A Phase II Study of Ofatumumab-High Dose Methylprednisolone Followed By Ofatumumab-Alemtuzumab in 17p Deleted or TP53 Mutated CLL

Abstract BACKGROUND: Even in the age of kinase inhibitors, the prognosis for patients (pts) with CLL with del(17p) or TP53 mutations remains poor, with the median PFS only 28 mo. for pts with relapsed/refractory del(17p) CLL treated with ibrutinib. High dose methylprednisolone (HDMP) and alemtuzumab (alem) both have activity in 17p disease and work independently of TP53. Prior work has demonstrated that giving HDMP/alem simultaneously is efficacious, but toxic. We hypothesized that giving these agents sequentially with ofatumumab (ofa) would maintain efficacy while decreasing toxicity. METHODS: This phase II study of ofa/HDMP followed by ofa/alem in CLL pts with 17p deletion or TP53 mutation employed a parallel 2-arm design (treatment-naive (TN) and relapsed/refractory (R/R)). Therapy was the same in both arms and included ofa/HDMP for 2-4 cycles (part A) followed by ofa/alem for 4-24 weeks, up to maximum response (part B). Responders could proceed to alloHSCT or a maintenance phase with ofa given q2 mo and alem given q2 wks (part C). Antimicrobial prophylaxis for PCP, HSV/VZV, and fungal infections was mandatory, as was G-CSF support. The primary objective was to estimate the ORR at the conclusion of the two-part induction therapy in both cohorts. Secondary objectives were to estimate the rate of CR, objective response by compartment, rate of MRD negativity by 4 color flow cytometry, PFS, and OS, rate at which transplant-eligible pts were able to proceed to alloHSCT, and to assess safety. Toxicity was assessed by IW-CLL and CTCAE v4.0. Response assessments by IW-CLL criteria were performed mid-way and at the end of parts A and B, and q6 mo. on part C. RESULTS: A total of 30 patients were enrolled. Baseline pt characteristics were as follows: TN (n=15): median age 64 (range 45-86), median WBC 58K, Hct 31, Plts 134, B2M 4.3, IGHV unmutated 79%, median %bone marrow (BM) involvement 80%. R/R (n=15): median age 65 (range 58-80), median WBC 31, Hct 33, Plts 114, B2M 4.5, IGHV unmutated 73%, median %BM involvement 60%, median # prior therapies 2 (range 1-4) including 9 pts with prior FCR or FR and 7 pts with prior BR. One patient in each arm had TP53 mutation without 17p deletion, and 4 pts had mut NOTCH1. The median number of copy number changes by SNP array was high, at 12.4 in the TN and 14 in the R/R cohorts. In the TN arm, 14/15 pts moved from part A->B, 5 moved from part B->C, and 5 moved on to alloHSCT in remission. The best ORR for the TN arm was 80% (67% PR, 13% CR), with 12/15 (80%) pts achieving BM MRD negativity. The TN 2-yr PFS and OS are 70% and 85%, respectively. In the R/R arm, 8/15 pts moved from part A->B, 4 moved from part B->C, and 5 moved on to alloHSCT in remission. The best ORR for the R/R arm was 68% (all PRs), with 8/15 (54%) pts achieving BM MRD negativity. The R/R 2-yr PFS and OS are 53% and 67%, respectively. Responses in both arms were independent of TP53 and NOTCH1 mutation status. Studywide, a greater number of somatic mutations was associated with shorter PFS and OS (HR 1.13 per mutation, 95% CI 1.02-1.25, p=0.015 and HR 1.185, 95% CI 1.047-1.341, p=0.0073, respectively). The most common grade 3/4 toxicities were: neutropenia (33%), thrombocytopenia (20%), anemia (10%). Infectious complications included pneumonia (5 cases, 1 Gr2, 3 Gr3, 1 Gr4), febrile neutropenia (2 cases, both Gr3), and cellulitis (1 case, grade 3). Four pts had low-level CMV reactivation, but no CMV infections occurred. Venous thromboembolism occurred in 3 pts. With a median follow-up time among survivors of 25 mo., 21 of the total 30 pts are still alive, and causes of death included: progressive disease n=6, infection n=3. 12/18 (67%) pts who were transplant eligible were able to proceed to HSCT. Discontinuations were due to: progressive/refractory disease (n=10, including 3 Richter's transformations (R/R n=2, TN n=1)), physician decision (n=2), and unacceptable toxicity (n=1). CONCLUSION: Ofa/HDMP followed by Ofa/alem is highly active for both TN and R/R CLL pts with del(17p) and/or TP53 mutation. In addition to a robust ORR, we observed a high rate of MRD-negativity in the bone marrow, which allowed most of the transplant-eligible pts to proceed to alloHSCT. Sequential dosing appears to reduce infectious complications compared to concurrent dosing. This regimen is a feasible option for pts with ultra-high risk CLL to facilitate maximal cytoreduction prior to alloHSCT. <> Disclosures Davids: Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy.

