yr old female) experienced renal failure and pulmonary edema shortly following start of the induction. Myelosuppression and neutropenic fever were common, but prolonged myelosuppression in responders was rare. In summary, clofarabine plus low-dose cytarabine achieves high response rates with a manageable toxicity profile and low induction mortality in pts ≥ age 60 with previously untreated AML. Longer follow up and comparisons with conventional therapy will help establish whether or not this combination also has a survival advantage. Disclosures: Faderl: Genzyme: Honoraria, Research Funding; Eisai: Research Funding. Off Label Use: clofarabine and decitabine in AML. Kantarjian:Genzyme: Research Funding; Eisai: Research Funding.

Cyclophosphamide, Adriamycin, Vincristine and Prednisone Plus Rituximab (CHOP-R) in Fludarabine (F) Refractory Chronic Lymphocytic Leukemia (CLL) or CLL with Autoimmune Cytopenia (AIC) or Richter's Transformation (RT): Final Analysis of a Phase II Study of the German CLL Study Group

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2860-2860
Author(s):  
Petra Jenke ◽  
Barbara Eichhorst ◽  
Raymonde Busch ◽  
Nadine Anheier ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Research Funding ◽  
Progression Free Survival ◽  
Response Rates ◽  
Median Number ◽  
Response Evaluation ◽  
Free Survival ◽  
Richter's Transformation ◽  
Grade 3

Abstract Abstract 2860 Introduction: In the last decade, important progress has been achieved in the treatment of CLL through the use of purine analog-based chemoimmunotherapies. Several conditions remain a challenge, often with a poor outcome. Amongst these therapeutic problems are Richter's transformation (RT), refractoriness to F-based therapies (Fref), and the occurrence of AIC, which are sometimes induced by F. Fref and RT pts have a very poor prognosis with an estimated overall survival (OS) of only 10 and 8 months (mos), respectively. Therefore, therapeutic alternatives are urgently warranted. CHOP-R has improved the outcome of pts with aggressive non-Hodgkin's lymphoma. To test the efficacy and tolerability of the CHOP-R regimen in CLL patients with RT, Fref, or AIC, the GCLLSG initiated a prospective phase II trial. Material and Methods: 62 patients were included in the study. Due to protocol violations, 2 patients were excluded. Within the group of Fref pts, the medical review detected 11 patients who had received pre-treatment with F (Fpret), but were not refractory according to the updated guidelines (Hallek et al., Blood 2008). Thus, 26 pts were classified as Fref/pret, 19 pts as AIC and 15 pts as RT. All patients received CHOP every 3 weeks (cyclophosphamide 750mg/m2, adriamycin 50mg/m2 and vincristine 1, 4mg/m2 d1; prednisone 100mg/m2 d1–5). Rituximab was added starting with the 2nd cycle (375mg/m2 on each d0, and 21 days after the last CHOP-R). RT pts received up to 8, Fref/pret and AIC up to 6 courses of CHOP-R. In case of PD after 3 cycles, pts went off-study. The primary endpoints were remission rate, quality and duration of response. Results: 79%, 73%, and 40% of AIC, Fref/pret, and RT pts were male, respectively. The median age was 65 years (y) for Fref/pret-pts, 