Assessment of Differences in Patient Populations Selected for or Excluded From Participation in Clinical Phase III Acute Myelogenous Leukemia Trials

2003 ◽  
Vol 21 (21) ◽  
pp. 3933-3939 ◽  
Author(s):  
Catherine Mengis ◽  
Stefan Aebi ◽  
Andreas Tobler ◽  
Werner Dähler ◽  
Martin F. Fey
Keyword(s):  
De Novo ◽  
Performance Status ◽  
Great Majority ◽  
Myelogenous Leukemia ◽  
University Hospital ◽  
Phase Iii ◽  
Trial Participation ◽  
Curative Intent ◽  
Phase Iii Trial ◽  
Significant Difference

Purpose: To compare patients treated in or outside clinical protocols, using de novo acute myeloid leukemia (AML) as a model disorder. Patients and Methods: We retrospectively compared the characteristics of all patients with de novo AML diagnosed in the referral area of our university hospital between 1985 and 1994. Results: Of a total of 170 AML patients, 45% were included in a phase III trial for the treatment of AML and 55% were treated outside a protocol. Another 45 patients were registered only at diagnosis but were treated elsewhere. Nonstudy patients differed significantly from patients included in clinical trials with respect to age and performance status at clinical presentation, comorbidity, and type of AML. The great majority of patients excluded from trial participation showed distinct exclusion criteria, such as advanced age and severe comorbidity. Study patients were treated significantly more often with curative intent and achieved better response and survival. Patients treated in an equivalent manner but outside a protocol showed no significant difference in survival compared with patients enrolled onto a trial. Conclusion: Study patients were not representative for the entire population of patients with AML; many patients were excluded from phase III trial participation for failure to meet stringent entry criteria. Therefore, results of phase III studies may not be extrapolated to all AML patients but should only be applied to patients who do not differ in substantial characteristics from the study population.

EXPERT study: Randomized phase III trial of radical surgery and postoperative mFOLFOX6 versus perioperative mFOLFOX6 plus cetuximab in patients with KRAS wild-type resectable colorectal liver metastases (CLMs).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 652-652 ◽  
Author(s):  
Yoshihiro Mise ◽  
Kiyoshi Hasegawa ◽  
Masaru Oba ◽  
Kensei Yamaguchi ◽  
Hiroyuki Uetake ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Medical Information ◽  
Radical Surgery ◽  
University Hospital ◽  
Phase Iii ◽  
Wild Type ◽  
Phase Iii Trial ◽  
Significant Difference ◽  
Group A ◽  
Group B

652 Background: Up-front radical surgery and adjuvant chemotherapy were regarded as one of the standard-of-care (SOC) in patients with resectablecolorectal liver metastases (CLMs), while perioperative chemotherapy plus surgery is also accepted. We conducted a multicenter randomized phase III trial to compare radical surgery and post-operative mFOLFOX6 with peri-operative mFOLFOX6 plus cetuximab in patients with KRAS wild-type resectable CLMs. Methods: Patients who had KRAS wild-type resectable CLMs having one to eight liver nodules without extrahepatic disease, were randomly assigned to groups: Group A (reference), hepatectomy and 12 cycles of post-operative mFOLFOX6: Group B (experimental), six cycles of preoperative mFOLFOX6 plus cetuximab (loading dose with 400mg/m2and thereafter 250mg/m2weekly), hepatectomy and six cycles of postoperative mFOLFOX6 plus cetuximab. Primary endpoint was progression-free survival (PFS). We hypothesized that 3-year PFS in Group B would be 25% with the hazard ratio (HR) being 0.75. Considering 3 year follow-up period with 5% of two-sided alpha error and 80% of power, target number were set as 500 (250 each). Study was registered in the University Hospital Medical Information Network (UMIN000007787). Results: This study was initiated since June 2012. However, the enrollment was terminated according to the recommendation from the monitoring committee on 2015 due to a slow accrual. A total of 77 patients (Group A 37 vs. Group B 40) were analyzed. Baseline characteristics were well-balanced between groups. Median numbers of liver mets were two each, ranging from one to eight. The HRs for PFS and overall survival (OS) showed no significant difference (PFS, HR = 1.18 [0.69-2.01], p = 0.54: OS, HR = 1.03 [0.46 – 2.29], p = 0.95). There were 3-year PFS of 35% in Group A vs. 30% in Group B, and 3-year OS: 86% vs. 74%, respectively. Conclusions: No additional survival benefits adding on peri-operative cetuximab were indicated, of which findings is consistent with the previous clinical studies, although there were small number of enrolled patients. Clinical trial information: UMIN000007787.

