The impact of cetuximab on the gemcitabine/cisplatin combination in first-line treatment of EGFR-positive advanced pancreatic cancer (APC): A randomized phase II trial of GISCAD

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4544-4544 ◽  
Author(s):  
S. Cascinu ◽  
R. Berardi ◽  
S. Siena ◽  
R. Labianca ◽  
A. Falcone ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
First Response ◽  
Randomized Phase Ii ◽  
Meta Analyses ◽  
The Impact ◽  
Egfr Antibody

4544 Background: Cetuximab, an EGFR antibody inhibitor, has been shown to increase the activity of gemcitabine (GEM) in APC. Based on data from randomised trials and meta-analyses suggesting that the combination of a GEM with a platinum analog significantly improves survival as compared to GEM alone, we assessed the activity and feasibility of a combination of GEM/cisplatin (CDDP) plus cetuximab. Methods: Multicenter, randomised two-arm phase II trial: GEM 1,000 mg/m2 day 1,8 and CDDP 35 mg/m2 day 1,8 every 21 days alone or in combination with cetuximab 250 mg/m2 weekly after a loading dose of 400 mg/m2. Treatment was limited to a maximum of 9 cycles. With 37 patients in each arm the power was 90% to select the truly better arm if the true between arm difference in response rate (RECIST) is at least 15%. The study was open for accrual until June 2005. Results: We present here the results of 74 patients including in the study. In all the patients, the first response rate are available (investigators’ assessment after 3 cycles) as well as toxicity data. Conclusions: Cetuximab does not seem to positively interact with GEM/CDDP combination in terms of activity especially concerning time to progression. Although toxicity was not increased by cetuximab, this combination should not be assessed in a phase III trial.The trial was supported in part by by Merck KGaA. [Table: see text] No significant financial relationships to disclose.

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

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

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

KRAS mutation status-stratified randomized phase II trial of GEMOX with and without cetuximab in advanced biliary tract cancer (ABTC): The TCOG T1210 trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4018-4018 ◽  
Author(s):  
Li-Tzong Chen ◽  
Jen-Shi Chen ◽  
Yee Chao ◽  
Chang-Sung Tsai ◽  
Yan-Shen Shan ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kras Mutation ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Phase Iii ◽  
Mutation Status ◽  
Randomized Phase Ii ◽  
Ecog Ps ◽  
The Impact ◽  
Kras Mutation Status

4018 Background: Gemcitabine/platinum combination is considered as globally acceptable standard care in patients with ABTC. Two recently published randomized trials showed adding EGFR antagonist, either erlotinib or cetuximab, does not further improve the clinical outcomes of gemcitabine/oxaliplatin (GEMOX)-treated ABTC patients. However, the impact of KRAS mutation status on the results of both studies was not properly addressed. Methods: A prospective, multicenter randomized, phase II trial to evaluate the therapeutic efficacies of adding cetuximab to GEMOX in patients with ABTC, in which eligible patients were stratified by status of KRAS mutation and ECOG PS, and tumor location then randomized to receive either GEMOX (gemcitabine 800 mg/m2, fixed-rate infusion and oxaliplatin 85 mg/m2, i.v., Q 2 weeks) or GEMOX plus cetuximab (500 mg/m2, i.v., Q 2 weeks, C-GEMOX). The primary endpoint was overall response rate (ORR). As an exploratory trial, 120 (60 per arm) patients was estimated to detect a two-tailed 10% difference in ORR (20% in GEMOX and 30% in C-GEMOX) with a significant level of a=0.2 and b=0.5. Results: Between Nov 2010 and May 2012, a total of 122 patients were accrued. The demography was male: 47.5%, median age: 60 y/o, ECOG PS 0/1: 28.7%/71.3%, IHCC/EHCC/GBC: 71.3%/16.4%/12.3%, KRAS mutation: 36.1%, with locally advanced/metastatic diseases: 32.0%/68.0%, and prior surgical resection: 41.8%. On intent-to-treat analysis, the ORR and DCR in the C-GEMOX (N=62) and GEMOX (N-60) arms was 27.3% vs 15.0% (p=0.1223) and 82.2% vs 60.0% (p=0.0090), respectively (Fisher’s exact test); while the median PFS was 7.1 vs 4.0 months (p= 0.0069) and median OS was 10.3 vs 8.8 months (p=0.4057), respectively (log-rank test). Planned subgroup analysis showed the 43 patients with KRAS mutated tumors benefited more from cetuximab therapy, with a DCR of 78.3% vs 38.1% (p=0.0132), median PFS of 7.0 vs 1.9 months (p=0.0351) and median OS of 10.3 vs 6.6 months (p=0.6924). Conclusions: Adding cetuximab significant improves the DCR and PFS of GEMOX in ABTC patients, notably in subpopulation with KRAS mutated tumors. Larger-scale phase III trial is warranted. Clinical trial information: NCT01267344.