66y in the AIC and 69y in the RT group. Binet stages for Fref/pret pts were: A: 8%; B: 27% C: 65 %. All but 3 AIC pts were at Binet stage C. Initial RT stages according to Ann Arbor were: II: 13%, III: 13%, IV 73%. The median number of previous therapies were 3 for Fref/pret, 2 for AIC and 2 for RT. A total of 314 cycles were administered, with a median number of 3 cycles for AIC and Fref pts and a median number of 4 cycles for the RT group. Due to toxicity 73% of cycles in the Fref/pret group, 66% in the AIC and 87% in the RT group were dose-reduced. 69% of Fref/pret-pts and 58% of AIC-pts received full 6 cycles of therapy and only 40% of RT-pts completed 8 cycles of therapy. Treatment was stopped in 6 pts because of PD. Due to treatment related toxicity treatment was stopped in 16 pts (27%). Treatment related mortality was 3% (2 pts). Treatment toxicity was reported according to NCI common toxicity criteria (CTC) version 2.0. Adverse events grade 3 or 4 for anemia, neutropenia and thrombocytopenia were documented in 75%, 55% and 65% of patients, respectively. Infections were the most common non-hematologic toxicity and occurred in 67%; severe infections CTC grade 3 or 4 occurred in 28%. All 26 Fref/pret-pts were available for response evaluation. CHOP-R achieved 54% PR, 35% SD and 12% PD. The median progression-free survival (PFS) and median treatment-free survival (TFS) were 11 and 14 mos. OS was 27 mos with a significant difference concerning F-ref (n=15) and F-pret (n=11) pts (17 vs. 35m; p=0.05). We evaluated the response of all 15 RT-pts with 60% PR, 7% CR, 13% SD and 20% PD. The PFS was 15 mos, TFS was 17 mos and OS 27 mos. 17 AIC pts were available for response evaluation with 82% PR, 6% SD and 12% PD. The PFS and TFS were only 14 and 16 mos. The OS was 50 mos. The population had a high incidence of unfavourable genetic markers: deletion of chromosome 17p [del(17p)] was detected in 24%, del(11q) in 34% and unmutated IGHV in 70%. 85% had high levels of serum thymidine kinase (sTK > 10 U/l), and 49% had high levels of ß2-microglobulin (ß2M > 3.5 mg/l). Patients with del(17p) had an unfavourable response rate and achieved significant less a PR or CR (36% vs. 76%; p=0.03). Multivariate analyses showed that del(17p) and ECOG performance status had a negative prognostic impact on OS (p<0.0001). Moreover the presence of a del(17p) predicted a short PFS (6 vs. 16.9 mos; p=0.001). Conclusion: CHOP-R achieves promising response rates in CLL patients with Fref and RT and very good response rates in patients with AIC. However, the progression-free survival and overall survival remain unsatisfactory. Therefore, CHOP-R might be used as induction therapy prior to allogeneic stem cell transplantation in physically fit patients. Disclosures: Eichhorst: Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Dreyling:Roche: Research Funding, Scientific advisory board, Speakers Bureau. Bergmann:Celgene: Honoraria. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fink:Hoffmann La Roche: travel grants. Fischer:Hoffmann La Roche:. Wendtner:Hofmann-La Roche: Consultancy, Honoraria, Research Funding. Hallek:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria.