scholarly journals EXPRESSION OF micro RNAs (miRNAs) IN MYELODYSPLASTIC SYNDROME (MDS)

2019 ◽  
Vol 141 (7-8) ◽  
pp. 226-232
Keyword(s):  
Gene Expression ◽  
Myelodysplastic Syndrome ◽  
Healthy Volunteers ◽  
Myelogenous Leukemia ◽  
University Hospital ◽  
Gene Expressions ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Micro Rnas ◽  
Significant Difference

Myelodisplasia or myelodysplastic syndrome (MDS) is the name for a group of heterogeneous clonal hematological disorders of hematopoietic stem cells followed by ineffective hematopoesis of one or more cell lines and the emergence of consequent cytopenias with increased risk of progression to acute myelogenous leukemia (AML). Micro Messenger Ribonucleic Acids (miRNAs) are short, non-coding RNA molecules that, apart from contributing to MDS pathogenesis, act as regulators of epigenetic mechanisms and also are recognized as potential prognostic markers for early diagnosis and classification of MDS. The aim of the study was to examine the levels of gene expression of specific miRNAs (hsa-miR-125a, hsa-miR-99b, hsa-miR-126 and hsa-miR-125b) in healthy volunteers plasma and MDS diagnosed patients. Gene expressions of miRNAs were determined at the Clinical Institute of Medical Biochemistry and Laboratory Medicine, Merkur University Hospital, accredited according to EN ISO 15189:2012, in plasma samples of four healthy volunteers and 33 MDS patients diagnosed at the Institute of Hematology of the Clinic for Internal Diseases of Merkur University Hospital, Reference Center of the Ministry of Health of the Republic of Croatia for Diagnosis and Treatment of MDS. Statistically significant difference in gene expression of miRNA in healthy volunteers compared to the MDS patients was not found (P [hsa-miR-125a] = 0.398; P [hsa-miR-99b] = 0.134; P [hsa- miR-126] = 0.305; P [hsa-miR-125b] = 0.079). MiRNA ratios of hsa-miR-125a and hsa-miR-99b in MDS patients were almost twice as high compared to normalized levels of gene expression in healthy volunteers (2.30 versus 1.90), and the level of change of miRNAs hsa-miR-125 and hsa-miR-99b was more than two times higher than the level of change of miRNA hsa-miR-125b. Finally, the results of the research indicate that the gene expression of miRNAs hsa-miR-125a and hsa-miR-99b could be regulated by the same mechanism and could be clinically relevant in MDS patients.

Gemcitabine Plus Capecitabine Compared With Gemcitabine Alone in Advanced Pancreatic Cancer: A Randomized, Multicenter, Phase III Trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group

2007 ◽  
Vol 25 (16) ◽  
pp. 2212-2217 ◽  
Author(s):  
Richard Herrmann ◽  
György Bodoky ◽  
Thomas Ruhstaller ◽  
Bengt Glimelius ◽  
Emilio Bajetta ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Performance Status ◽  
Single Agent ◽  
Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
Metastatic Pancreatic Cancer ◽  
Karnofsky Performance Score ◽  
Phase Iii Trial ◽  
Good Performance Status ◽  
Grade 3

PurposeThis phase III trial compared the efficacy and safety of gemcitabine (Gem) plus capecitabine (GemCap) versus single-agent Gem in advanced/metastatic pancreatic cancer.Patients and MethodsPatients were randomly assigned to receive GemCap (oral capecitabine 650 mg/m2twice daily on days 1 to 14 plus Gem 1,000 mg/m2by 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m2by 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks). Patients were stratified according to center, Karnofsky performance score (KPS), presence of pain, and disease extent.ResultsA total of 319 patients were enrolled between June 2001 and June 2004. Median overall survival (OS) time, the primary end point, was 8.4 and 7.2 months in the GemCap and Gem arms, respectively (P = .234). Post hoc analysis in patients with good KPS (score of 90 to 100) showed a significant prolongation of median OS time in the GemCap arm compared with the Gem arm (10.1 v 7.4 months, respectively; P = .014). The overall frequency of grade 3 or 4 adverse events was similar in each arm. Neutropenia was the most frequent grade 3 or 4 adverse event in both arms.ConclusionGemCap failed to improve OS at a statistically significant level compared with standard Gem treatment. The safety of GemCap and Gem was similar. In the subgroup of patients with good performance status, median OS was improved significantly. GemCap is a practical regimen that may be considered as an alternative to single-agent Gem for the treatment of advanced/metastatic pancreatic cancer patients with a good performance status.