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Bendamustine, Ofatumumab and High-Dose Methylprednisolone (BOMP) in Relapsed/Refractory CLL: Results of a Planned Interim Analysis of the French CLL Intergroup ICLL01 Phase II Trial

Blood ◽

10.1182/blood.v124.21.3341.3341 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3341-3341 ◽

Cited By ~ 3

Author(s):

Sophie de Guibert ◽

Marie-Sarah Dilhuydy ◽

Loic Ysebaert ◽

Laurence Sanhès ◽

Sylvain Choquet ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Interim Analysis ◽

Research Funding ◽

Tp53 Mutation ◽

Phase Ii Trial ◽

Risk Group ◽

High Dose ◽

Color Flow ◽

High Dose Methylprednisolone

Abstract Introduction: For relapsed or refractory (R/R) CLL patients (pts), combination of bendamustine and rituximab appears safe and effective (Fischer 2011). Ofatumumab monotherapy gives 58% ORR in heavily pre-treated (median 4 prior lines) R/R CLL pts (Wierda JCO 2010). High doses (HD) steroids are also active in poor prognosis pts with bulky nodal involvement or p53 impairment (Castro 2008, Xu 2010). We report a planned interim analysis of the ICLL01-BOMP phase II trial evaluating the association of Bendamustine, Ofatumumab and high-dose MethylPrednisolone for fit R/R CLL pts after 1-3 previous lines (NCT01612988). Patients and Methods: Primary endpoint was CR rate after 6 cycles (cy) of the BOMP regimen [i.e. bendamustine (70 mg/m2 d1, d2), ofatumumab (1000 mg d1;15 on cy#1-2 and d1 on cy#3-6) and HD methylprednisolone (1 g/m2 d1-3)]. The c#1 was preceded by an ofatumumab (300 mg) prephase. Response evaluation (IWCLL 2008) was done 3 months (m) after the last cy along with blood and bone marrow 10-color flow MRD analysis. Results: Among the 55 pts of this analysis, median age was 64 years (44-76). CIRS-G comorbidity score was 2-6 in 61% and pts had received 2-3 lines in 37% of the cases. Prior FCR-like regimens (50 (91%) patients) had been followed by relapse within 2y in 22/55 and 5/55 pts were fludarabine-refractory (FR). IGVH was unmutated (UM) in (47/52) 90.4%. Karyotypes were complex in 18/46 (39%) cases. Distribution according to FISH hierarchical model was: del(17p) in 15 (27%), del(11q) in 14 (26%), trisomy 12 in 4 (7%), del(13q) in 17 (31%) and normal in 5 (9%). Mutations on the TP53, SF3B1 and NOTCH1 genes occurred in 17 (31%), 14 (26%) and 5 (9%) pts, respectively. According to published risk stratification (Zenz, 2012), 34/55 pts (62%) belonged to the “highest-risk” group with either TP53 disruption (deletion and/or mutation) (n=19) and/or early relapse within 2 years post-FCR (n=22). The remaining patients belonged to either the “high-risk” group (UM-IGVH and/or Highb2mic and/or del11q) accounting for 17 pts (31%) or to the “low-risk” group (or non evaluable) accounting for 4 (7%) pts. Overall, 292 BOMP cy (mean 5.3 cy/pts) were delivered. Safety analysis recorded 158 grade 3-4 adverse events (G3-4/AE) with according to cy: neutropenia: 20.8%, thrombocytopenia: 11.3%, anemia: 2.4%, infection: 5,8%, hyperglycemia: 7,5%, liver enzyme elevation: 1,4%, cutaneous reaction: 1,4%, ofatumumab infusion related reaction: 0,3% and other AE: 3,4%. Overall 43 out of 55 pts (78.2%) had at least one G3-4/AE. Twenty-eight severe adverse events were reported in 20 pts. Treatment interruption before planned 6 cy occurred for pts' decision (n=3), excessive toxicity (n=5) or early progressive disease (PD) (n = 4). Response in the ITT population was 76.4% ORR with 20% CR (n=11), 56.4% PR (n=31 including 5 nPR and 1 CRi), 9.1% stable disease (n=5), 10.9% PD (n=6) and 3.6% (n=3) non evaluable. Blood MRD obtained in 45 pts was negative (<10-4) in 13 (28.8%) cases. Following evaluation, 5 responding pts (9%) had RIC allogeneic (RIC-Allo) transplantation with a persistent remission. With median follow-up of 16.2 (5.1-23.6) months (m) we observed 9 deaths, related to PD (n=5), EBV-induced lymphoproliferation (n=1), PML encephalitis (n=1), sepsis/pancytopenia (n=1) or unknown origin (n=1). We recorded 22 relapses (including 4 Richter Syndromes) resulting in treatment in 17 cases, with a BTK inhibitor in 8 cases. The median OS has not been reached (estimation 84% at 18 m) (Fig 1B). The median PFS was 18.4 m (95%CI, 14.6-22.2) and the median time to next treatment 17.6 m (95%CI, 12.9-22.4). With 5 cases censored at time of RIC-Allo, the PFS (censored analysis) was 17.5 m (95%CI, 13.2-21.8). (Fig 1A) After univariate analysis, ORR was lower in the “highest-risk” (64,6%, p=0.01), del(17p) (40%, p=0.003), TP53 mutation (47.1%, p=0.01) and complex karyotype (61.2%, p=0.024) groups. PFS was shorter in the “highest-risk” (14 m, p=0.046), FR (4.96 m, p<0.001), del(17p) (9.5 m, p=0.017) and TP53 mutation (9.5 m, p=0.007) groups. Conclusion: Relapse treatment of CLL is a challenge especially after prior FCR-like treatments, accounting for >90% of this trial population. These results in terms of response and survival appear noteworthy considering that >60% are “highest-risk” pts. This study provides important information for forthcoming comparison with next emerging CLL therapies. Figure 1 Figure 1. Disclosures de Guibert: Roche: Honoraria. Feugier:Roche: Honoraria. Schuh:Roche, Gilead, GSK, NAPP, Celgene: Honoraria. Leblond:Roche: Honoraria, Speakers Bureau. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding.