Phase II Trial of Ofatumumab (OFA) for Older Patients and Patients Who Refuse Fludarabine-Based Regimens with Previously Untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 719-719 ◽  
Author(s):  
Ian W. Flinn ◽  
William N. Harwin ◽  
Patrick Ward ◽  
Habib H. Doss ◽  
Steven W. Papish ◽  
...  
Keyword(s):  
Overall Survival ◽  
Nk Cell ◽  
Single Agent ◽  
Age Groups ◽  
Progression Free Survival ◽  
Response Rates ◽  
Lymphocytic Leukemia ◽  
Induction Treatment ◽  
Front Line ◽  
Grade 3

Abstract Abstract 719 Background: Fludarabine (FLU), cyclophosphamide and rituximab or other FLU based regimens have shown improvement in response rates, progression-free survival, and in some studies overall survival in patients (pts) with previously untreated CLL or SLL. However, the value of FLU based therapies in older pts is less clear with both clinical trial and retrospective analyses showing no improvement in progression-free and overall survival with FLU based therapy. In contrast, regimens that contain rituximab appear to provide benefit across all age groups. OFA is a fully human Immunoglobulin G1 kappa, monoclonal antibody that targets a unique epitope on the CD20 molecule. Pre-clinical data indicate that OFA has greater NK cell and monocyte mediated killing, complement dependent cytotoxicity, and direct killing against CLL cells. Based on pre-clinical and clinical studies indicating possible increased efficacy of OFA in pts with CLL, our aim was to develop an antibody-only regimen for older pts and pts who refuse FLU-based regimens. Methods: Eligible pts had previously untreated CD20+ B-cell CLL(B-CLL) or SLL according to NCI criteria, ECOG PS of ≤2, and were either ≥ 65 years of age, or pts 18–64 years of age who had declined FLU-based regimens. All pts in this study received OFA as an IV infusion once weekly for a total of 8 weeks. To reduce the possibility of infusion reactions, the first dose of OFA was administered at a dose of 300mg. If the initial 300mg dose of OFA was well tolerated, without occurrence of any infusion associated AEs of ≥ grade 3, subsequent doses of OFA (i.e., Week 2 through Week 8) were given at a dose of 2000mg for cohort 1 and 1000mg for cohort 2. Eight weeks after the 8-week induction treatment (tx) ended; pts were assessed for response to the tx. Pts who progressed received no further tx. Pts who responded to the tx or who did not have disease progression received maintenance therapy - OFA at a dose of 2000mg IV for cohort 1 and 1000mg for cohort 2 every 2 months for 2 years (for a total of 12 doses, in the absence of PD or intolerable toxicity) beginning 3 months after the last dose of OFA. Results: Between 8/2010 and 12/2011, 77 pts were accrued (44 pts on cohort 1, 33 pts on cohort 2), median FU for Cohort 1 was 16.1 months (11.6–20.9) and Cohort 2 7.2 months (3.6–10.7). Median age of cohort 1 was 69 (range 47–88) and cohort 2 was 75 (range 50–93). Rai stage at study entry was I/II/III/IV (cohort 1 15/5/11/14 and cohort 2 9/10/7/7). All pts have completed induction therapy. The most common reason for early discontinuation was due to progressive disease (7 pts). Neutropenia was the most common grade 3/4 hematologic adverse event (10 pts). There were no G3 related non-hematologic AEs in either cohort. Two pts have died (1 due to MI, 1 due to CVA). Response by NCI 1996 criteria and IWCLL 2008 criteria and FISH category are shown below; at the time of this analysis 44 pts on C1 and 22pts on C2 were evaluable for response. Kaplan-Meier estimate of PFS is 74% at 15 months for cohort 1. Time to event data for cohort 2 are immature at this analysis but PFS but will be presented at the meeting. Conclusions: OFA, when given as a single agent, is well tolerated as front-line therapy in pts with CLL/SLL. Response rates and PFS compare favorably to our previous studies with rituximab using the same response criteria, particularly when differences in the age of pts entered onto the study are considered. The optimal single-agent dose of OFA in the front-line setting remains to be determined. Further follow-up of these data my provide insight in the dose/response relationship. Disclosures: Off Label Use: Ofatumumab as front-line treatment for CLL/SLL.

A phase II multicenter trial of paclitaxel and carboplatin in women with advanced or recurrent malignant mixed müllerian tumors (MMMT) of the uterus

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5589-5589 ◽  
Author(s):  
L. M. Ramondetta ◽  
R. A. Lacour ◽  
E. D. Euscher ◽  
R. B. Iyer ◽  
E. N. Atkinson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Median Overall Survival ◽  
Treatment Initiation ◽  
Response Rate ◽  
Multicenter Trial ◽  
Study Entry ◽  
Free Interval ◽  
Grade 3