Prospective randomized phase II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: A study of the CESAR Central European Society for Anticancer Drug Research-EWIV.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4035-4035 ◽  
Author(s):  
Heike Richly ◽  
Luise Maute ◽  
Gerhard Heil ◽  
Jörn Rüssel ◽  
Elke Jäger ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Time To Progression ◽  
Overall Response ◽  
Randomized Phase Ii

4035 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours, but PDAC is still associated with a poor prognosis in advanced disease with an overall 5-year survival of only about 15%. Therefore there is a need for new treatment strategies. To improve the standard therapy with gemcitabine we initiated a prospective randomized phase-II trial with gemcitabine (GEM) vs. gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. Methods: Patients (N=113) with locally advanced or metastatic PDAC were prospectively randomized to receive gemcitabine alone (GEM) at a dosage of 1000 mg/m² day 1, 8, 15 q28 or to a combination of gemcitabine and sunitinib (SUNGEM) at a dosage of GEM 1000 mg/m² d1+8 and sunitinib 50mg p.o. d1-14, qd21 (based on a phase-I trial). The primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS), time to progression (TTP), overall response rate (ORR) and toxicity. Results: The confirmatory analysis of PFS was based on the ITT population (N=106). The median PFS was 13.3 weeks (95 %-Cl: 10.4-18.1 weeks) in the GEM group and 11.6 weeks in the SUNGEM arm (95 %-Cl: 7.0-18.0 weeks) (one-sided logrank: p=0.74). The 6-month PFS rate was 26.8 % (95 %-Cl: 15.4-39.5 %) in GEM arm and 25.0 % in SUNGEM arm (95 %-Cl: 14.0-37.8 %). The overall response rate was 6.1 % (95 %-Cl: 0.7-20.2 %) in the GEM arm and was a slightly but not significantly higher for the SUNGEM arm with 7.1% (95%-Cl: 0.9 – 23.5%).The median time to progression (TTP) was 14.0 weeks (95 %-Cl: 12.4-22.3 weeks) for the GEM arm and 18.0 weeks (95 %-Cl: 11.3-19.3 weeks) for the SUNGEM arm (two-sided logrank: p=0.60). The median OS was 30.4 weeks (95 %-Cl: 18.1-37.6 weeks) for the SUNGEM and 36.7 weeks (95 %-Cl: 20.6-49.0 weeks) for the GEM arm (two-sided logrank: p=0.44). With regard to toxicities, at least one AE of grade 3 or 4 was reported in 78.8% in the SUNGEM arm and 72.2% in the GEM arm. Conclusions: The combination of gemcitabine plus sunitinib (SUNGEM) did not improve the PFS in locally advanced or metastatic PDAC compared to gemcitabine alone. Clinical trial information: NCT00673504.

scholarly journals Neo-CheckRay: radiation therapy and adenosine pathway blockade to increase benefit of immuno-chemotherapy in early stage luminal B breast cancer, a randomized phase II trial

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Alex De Caluwé ◽  
Laurence Buisseret ◽  
Philip Poortmans ◽  
Dirk Van Gestel ◽  
Roberto Salgado ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Radiation Therapy ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Primary Breast Tumor ◽  
Immune Priming ◽  
Luminal B ◽  
Randomized Phase Ii ◽  
The Impact