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High-dose busulfan and cyclophosphamide with autologous bone marrow transplantation support in advanced malignancies in children: a phase II study.

Journal of Clinical Oncology ◽

10.1200/jco.1986.4.12.1804 ◽

1986 ◽

Vol 4 (12) ◽

pp. 1804-1810 ◽

Cited By ~ 67

Author(s):

O Hartmann ◽

E Benhamou ◽

F Beaujean ◽

J L Pico ◽

C Kalifa ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Phase Ii ◽

Marrow Transplantation ◽

Residual Disease ◽

Phase Ii Study ◽

Autologous Bone Marrow Transplantation ◽

Autologous Bone Marrow ◽

Terminal State ◽

High Dose

Twenty children with advanced, nonleukemic malignancies entered a phase II study of high-dose busulfan-cyclophosphamide followed by bone marrow transplantation (BMT). All had disease refractory to conventional and/or high-dose chemotherapy (HDC). There were ten neuroblastoma patients, six non-Hodgkin's lymphoma, three Ewing's sarcoma, and one rhabdomyosarcoma. Eight had primarily resistant disease, ten were in second progressive relapse, and two in third progressive relapse. One patient was not evaluable for response. Among the 19 evaluable patients the responses observed were complete response (CR), seven; partial response (PR), three; objective effect, five; and failure, four. However, survival was poor: 15 patients died, two are alive with disease, and three are alive with no evidence of disease (NED) at 8+, 11+, 14+ months post-BMT. Toxicity was high but considered as acceptable, taking into account the terminal state of these patients. Seven treatment-related deaths were observed. This combination therapy proved to be highly effective, with a response rate of 50%, and its value for eradication of residual disease in less advanced patients should be investigated.

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Final Results of Lower Dose Fludarabine (F) and Cyclophosphamide (C), and High Dose Rituximab (R), (FCR-Lite) for Patients with Untreated Chronic Lymphocytic Leukemia (CLL).

Blood ◽

10.1182/blood.v110.11.2037.2037 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2037-2037

Author(s):