5589 Background: Systemic therapy for advanced malignant mixed müllerian tumor of the uterus (MMMT) after surgery has been disappointing. Currently, the most common treatment regimen is ifosfamide and platinum. Moderate success has been documented using paclitaxel in MMMT of the ovary. The purpose of this study is to evaluate carboplatin and paclitaxel in patients with advanced (IIIb-IVb) and recurrent MMMT of the uterus. Methods: A single arm, prospective, non-randomized phase II trial opened in October 2001. The planned sample size is 37 evaluable patients, with time to progression and response rate as the primary endpoints. Patients receive carboplatin (AUC 5) and paclitaxel (175 mg/m2) every 21 days. Patients treated adjuvantly receive a total of 6 cycles or until progression or toxicity. Patients with disease present at study entry are treated until progression or toxicity. Results: To date, 18 patients have been enrolled. Seven patients received adjuvant treatment and 11 patients had documented disease at study entry. In the adjuvant group, the median progression-free interval was 15.8 months and median overall survival from treatment initiation was 20.2 months. Four of these 7 patients (57%) continue to be followed with a median follow-up of 19.2 months. In the patients with documented disease, the median progression- free interval was 7.8 months and the median overall survival from treatment initiation was 12.4 months. In this group, there were 3 complete and 4 partial responses (63.6% response rate). Over 45% of patients with disease at study entry are alive with a median follow-up of 14.0 months. Four patients experienced grade 4 granulocytopenia. Only two (11%) had treatment-limiting toxicity, one with grade 3 neuropathy and one with grade 3 fatigue. Conclusions: Carboplatin and paclitaxel appear to have improved tolerability and response rate (63.6%) compared to previous reports of ifosfamide and cisplatin (33% RR) in treating MMMT of the uterus. This regimen seems extremely promising and we are awaiting the final results of this trial. No significant financial relationships to disclose.

Results of the X-PECT study: A phase III randomized double-blind, placebo-controlled study of perifosine plus capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA3501-LBA3501 ◽  
Author(s):  
Johanna C. Bendell ◽  
Thomas J. Ervin ◽  
Neil N. Senzer ◽  
Donald A. Richards ◽  
Irfan Firdaus ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Phase Ii ◽  
Median Overall Survival ◽  
Phase Iii ◽  
Controlled Study ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Randomized Phase Ii ◽  
Phase Iii Study

LBA3501 Background: Perifosine (P) is an oral, synthetic alkylphospholipid that inhibits or modifies signal transduction pathways including AKT, NFkB and JNK. A randomized phase II study examined P-CAP vs. CAP in pts with 2nd or 3rd line mCRC. This study showed improvement in mTTP (HR 0.254 [0.117, 0.555]) and mOS (HR 0.370 [0.180,0.763]). Based on these results, a randomized phase III study of P-CAP vs. CAP with a primary endpoint of overall survival (OS) in pts with refractory mCRC was initiated. Methods: The study was a prospective, randomized, double-blind, placebo-controlled randomized phase III trial. Eligible pts had mCRC which was refractory to all standard therapies. Pts randomized 1:1 to Arm A = P-CAP (P 50 mg PO QD + CAP 1000 mg/m2PO BID d1-14) or Arm B = CAP (placebo + CAP 1000 mg/m2 PO BID d 1-14). Cycles were 21 days. Baseline tumor block collection and a biomarker cohort of pts with pre- and on-treatment tumor and blood samples were performed. Results: Between 3/31/10 and 8/12/11, 468 pts were randomized, 234 pts were in each arm. Baseline demographics were balanced between the arms: age < 65y (A: 65%, B: 58.5%), male (A: 57.7%, B: 53.0%), ECOG PS 0 (A: 39.7%, B: 39.7%), K-ras mutant (A: 50.4%, B: 51.3%), and median number of prior therapies (A: 4, B: 4). As of 3/19/12, median follow up was 6.6 months. Median overall survival: Arm A = 6.4 mo, Arm B = 6.8 mo, HR 1.111 [0.905,1.365], p = 0.315. Median overall survival for K-ras WT pts: Arm A = 6.6 mo, Arm B = 6.8 mo, HR 1.020 [0.763,1.365], p = 0.894; K-ras mutant pts: Arm A = 5.4 mo, Arm B = 6.9 mo HR 1.192 [0.890,1.596], p = 0.238. Conclusions: Despite promising randomized phase II data, this phase III study shows no benefit in overall survival adding perifosine to capecitabine in the refractory colorectal cancer setting. Response rate, progression free survival, and safety data will be presented. Biomarker analysis is pending to see if subgroups of patients may have potential benefit.

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