Abstract Background Residual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes. Pathological complete response (pCR) rate, however, is lower for luminal B BC in comparison to the triple negative (TNBC) and HER2+ subtypes. The addition of immune checkpoint blockade (ICB) to NACT has the potential to increase pCR rate but is hampered by the lower immunogenicity of luminal B BC. Novel strategies are needed to stimulate the immune response and increase the response rate to ICB in luminal B BC. Methods The Neo-CheckRay trial is a randomized phase II trial investigating the impact of stereotactic body radiation therapy (SBRT) to the primary breast tumor in combination with an anti-CD73 (oleclumab) to increase response to anti PD-L1 (durvalumab) and NACT. The trial is designed as a three-arm study: NACT + SBRT +/− durvalumab +/− oleclumab. The result at surgery will be evaluated using the residual cancer burden (RCB) index as the primary endpoint. Six patients will be included in a safety run-in, followed by a randomized phase II trial that will include 136 evaluable patients in 3 arms. Inclusion is limited to luminal B breast cancers that are MammaPrint genomic high risk. Discussion combination of ICB with chemotherapy in luminal B BC might benefit from immune priming agents to increase the response rate. As none have been identified so far, this phase II trial will evaluate SBRT and oleclumab as potential immune priming candidates. Trial registration trial registered on ClinicalTrials.gov (NCT03875573) on March 14th, 2019.

Randomized phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel combination therapy for locally advanced pancreatic cancer (JCOG1407).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4017-4017
Author(s):  
Masato Ozaka ◽  
Makoto Ueno ◽  
Hiroshi Ishii ◽  
Junki Mizusawa ◽  
Hiroshi Katayama ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Response Rate ◽  
Controlled Trial ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Locally Advanced Pancreatic Cancer ◽  
Free Survival ◽  
Randomized Phase Ii

4017 Background: FOLFIRINOX, consisting of leucovorin (LV), fluorouracil (FU), irinotecan (IRI) and oxaliplatin (L-OHP), and GnP, consisting of gemcitabine (GEM) plus nab-paclitaxel (nPTX), have shown superior efficacy over GEM in patients (pts) with metastatic pancreatic cancer. Although several studies have reported the efficacy of FOLFIRINOX or GnP for pts with locally advanced pancreatic cancer (LAPC), no randomized controlled trial to compare the two regimens has been conducted in those pts. To select the most promising chemotherapy for LAPC, a randomized phase II selection design trial (JCOG1407) was conducted to compare between modified FOLFIRINOX (FOLFIRINOX with dose reduction of IRI and without bolus FU; Arm A) and GnP (Arm B) for pts with LAPC. Methods: In Arm A, 85 mg/m2 of L-OHP, 200 mg/m2 of l-LV, 150 mg/m2 of IRI, followed by 2,400 mg/m2 of continuous FU over 46 hours are infused every 2 weeks. In Arm B, 125 mg/m2 of nPTX followed by 1,000 mg/m2 of GEM are infused on days 1, 8, and 15 every 4 weeks. The primary endpoint was overall survival (the proportion of 1-year OS), and secondary endpoints included progression-free survival (PFS), distant metastasis-free survival (MFS) and response rate in pts with target lesions. The planned sample size was 124 pts to select more effective regimen in 1-year OS with a probability of at least 0.85 and to test the null hypothesis of 53% in 1-year OS with a one-sided alpha of 5% and 80% Results: From 2015 to 2019, a total of 126 pts was enrolled from 29 Japanese institutions, and were allocated to Arm A (n = 62) or Arm B (n = 64). The median (range) age was 66 (44-75) years and 58.7% were male. At the analysis, after a median (range) follow-up of 1.52 (0.55-3.99) years, 75 (59.5%) pts died. The proportion of 1-year OS was better in Arm B, 77.4% [95% CI 64.9–86.0] vs. 82.5% [95% CI 70.7–89.9], but 2-year OS was better in Arm A, 48.2% [95% CI 33.3–61.7] vs. 39.7% [95% CI 28.6–52.5]. Median OS was 2.0 years [95% CI 1.6-2.7] in Arm A and 1.8 years [95% CI 1.5-2.0] in Arm B. 1-year PFS for Arm A/B was 47.5 % [95% CI 34.5-59.4]/40.2% [95% CI 27.8-52.3], and 1-year MFS was 64.2 % [95% CI 50.9-74.8]/57.3% [95% CI 43.9-68.6]. Arm A was better OS in pts with CA19-9 <1000 U/mL and the opposite trend was observed in pts with CA19-9>1000 U/mL. Response rate was 30.9% [95% CI 19.1-44.8] in Arm A, and 41.4% [95% CI 28.6-55.1]) in Arm B. Incidences of grade 3-4 non-hematological toxicities for Arm A and Arm B were 66.1% and 67.2%, respectively. There was no treatment-related death. Conclusions: This study was the first randomized trial comparing the two regimens. The 1-year OS of the primary endpoint in GnP was better than mFOLFIRINOX, but mFOLFIRINOX achieved longer survival in 2-year OS. It is required to confirm longer OS and safety profiles which regimen should be selected as a standard regimen in LAPC. Clinical trial information: jRCTs031180085.

