A phase II study of high-dose celecoxib and metronomic 'low-dose' cyclophosphamide and methotrexate in patients with relapsed and refractory lymphoma

Abstract Nitric oxide (NO) is an important inflammatory mediator produced from arginine. NO has a multitude of functions which could impact favorably on vaso-occlusion in sickle cell disease (SCD) including improvement in endothelial dysfunction, increased blood flow and a decrease in antioxidant stress. SCD patients have low NO and arginine levels. In preliminary animal studies using the sickle mouse model, arginine supplementation decreased the mean corpuscular hemoglobin concentration and the percentage of dense cells via a reduction in Gardos channel activity1. In humans with SCD, oral arginine increased NO levels in patients with vaso-occlusive crisis but not when patients were at well. In an attempt to determine if daily oral arginine would result in an increase in NO and other beneficial effects, the CSCC launched a multi-institution, blinded, phase II study of arginine in SCD. Children and adults were treated for three months with one of two doses of arginine (.05g/kg/day or .1 g/kg/day) or placebo. The pediatric and adult cohorts were analyzed separately. For this phase II study, the following laboratory values were chosen as surrogates for clinical benefit: NOx, RBC Gardos channel activity, RBC density, sVCAM, nitrotyrosine, ektacytometry, endothelin-1, and fetal hemoglobin. To determine the impact of arginine on these laboratory measures, patients had 3 baseline assessments in the 4 weeks prior to starting therapy with arginine. An average of these 3 measurements was used to determine change from baseline during therapy with arginine. Laboratory outcomes after one month and three months of therapy with arginine were compared with the average baseline measurement. This report summarizes the results of the pediatric cohort of patients. Fifty-one children were enrolled in the study and 48 completed at least one month of study drug making them evaluable. Arginine levels did not change significantly during treatment in any of the arms. The average percent change from baseline to 3 months on study drug being +18% for placebo, +35% for low dose arginine, and +19% for high dose arginine). None of the three primary outcome variables (NO, Gardos channel activity, RBC density) changed significantly with arginine therapy after one month or after 3 months of arginine. After 3 months of study drug, the average percentage change from baseline in NO was −33% for low dose arginine, +4% for high dose arginine, and +8% for placebo. Gardos channel activity changes were −1% for low dose, +3% for high dose, and +9% for placebo. RBC density changes were +10% for low dose, +11% for high dose, and −6% for placebo. Similarly, none of the other outcome variables changed with treatment at either one or 3 months. There were no significant differences in adverse events between the three treatment groups. Our data indicate that oral arginine therapy does not seem to provide clinical benefit for pediatric patients with SCD based on assessment of these selected laboratory outcomes. It is possible that the doses of arginine used in this study were not sufficient to produce significant changes in the laboratory measures chosen. It is also possible that children, due to less severe arginine deficiency, did not respond as well as adults with SCD. Supported by NHLBI U54HL070587.

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LOW-DOSE LENALIDOMIDE COUPLED with LOW-DOSE Cytarabine INDUCES COMPLETE REMISSION of Elderly ACUTE Myeloid LEUKEMIA PATIENTS with Unfavorable Citogenetics: PRELIMINARY RESULTS of A PHASE II STUDY,

Blood ◽

10.1182/blood.v118.21.3627.3627 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3627-3627

Author(s):