Ahmad A. Tarhini ◽

S. Land ◽

L. Pietragallo ◽

A. Laman ◽

M. Sulecki ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Response Rate ◽

Residual Disease ◽

Lymphocytic Leukemia ◽

High Dose ◽

Color Flow ◽

Major Toxicity ◽

Grade 3 ◽

Age Range

Abstract Introduction Standard FCR therapy in untreated CLL patients (F-25 mg/m2 d1–3 q 4wk; C-250 mg/m2 d 1–3 q 4wk; R-500 mg/m2 d1 q 4wk for 6 cycles) was reported to have complete remissions (CR) of 70% and overall responses (OR) of 95% (J Clin Oncol2005;23:4079). The major toxicity was grade 3/4 neutropenia during 52% of treatment courses. One approach to decrease neutropenia without compromising efficacy could be by reducing the doses of F and C and increasing the dose of R. Methods We conducted a phase II study for previously untreated advanced CLL patients treated with FCR-Lite (F-20mg/m2 d1–3 q 4 wk; C-150 mg/m2 d1–3 q 4 wk; R-500mg/m2 d1 and d14 q 4wks; maintenance R-500 mg/m2 ×1 q 3 months until progression). A Simon two-stage design was used where 15 patients were accrued in the first stage and because of acceptable toxicity and response rate in stage I an additional 35 patients were treated. The primary endpoint was response rate. Results A total of 50 patients were entered into this study and 42 are currently evaluable. There were 29 male and 13 female patients with an age range of 36–85 years (median 58) treated with a total of 236 courses of FCR-Lite. All 42 patients were evaluable for toxicity. Grade 3/4 neutropenia occurred during 29 (12%) courses with two episodes of neutropenic fever. One patient had cellulitis, another had pneumonia (not neutropenic). Grade 3/4 thrombocytopenia occurred during 7 (3%) courses and grade III/IV anemia during 6 (2.5%) courses. Among the 40 evaluable patients for response, the CR rate was 85%, PR rate was 15% with an OR rate of 100%. All of the CR patients were tested by flow cytometry and had <1% CD5+/CD19+ cells in their bone marrow after therapy. One patient with potential CR was excluded due to the absence of follow up bone marrow biopsy. Minimal residual disease (MRD) was tested by four color flow cytometry (sensitivity 0.01%) in 8 patients with CR (Genzyme Genetics Corp.). Seven had no evidence of MRD at 7, 8, 8, 14, 22, 25 and 30 months respectively, post CR, and one patient had 0.03% and 0.06% when tested at 12 and 18 months post CR respectively. Conclusions Our results in 42 patients suggest FCR-Lite is highly effective with considerably less grade 3/4 neutropenia than standard FCR. Complete responders had no detectable CD5+/CD19+ cells in their bone marrow following FCR-Lite. MRD testing is currently underway for all patients.

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Phase II Study of High Dose Lenalidomide as Initial Treatment for Older Acute Myeloid Leukemia Patients: Early Results Show a Significant Reduction of Bone Marrow Blasts after 14 Days of Therapy.

Blood ◽

10.1182/blood.v110.11.916.916 ◽

2007 ◽

Vol 110 (11) ◽

pp. 916-916 ◽

Cited By ~ 3

Author(s):

Todd A. Fehniger ◽

Alissa Nelson ◽

Kathryn Trinkaus ◽

Camille N. Abboud ◽

Amanda F. Cashen ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Phase Ii ◽

Myeloid Leukemia ◽

Phase Ii Study ◽

Active Agent ◽

Trisomy 13 ◽

High Dose ◽

Days Of Therapy ◽

Acute Myeloid

Abstract AML patients over the age of 60 years have a poor prognosis, share disease characteristics with myelodysplastic syndrome (MDS) patients, and warrant novel therapeutic approaches. Lenalidomide has immunomodulatory and anti-neoplastic properties which can induce morphologic and cytogenetic responses in MDS patients, including those with excess blasts. We hypothesized that lenalidomide may be active against AML, and have employed a high dose strategy without dose reductions for hematologic toxicities. Here, we report preliminary results from a phase II study of high dose lenalidomide for front-line treatment of AML ≥ 60 without chromosome 5q deletion or favorable cytogenetics. Treatment included 2 cycles of high dose lenalidomide (50mg/day x 14 days, 30 days of rest, 50mg/day x 21 days), followed by maintenance therapy (10 mg/day) in non-progressing patients. Fifteen patients were enrolled in the first stage between 2/27/07 and 8/3/07. Median age was 71 years (range 60–86 years); ECOG performance status was 0 (4/15, 27%), 1 (10/15, 67%), or 2 (1/15, 7%); 11/15 (73%) patients were male; and 5/15 (33%) patients had prior MDS. Cytogenetics were normal (n=9), loss of chromosome 7 (n=2), loss of chromosome 20 (n=1), trisomy 13 (n=1), or complex (n=2). Overall, the treatment regimen was well tolerated. In the first stage of the study, 12/15 patients are evaluable for day 15 bone marrow and peripheral blood blast changes following the initial high dose lenalidomide cycle (50 mg/day x 14 days). Pre-therapy WBC counts (mean ± SEM) were 13,825 ± 4,447/uL (range 1,100–45,300/uL) and day 15 WBC counts were 4,742 ± 2,136/uL (range 300–24,400/uL). Day 15 bone marrow myeloblast percentages were significantly reduced in 9/12 patients (mean ± SEM decrease of 53 ± 10%, P=0.01, range 18–100%). In addition, the bone marrow blast index (% cellularity x fraction of blasts) decreased significantly after 14 days of high dose lenalidomide (mean ± SEM reduction of 66 ± 11%, P=0.02). Moreover, 5/8 patients with circulating blasts at diagnosis showed clearance of their peripheral blasts at day 15. These findings suggest that lenalidomide is an active agent against acute myeloid leukemia. Results on AML blast changes, response by international working group criteria, and toxicities in this patient cohort with ≥4 months of follow-up will be updated and presented.