Phase II Trial of 4′-Epi-Doxorubicin in Locally Advanced or Metastatic Gastric Cancer

1988 ◽  
Vol 74 (3) ◽  
pp. 313-315 ◽  
Author(s):  
Eduardo Cazap ◽  
Roberto Estevez ◽  
Mario Bruno ◽  
Daniel Levy ◽  
Carlos Algamiz ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Adenocarcinoma ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Metastatic Gastric Cancer ◽  
Phase Iii ◽  
Future Studies ◽  
Phase Iii Trials

Patients with locally advanced or metastatic gastric adenocarcinoma received an i.v. bolus of 4′-epi-doxorubicin, 75/mg/m2/cycle, every 21 days. Partial responses were observed in 5 of 23 evaluable patients (21.7%). Treatment was generally well tolerated and toxicity was mild. The response rate to epirubicin appears to be very similar to that reported for doxorubicin. Larger doses of epirubicin could be safely used in future studies, and further evaluation of epirubicin in phase III trials is indicated.

Randomized Phase II Trial of Docetaxel Plus Thalidomide in Androgen-Independent Prostate Cancer

2004 ◽  
Vol 22 (13) ◽  
pp. 2532-2539 ◽  
Author(s):  
William L. Dahut ◽  
James L. Gulley ◽  
Philip M. Arlen ◽  
Yinong Liu ◽  
Katherine M. Fedenko ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Weight ◽  
Phase Ii ◽  
Low Molecular Weight Heparin ◽  
Phase Ii Trial ◽  
Low Molecular Weight ◽  
Randomized Phase Ii ◽  
The Impact ◽  
Docetaxel Group ◽  
Androgen Independent

Purpose Both docetaxel and thalidomide have demonstrated activity in androgen-independent prostate cancer (AIPC). We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC. Methods Seventy-five patients with chemotherapy-naïve metastatic AIPC were randomly assigned to receive either docetaxel 30 mg/m2 intravenously every week for 3 consecutive weeks, followed by a 1-week rest period (n = 25); or docetaxel at the same dose and schedule, plus thalidomide 200 mg orally each day (n = 50). Prostate-specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline, and time to progression. Results After a median potential follow-up time of 26.4 months, the proportion of patients with a greater than 50% decline in PSA was higher in the docetaxel/thalidomide group (53% in the combined group, 37% in docetaxel-alone arm). The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group (P = .32). At 18 months, overall survival in the docetaxel group was 42.9% and 68.2% in the combined group. Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group. Conclusion In this randomized phase II trial, the addition of thalidomide to docetaxel resulted in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC. After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses, the combination regimen was well tolerated. Larger randomized trials are warranted to assess the impact of this combination.

Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial

2018 ◽  
Vol 36 (5) ◽  
pp. 446-453 ◽  
Author(s):  
Piet Ost ◽  
Dries Reynders ◽  
Karel Decaestecker ◽  
Valérie Fonteyne ◽  
Nicolaas Lumen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Specific Antigen ◽  
Phase Iii ◽  
Curative Intent ◽  
Free Survival ◽  
Local Progression ◽  
Randomized Phase Ii

Purpose Retrospective studies suggest that metastasis-directed therapy (MDT) for oligorecurrent prostate cancer (PCa) improves progression-free survival. We aimed to assess the benefit of MDT in a randomized phase II trial. Patients and Methods In this multicenter, randomized, phase II study, patients with asymptomatic PCa were eligible if they had had a biochemical recurrence after primary PCa treatment with curative intent, three or fewer extracranial metastatic lesions on choline positron emission tomography–computed tomography, and serum testosterone levels > 50 ng/mL. Patients were randomly assigned (1:1) to either surveillance or MDT of all detected lesions (surgery or stereotactic body radiotherapy). Surveillance was performed with prostate-specific antigen (PSA) follow-up every 3 months, with repeated imaging at PSA progression or clinical suspicion for progression. Random assignment was balanced dynamically on the basis of two factors: PSA doubling time (≤ 3 v > 3 months) and nodal versus non-nodal metastases. The primary end point was androgen deprivation therapy (ADT)–free survival. ADT was started at symptomatic progression, progression to more than three metastases, or local progression of known metastases. Results Between August 2012 and August 2015, 62 patients were enrolled. At a median follow-up time of 3 years (interquartile range, 2.3-3.75 years), the median ADT-free survival was 13 months (80% CI, 12 to 17 months) for the surveillance group and 21 months (80% CI, 14 to 29 months) for the MDT group (hazard ratio, 0.60 [80% CI, 0.40 to 0.90]; log-rank P = .11). Quality of life was similar between arms at baseline and remained comparable at 3-month and 1-year follow-up. Six patients developed grade 1 toxicity in the MDT arm. No grade 2 to 5 toxicity was observed. Conclusion ADT-free survival was longer with MDT than with surveillance alone for oligorecurrent PCa, suggesting that MDT should be explored further in phase III trials.

Imatinib 800 mg: Preliminary Results of a Phase II Trial of the GIMEMA CML Working Party in Intermediate Sokal Risk Patients and Status-of-the-Art of an Ongoing Multinational, Prospective Randomized Trial of Imatinib Standard Dose (400 mg Daily) vs High Dose (800 mg Daily) in High Sokal Risk Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1098-1098
Author(s):  
Gianantonio Rosti ◽  
Giovanni Martinelli ◽  
Fausto Castagnetti ◽  
Nicoletta Testoni ◽  
Giorgina Specchia ◽  
...  
Keyword(s):  
High Risk ◽  
Randomized Trial ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Standard Dose ◽  
Phase Iii ◽  
High Dose ◽  
Molecular Response ◽  
Risk Patients

Abstract The conventional treatment of chronic myeloid leukemia (CML) in early chronic phase (ECP) is imatinib 400 mg daily. The estimated rates of major (MCgR) and complete cytogenetic response (CCgR) at 42 months are 91% and 84%, respectively (IRIS Trial - F Guilhot, ASH 2004), with a survival free from accelerated and blastic phase of 84%. The rates of CCgR are significantly different according to Sokal score, being 91%, 84% and 69% for low, intermediate and high risk categories. Phase I and II trials of imatinib have clearly shown a dose-response effect; more importantly, a single center phase II trial of imatinib 800 mg in ECP showed significantly better results vs standard dose, in terms of CCgR (90% vs 74%) and of complete molecular response (28% vs 7% at 18 months) [H. Kantarjian et al, Blood 103 (8), 2004]. The GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) CML WP is conducting a phase II trial of imatinib 800 mg in intermediate Sokal risk in ECP (trial CML/021). Overall, 89 pts (mean age 53 yrs) have been enrolled. Fourty-four patients completed 6 months of treatment: the complete hematological response rate is 100%; the MCgR and CCgR are 90% and 81%, respectively. The 6 months CCgR rate of this trial parallels the IRIS trial one in intermediate risk cases (84%), with a much shorter treatment period. The major molecular response rate at 6 months (RTQ-PCR as ratio BCR-ABL/ABL) is 56% (cut-off ≤ 0.12%) or 41% (cut-off ≤0.05%). The compliance to the treatment improved time by time, being 47% the patients receiving ≥ 80% of the scheduled dose between months 1–3 and 60% between months 4 - 6. A second project, exploring imatinib high dose, is reserved to high risk cases: a multinational working group, within the frame of Leukemianet CML WP, is conducting a phase III randomized trial (1:1) of imatinib 400 mg vs 800 mg in high Sokal risk in ECP. By July 31, 2005, 80 patients have been enrolled: GIMEMA CML WP (44 pts), Nordic Countries - Sweden, Denmark, Norway and Finland (25 pts), Turkey (10 pts) and Israel (1 pt).