Giuseppe Visani ◽

Felicetto Ferrara ◽

Francesco Di Raimondo ◽

Maria Rita Caraci ◽

Tiziana Izzo ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Phase Ii ◽

Myeloid Leukemia ◽

Low Dose ◽

Phase Ii Study ◽

High Dose ◽

Combination Regimen ◽

Blast Count ◽

Low Dose Cytarabine ◽

Acute Myeloid

Abstract Abstract 3627 We designed a phase II study to assess the antitumor efficacy of the combination regimen with low-dose lenalidomide and low-dose cytarabine in patients with acute myeloid leukemia (AML) aged >70 years. Twenty-one patients (median age 76 years, range: 70–80) were consecutively enrolled in the study. Median white blood cell count at diagnosis was 11.920 x109/l (range: 0.59–46.8×109/l), whereas median haemoglobin was 8.9 g/dl and median platelet count was 30×109/l. Four out of 21 patients had a normal karyotype, whereas 17/21 presented with an intermediate or unfavourable karyotype. Twelve patients had a de novo AML, whereas 9 patients had a secondary AML (5 after MDS, 1 after a CMPD, 1 after myelofibrosis, 2 after chemo-radiotherapy for a breast cancer). All patients received low-dose lenalidomide (10 mg/day orally, days 1–21) and low-dose cytarabine (20mg twice day subcutaneously, days 1–15). Therapy was repeated every 6 weeks, up to 6 cycles. Six out of 21 patients died in aplasia while receiving the first induction cycle of therapy, and are not evaluable for response. One patients is still completing the first cycle. Fourteen patients completed at least one cycle of therapy and are evaluable for response. Among these patients, 8/14 (57%) cleared peripheral blood blasts at the end of the second week of the first cycle, with recovery of normal WBC, hemoglobin and platelets values after a median of 31 days (range: 27–42) from the start of chemotherapy. Six out of 8 responding patients are still in morphologic, cytogenetic and FISH CR after 14, 12, 10, 7, 3 and 3 months from the start of therapy, respectively. Two patient died while in CR after receiving, respectively, the second and the third cycle of therapy due to a multi organ failure after an infectious complication. The other 6 patients who completed at least one cycle of therapy did not respond at all and rapidly died due to progressive disease. At present, out of 8/14 (57%) patients evaluable for response that obtained CR, 6/14 (42%) are alive in continuous CR and two died in CR. Notably, all responding patients presented with low blast count and unfavorable cytogenetics at diagnosis. In conclusion, low-dose lenalidomide has clinical activity, when coupled with low-dose cytarabine, in an extremely poor-prognosis subset of AML. Considering the scarce compliance of elderly, frail AML patients to high-dose therapy, the low dose schedule could be particularly profitable, specially for patients with low blast count and unfavorable cytogenetics. The study was registered at EMA with the EUDRACT no 2008–006790–33. Acknowledgments: Celgene is acknowledged for providing Lenalidomide for the patients. The study was supported in part by AIL Pesaro Onlus. Conflict-of-interest disclosure: The Authors declare no competing financial interests. Disclosures: Di Raimondo: celgene: Honoraria.

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Phase II Study of Low Dose and High Dose Conjugated Estrogen for Androgen Independent Prostate Cancer

The Journal of Urology ◽

10.1016/j.juro.2007.01.119 ◽

2007 ◽

Vol 177 (6) ◽

pp. 2146-2150 ◽

Cited By ~ 15

Author(s):

Mark Pomerantz ◽

Judith Manola ◽

Mary-Ellen Taplin ◽

Glenn Bubley ◽

Margaret Inman ◽

...

Keyword(s):

Prostate Cancer ◽

Phase Ii ◽

Low Dose ◽

Phase Ii Study ◽

High Dose ◽

Conjugated Estrogen ◽

Androgen Independent

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Faculty Opinions recommendation of High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14486.471988 ◽

2006 ◽

Author(s):

Ron Paquette

Keyword(s):

Myelodysplastic Syndrome ◽

Phase Ii ◽

Lower Risk ◽

Phase Ii Study ◽

High Dose ◽

Darbepoetin Alpha

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Faculty Opinions recommendation of Phase II study of an AKT inhibitor MK2206 in patients with relapsed or refractory lymphoma.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725675529.793539755 ◽

2017 ◽

Author(s):

Won Seog Kim

Keyword(s):

Phase Ii ◽

Phase Ii Study ◽

Akt Inhibitor ◽

Refractory Lymphoma

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A phase II study of high-dose cisplatin and VP-16 in neuroblastoma: a report from the Société Française d'Oncologie Pédiatrique.

Journal of Clinical Oncology ◽

10.1200/jco.1987.5.6.941 ◽

1987 ◽

Vol 5 (6) ◽

pp. 941-950 ◽

Cited By ~ 43

Author(s):

T Philip ◽

R Ghalie ◽

R Pinkerton ◽

J M Zucker ◽

J L Bernard ◽

...

Keyword(s):

Hearing Loss ◽

Phase Ii ◽

Phase Ii Study ◽

Bone Marrow Involvement ◽

Stage Iv ◽

Observation Time ◽

Phase Iii ◽

High Dose ◽

Initial Stage ◽

Duration Of Response

Forty-seven children or adolescents with initial stage IV (42 patients) or stage III (five) advanced neuroblastoma (12 were progressing after relapse and 35 had never reached complete remission [CR] after conventional therapy) were included in a phase II study of the combination of high-dose VP-16 (100 mg/m2/d X 5) and high-dose cisplatin (CDDP) (40 mg/m2/d X 5). Twenty patients had received prior CDDP therapy (total dose, 100 to 640 mg/m2; median, 320 mg/m2) and 38 of 47 had bone marrow involvement when included in the study. The overall response rate was 55%, with 22% CR. Duration of response was 5 to 18 months, with a median of 10 months. Eight patients are still disease free, with a median observation time of 13 months, but all had received additional therapy after two courses of this regimen. Gastrointestinal toxicity was frequent but tolerable. Myelosuppression was severe but of brief duration, ie, nadir of neutrophils was observed at day 15 with 95% of the patients recovering a normal count before day 28, and nadir of platelet count was at day 17 with only two severe and reversible episodes of bleeding. The overall incidence of sepsis was 8% (seven of 92 courses), with no death related to infection. No acute renal failure was observed after two courses, and only three of 47 children experienced a clear reduction of renal function. After two courses, only two children showed a hearing loss in the 1,000 to 2,000 Hz range, although hearing loss above the 2,000 Hz level was frequently encountered. It is concluded that high-dose VP-16 and CDDP is an effective regimen in advanced neuroblastoma with acceptable toxicity. Phase III studies are needed in previously untreated patients. J Clin Oncol 5:941-950.

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