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A phase II study of two induction schedules of high dose carboplatin (HDC) vs weekly paclitaxel/gemcitabine (WPG) followed by paclitaxel/carboplatin/gemcitabine (PCG) in advanced ovarian cancer (AOC)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.15062 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 15062-15062

Author(s):

G. Bolis ◽

G. Polverino ◽

C. Sciatta ◽

G. Scarfone ◽

G. Scambia

Keyword(s):

Phase Ii ◽

Residual Disease ◽

Phase Ii Study ◽

Active Agent ◽

Advanced Ovarian Cancer ◽

Figo Stage ◽

High Dose ◽

Stage Iiic ◽

Standard Regimen ◽

Grade 3

15062 Background: Patients (pts) with newly diagnosed AOC generally receive platinum plus taxane therapy. G represents a new active agent to improve the standard regimen. To investigate the safety of two schedules of induction treatments both followed by triplet PCG we have drafted a phase II study. Methods: 14 pts, suboptimally debulked (FIGO stage IIIc) entered the study. HDC ( AUC 7,5) was administered for 2 courses every 21 days ( arm A) and P ( 80 mg/sqm, d 1,8,15,22) + G ( 2500 mg/sqm, d 1,15) (arm B). Both regimens have been followed by standard triplet P ( 175 mg/sqm, d1) + C ( AUC 5, d1) + G ( 800 mg/sqm, d1,8) every 21 days for a total of 6 courses. Antiemetics, corticoids, antihistaminics and ranitidine have been added. Results: The median age was 57 y (39–68). Histology was serous in 64.3%, mixed 14.3% and other 21.4%. All pts had Grade 3 tumor but one. Seven pts received arm A schedule and 7 arm B both followed by PCG regimen. Worst haematological toxicities ( in term of nadir) observed in all courses for all pts were neutropenia G4 ( 42.8% arm A vs 71.4% arm B), anemia G2 (71.4% arm A vs 57.1% arm B), thrombocytopenia G2 ( 57.1% arm A vs 42.8% arm B). Most common non haematological toxicities were alopecia and mild nausea/vomiting. Mild paresthesias in both regimens were observed. No sepsis or neutropenic fever nor unespected toxicity or treatment-related deaths were observed. 71.4% of pts completed foreseen schedules of treatments. 78.5% of pts received erytropoietin and 28.5% G-CSF support. Conclusions: HDC and weekly PG followed by triplet PCG are feasible and safety regimens in AOC pts ( residual disease > 1 cm). Further phase II-III setting study using these schedules will be conducted. No significant financial relationships to disclose.

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Phase II study of irinotecan, 5-fluorouracil (5-FU) and leucovorin combination chemotherapy in taxane and cisplatin-based chemotherapy-refractory metastatic gastric cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15599 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15599-e15599

Author(s):

J. Yoon ◽

S. Cho ◽

W. Bae ◽

J. Hwang ◽

H. Shim ◽

...

Keyword(s):