Randomized Phase II Study of Combined Epigenetic Therapy: Decitabine Vs. Decitabine and Valproic Acid in MDS and AML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 228-228 ◽  
Author(s):  
Jean-Pierre Issa ◽  
Ryan Castoro ◽  
Farhad Ravandi-Kashani ◽  
Stefan Faderl ◽  
Xuelin Huang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Valproic Acid ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Epigenetic Therapy ◽  
Overall Response ◽  
First Response ◽  
Randomized Phase Ii

Abstract Introduction: Inhibition of DNA methylation (DNMTi) by decitabine (DAC) or azacitidine is a form of epigenetic therapy that is clinically effective in the treatment of MDS and AML. In-vitro, histone deacetylase inhibition (HDACi) following DNA hypomethylation induction results in synergistic enhancement of gene expression activation, but the effects of HDACi on the cell cycle can also interfere with DNTMi activity, resulting in schedule dependent antagonism. Phase I/II studies of the combination of DNMTi and HDACi have shown some promise, triggering randomized studies. Methods: We conducted a randomized phase II study of DAC at 20 mg/m2 IV/1 hour daily ×5 q4 weeks vs. DAC at a similar dose + Valproic acid (VPA) 50 mg/kg PO daily ×7 starting on day 1 of DAC. Eligibility included MDS (FAB), IPSS&gt;0 or AML, age &gt;60 (excluding APL and CBF AML). An adaptive randomization design based on a composite score of CR, response and survival was used after the 40th patient to assign patients to the superior arm. DNA methylation was measured by bisulfite pyrosequencing on peripheral blood mononuclear cells prior to and during treatment. Results: 76 patients were enrolled on the study, 2 of whom received no therapy and are excluded from analysis. These included 8 patients with CMML (median age 72), 23 patients with AML (median age 71 (63–81), median BM blasts 40% (30–87), median WBCs 5.4 (1.1–97)) and 43 patients with MDS (median age 66 (36–89), IPSS Int1 (10), Int2 (19) and high (14)). Cytogenetics were abnormal in 40 patients (54%), most with complex or poor risk karyotypes. 42 patients (57%) were randomized to DAC alone. Overall, the median number of courses given so far is 4 (1–17) and 27 patients (36%) remain on therapy, at a median follow-up of 14 months. Response data are available for 67 patients (7 are too early). Overall, responses were seen in 31 patients (46%), with CR in 23 (34%) and other responses in 8 (12%). Overall response rate was 39% in AML, 71% in CMML and 46% in MDS. In patients receiving decitabine alone, the overall response rate was 17/40 (43%), compared to 14/27 (52%) in those randomized to DAC+VPA (p=NS). Median time to first response was 64 days (18–194) with DAC alone compared to 57 days (23–123) with DAC+VPA (p=NS). VPA added significant neurotoxicity to the regimen, with several patients discontinuing the drug due to somnolence or confusion. Median survival was 8.7 months in AML and 14.9 months in MDS (p=0.04). Kaplan-Meier analysis showed no difference in survival between DAC and DAC+VPA in the first year after therapy. DNA methylation analysis showed a similar degree of LINE demethylation in both arms, Conclusions: Preliminary analysis of this randomized study suggests that adding VPA to DAC only marginally improves response rate and time to first response and has no impact on survival in MDS and AML. It remains to be seen (in randomized studies) whether more potent HDACi will show greater evidence of clinical synergy with DNMTi.

Sign in / Sign up

Export Citation Format

Share Document