Gastric Cancer ◽

Phase Ii ◽

Combination Chemotherapy ◽

Phase Ii Study ◽

Performance Status ◽

Haematological Toxicity ◽

Metastatic Gastric Cancer ◽

High Dose ◽

Ecog Performance Status ◽

Grade 3

e15599 Background: The role of the second line chemotherapy in advanced gastric cancer was not clear, but possibility of prolongation of survival is open question. Irinotecan is promising agents in gastric cancer and this phase II study evaluated the efficacy and safety of combination chemotherapy with irinotecan, high dose of 5-fluorouracil (5-FU) and leucovorin in taxane and cisplatin based chemotherapy refractory metastatic gastric cancer. Methods: Eligible criteria were as followed; histologic confirmed adenocarcinoma of stomach, previously treated with taxane and cisplatin, age≥18, Eastern Clinical Oncology Group (ECOG) performance status of 1 or less, adequate organ function. Irinotecan (150 mg/m2) as a 30-min infusion and leucovorin (200 mg/m2) as a 15-min infusion were given on day 1, followed by 5-FU 400 mg/m2bolus infusion then 5-FU 2,400 mg/m2 as a 48-hour continuous infusion. This cycle was repeated every 2 weeks until disease progression or unacceptable toxicities. Results: Thirty-four patients were enrolled. The median age was 57 years (range 27–73 years), and the ECOG performance status of all patients was 1. All patients were evaluable for safety and survival and twenty seven patients (79.4%) were evaluable for tumor response. The overall response rate was 18.5% (95% CI: 3.9–33.1). The median progression free survival and overall survival were 4.6 (95% CI: 2.4–6.9) and 9.3 months (95% CI: 5.2–13.4), respectively. Greater than grade 3 haematological toxicities were neutropenia in nine (26.5%), febrile neutropenia in one (2.9%) and thrombocytopenia in one patient (2.9%). The major non-haematological toxicity was asthenia, but most of patients showed grade 1 or 2. Greater than grade 3 non- haematological toxicities were elevated AST/ALT in four (11.8%), hyperbilirubinemia in two (5.9%), nausea in two patients (5.9%). Conclusions: This results showed that the combination chemotherapy with irinotecan, 5-FU and leucovorin was well tolerated and active in taxane and cisplatin refractory patients. No significant financial relationships to disclose.

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Multicenter Phase II Study of Bimonthly High-Dose Leucovorin, Fluorouracil Infusion, and Oxaliplatin for Metastatic Colorectal Cancer Resistant to the Same Leucovorin and Fluorouracil Regimen

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.11.3560 ◽

1999 ◽

Vol 17 (11) ◽

pp. 3560-3568 ◽

Cited By ~ 206

Author(s):

Thierry André ◽

Mohamed A. Bensmaine ◽

Christophe Louvet ◽

Eric François ◽

Virginie Lucas ◽

...

Keyword(s):

Colorectal Cancer ◽

Peripheral Neuropathy ◽

Metastatic Colorectal Cancer ◽

Phase Ii ◽

Response Rate ◽

Phase Ii Study ◽

Progression Free Survival ◽

High Dose ◽

Median Response ◽

Grade 3

PURPOSE: To evaluate the objective tumor response rates and toxicities of leucovorin (LV) plus fluorouracil (5-FU) cancer regimen combined with oxaliplatin (85 mg/m2) every 2 weeks on metastatic colorectal cancer patients with documented proof of progression while on bimonthly LV and 5-FU alone. PATIENTS AND METHODS: One hundred patients were enrolled onto this study and 97 received the study drugs between October 1995 and December 1996. Eighty-nine patients were eligible for per-protocol efficacy analysis with documented proof of progression on one of the following two treatments: LV 500 mg/m2 and continuous 5-FU infusion 1.5 to 2 g/m2/22 hours, days 1 through 2 every 2 weeks (FOLFUHD); or LV 200 mg/m2, bolus 5-FU 400 mg/m2, and continuous 5-FU infusion 600 mg/m2/22 hours, days 1 through 2 every 2 weeks (LV5FU2). In our study, 40 patients received FOLFUHD + 85 mg/m2 of oxaliplatin day 1 (FOLFOX3) and 57 patients received LV5FU2 + 85 mg/m2 of oxaliplatin day 1 (FOLFOX4). RESULTS: Of the 97 patients treated, 20 partial responses were observed (FOLFOX3/4: response rate, 20.6%; 95% confidence interval, 13% to 31.1%; FOLFOX3: response rate,18.4%; FOLFOX4: response rate, 23.5%). For patients treated with FOLFOX3/4, the median response duration for was 7.5 months, and the major toxicities were peripheral neuropathy and neutropenia. The incidence of grade 3 (National Cancer Institute common toxicity criteria) peripheral neuropathy was 20.6%; whereas the overall incidence of grade 3 to 4 neutropenia was 27.8%, 15%, and 36.9% for FOLFOX3/4, FOLFOX3, and FOLFOX4, respectively (P = .02). From the start of treatment, median progression-free survival was 4.7, 4.6, and 5.1 months for FOLFOX3/4, FOLFOX3, FOLFOX4, respectively, and median overall survival was 10.8, 10.6, and 11.1 months, respectively. CONCLUSION: This phase II study of oxaliplatin at 85 mg/m2 in combination with bimonthly LV plus 5-FU in patients with colorectal cancer resistant to LV plus 5-FU alone confirms the enhanced antitumor activity of oxaliplatin in combination with 5-FU.

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Phase II study of cytarabine and etoposide in children with refractory or relapsed non-Hodgkin's lymphoma: a study of the French Society of Pediatric Oncology.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.4.661 ◽

1990 ◽

Vol 8 (4) ◽

pp. 661-665 ◽

Cited By ~ 39

Author(s):

J C Gentet ◽

C Patte ◽

E Quintana ◽

C Bergeron ◽

H Rubie ◽

...

Keyword(s):

Bone Marrow ◽

B Cell ◽

Continuous Infusion ◽

Phase Ii ◽

Phase Ii Study ◽

Hodgkin's Lymphoma ◽

High Dose ◽

Refractory Disease ◽

Cns Disease ◽

Non Hodgkin's Lymphoma

Twenty-five children or adolescents with relapsed or refractory non-Hodgkin's lymphoma (NHL) were included in this phase II study of the combination of cytarabine (ARA-C) 50 mg/m2/d by 12 hours continuous infusion day 1 to day 5, ARA-C 3 g/m2/d in 3 hours day 1 to day 4, and etoposide (VP 16) 200 mg/m2 daily from day 1 to day 4. Twelve patients had B-cell, 12 T-cell, and one non-T, non-B-cell lymphoma; according to Murphy's staging system, 15 had stage III and nine stage IV disease with bone marrow involvement at diagnosis. All had previously received ARA-C by push or continuous infusion. Two patients had received epipodophyllotoxins. At the time of the study, three children had initial refractory disease, 18 were in first relapse (14 on therapy), two in first refractory relapse, and two in second relapse (on therapy). The overall response rate (RR) was 60%: eight complete responses (CRs), seven partial responses (PRs) (two became CRs after a second course). The RR was 66% (four CRs plus four PRs) in B-cell and 54% (four CRs, three PRs) in non-B-cell NHL. It was 20% (one PR per five patients) in initial or relapsed refractory disease. In four patients with measurable CNS disease, there were three CRs. Duration of response was nonassessable since all the responding patients received high-dose polychemotherapy followed by autologous bone marrow transplantation (ABMT) (five are alive with long follow-up [FU]). Toxicity was marked mostly by pancytopenia for 2 weeks, and half the patients encountered a grade-3 infection. One severe diarrhea was observed. In conclusion, high-dose ARA-C (HD-ARA-C) and VP 16 are an effective regimen in relapsed NHL, especially with CNS disease, and its toxicity is acceptable with regards to the prognosis of the disease.

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A Phase II Study of Dasatinib in Patients with Chronic Myeloid Leukemia (CML) in Lymphoid Blast Crisis or Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Who Are Resistant or Intolerant to Imatinib: The ‘START-L’ CA180015 Study.

Blood ◽

10.1182/blood.v106.11.42.42 ◽

2005 ◽

Vol 106 (11) ◽

pp. 42-42 ◽

Cited By ~ 7

Author(s):

Oliver G. Ottmann ◽

G. Martinelli ◽

H. Dombret ◽

H. Kantarjian ◽

A. Hochhaus ◽

...

Keyword(s):

Bone Marrow ◽

Dose Reduction ◽

Phase Ii ◽

Phase Ii Study ◽

Blast Crisis ◽

Cytogenetic Response ◽

Molecular Response ◽

Hematologic Response ◽

Grade 3

Abstract Patients with CML in lymphoid blast crisis (LBC-CML) or advanced Ph+ ALL have an unsatisfactory and only brief response to imatinib mesylate (IM). Moreover, treatment options in pts who failed IM are extremely limited. Dasatinib (BMS-354825) is a novel, oral kinase inhibitor that targets BCR-ABL and SRC kinases, and has shown promising clinical activity in a Phase I dose escalating study in patients with BCR-ABL-positive leukemias. Between January 2005 and June 2005, 77 pts (42 CML-LBC and 35 Ph+ ALL) who had failed IM-based therapy were enrolled in this multinational Phase II study investigating the safety and efficacy of dasatinib. This preliminary analysis summarizes data on the first 28 pts accrued (13 CML-LBC and 15 Ph+ ALL) who were accrued prior to March 20, 2005. Dasatinib was administered orally at 70 mg twice daily (BID) on a continuous daily dosing schedule; dose escalation to 100 mg BID or dose reduction to 50 mg and 40 mg BID were allowed for poor initial response or persistent toxicity, respectively. Complete blood counts were performed weekly and bone marrow evaluation, including cytogenetic analysis, was scheduled every month. Mutation analyses were performed in all pts. 27 pts were IM resistant and 1 was IM intolerant; 17 (61%) pts had received prior IM doses >600 mg/day, 13 (46%) pts received IM for <1 year and 12 pts (43%) previously underwent stem cell transplantation. Response on prior IM regimen included complete hematologic response (CHR) in 19 (68%) pts and major cytogenetic response (MCyR) in 11 (39%) pts. Median time from leukemia diagnosis was 16.6 months (range 4.9–101.6). Median age was 44 years (range 20–84) and 61% of pts were male. At baseline, median platelet count was 37 x 103/mm3 (range 7–360) with median peripheral blood blasts of 35% (range 0–90) and median blasts in bone marrow of 81% (1–100). Dasatinib doses were escalated in 8 (29%) pts and 3 (11%) pts required dose reduction. 13 pts had a major hematologic response (7 CHR and 6 no evidence of leukemia, [CHR without complete recovery of PMN or platelets]) and 12 pts had a cytogenetic response within 1–3 months (11 complete and 1 minor). 9/13 pts (69% of responding pts) maintained their response after a median follow-up of 14+ weeks (range 10+ - 24+). Complete clearing of extramedullary sites was documented. Analysis of molecular response is ongoing. The majority of pts had grade 3 or 4 myelosuppression, which was pre-existing in most cases (63% with grade 3–4 neutropenia and 58% with grade 3–4 thrombocytopenia had the same grade at study entry); PMN <500/mm3 in 64% of pts and platelets <25 x 103/mm3 in 71% of pts. Non-hematologic toxicities included grade 1 and 2 peripheral edema (3 pts) and grade 1 facial edema (2 pts). GI intolerance was infrequent. In conclusion, dasatinib has significant and clinically meaningful efficacy in this heavily pretreated population of LBC-CML and Ph+ ALL pts with acquired resistance to imatinib. Updated data on all 77 patients with a minimum of 6 months’ follow-up will be presented.

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A Phase II Study of Dasatinib in Relapsed and Refractory Chronic Lymphocytic Leukemia (CLL/SLL).

Blood ◽

10.1182/blood.v110.11.3126.3126 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3126-3126 ◽

Cited By ~ 7

Author(s):

Philip C. Amrein ◽

Eyal C. Attar ◽

Tak Takvorian ◽

Ephraim P. Hochberg ◽

Karen Ballen ◽

...

Keyword(s):

Bone Marrow ◽

Phase Ii ◽

Phase Ii Study ◽

Performance Status ◽

Lymphocytic Leukemia ◽

Electrolyte Imbalance ◽

Fish Analysis ◽

Bone Marrow Biopsies ◽

Lyn Kinase ◽

Grade 3

Preclinical studies have shown that proliferation and survival of CLL cells are associated with overexpression of the Lyn kinase protein, and in vitro inhibition of Lyn kinase leads to apoptosis of the CLL cells (Contri, J Clin Invest 2005). Because dasatinib inhibits Lyn kinase in CML cells at doses easily achievable in patients, we undertook this phase II study of dasatinib in patients with previously treated CLL/SLL. Patients were required to be over 18 years of age, have a diagnosis of CLL/SLL by flow cytometry/immunostains, and have failed at least 1 course of treatment with a fludarabine-containing regimen or at least 2 courses of non-fludarabine containing regimens. The starting dose of dasatinib was 140 mg daily by mouth. This dose could be reduced to 100 mg or 80 mg daily for toxicity. At baseline all patients had bone marrow biopsies and CT scans, and these were repeated at 2 months. Sequential blood and bone marrow samples were tested for Lyn kinase activity. The design of the study provided for 2 phases such that if 3 responses were seen among the first 15 patients, the trial would expand to enroll another 20 patients. Among the first 9 patients enrolled there were 4 male and 5 female subjects with a median age of 59 years (40–78 years). ECOG performance status was 0 in 4 subjects, 1 in 3, and 2 in 2 subjects. All patients had previously received fludarabine: 1 subject had 1 prior treatment, 3 had 2 prior treatments, 3 had 3 prior treatments, and 2 had 4 prior treatments. By cytogenetic/FISH analysis there were 2 patients with del(17p) and another 4 patients with del(11q). All patients required treatment by NCI Working Group criteria. The major toxicity encountered was myelosuppression: grade 3 + 4 neutropenia in 7 subjects, grade 3 + 4 thrombocytopenia in 5 subjects. Gastrointestinal toxicity was minor with only 1 subject experiencing grade 3 diarrhea. One subject developed a grade 2 pleural effusion. There was 1 patient with an electrolyte imbalance consisting of a transient serum K=6.8, and in 1 patient there was a transiently prolonged QTc of 516 ms. There were no fatal events, and all toxicities were reversible. The median duration of treatment on study was 9 weeks with a range of 4 to 23 weeks. The clinical response data of the first 15 patients will be presented along with the correlative studies of Lyn kinase inhibition by dasatinib.

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