Prognostic Significance Of TP53 mutations and Single Nucleotide Polymorphisms In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4971-4971
Author(s):  
Simon B. Zeichner ◽  
Sarah Alghamdi ◽  
Gina Elhammady ◽  
Robert Poppiti ◽  
Amilcar Castellano-Sanchez
Keyword(s):  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
De Novo ◽  
Performance Status ◽  
Nucleotide Polymorphisms ◽  
Complex Karyotype ◽  
Single Nucleotide ◽  
Tp53 Mutations ◽  
Significant Difference ◽  
De Novo Aml

Abstract Background The response to treatment and overall survival (OS) of patients with acute myeloid leukemia (AML) is variable, with a median OS ranging from several months to more than 10 years. Age at diagnosis, performance status (PS), and karyotype expression have long been established in prognostication. Loss of TP53, a tumor suppressor gene located on the short arm of chromosome 17, is one of the most frequent genetic abnormalities in human cancer and is one of the more promising prognostic markers for AML. Studies have shown that TP53 mutations are present in 5-25% of all AML patients, in 70% of those with complex karyotypes, and are associated with old age, chemotherapy resistance, and worse OS. Single nucleotide polymorphisms (SNPs), changes in DNA seen in an appreciable amount of the population, have been examined in AML and studies have suggested a possible correlation with worse outcomes. Using genetic sequencing, we set out to look at our own experience with AML, and hypothesized TP53 mutations and SNPs would mimic the literature, occurring in a minority of patients, and conferring a worse OS. Methods We performed a pilot study of randomly selected, newly diagnosed AML patients at Mount Sinai Medical Center, diagnosed from 2005-2008 (n =10). Immunohistochemical (IHC) analysis of bone marrows and peripheral blood smears was assessed via DO-1 antibody on paraffin embedded tissue. Conventional cytogenetic analyses were performed on short-term cultured bone marrow and peripheral blood cells with the use of the GTG-banding technique. TP53 PCR sequencing was performed using DNA from bone marrow smears using the Sanger sequencing platform and resolved by capillary electrophoresis. Analysis was performed using Mutation Surveyor software with confirmation of the variants using the COSMIC and dbSNP databases. Descriptive frequencies and median survivals were calculated for demographic information, prognostic factors, and treatment variables. A univariate analysis was performed. Results The majority of patients in our pilot study were older than age 60 (80%), male (60%), Hispanic (60%), and had a poor PS (ECOG 2-3: 60%). Most patients had de-novo AML (50%) with an intermediate (50%) non-complex (70%) karyotype and a TP53 P72R SNP (50%). Fewer than half of these patients harbored TP53 mutations (40%). There was no significant difference in OS based on sex, AML history, risk-stratified karyotype, or TP53 mutation. There was a trend toward improved survival among patients younger than age 60 (11, 4 mo, p = 0.09), of Hispanic ethnicity (8, 1 mo, p = 0.11), and those not harboring P72R (8, 2, p = 0.10). There was a significant improvement in survival among patients with a better PS (28, 4 mo, p = 0.01) and those who did not have a complex karyotype (8, 1 mo, p = 0.03). Among patients with a TP53-mutation, there were a larger number of individuals who were younger than age 60 (25.0, 16.7%), who were male (75.0, 50.0%), had a good performance status (ECOG 0-1: 50.0, 16.7%), had de-novo AML (50.0, 66.7%), and who had an adverse karyotype (50.0, 33%). Patients with a P72R SNP were more often male (80, 40%) and had a worse PS (ECOG 2-3: 80, 40%) with AML secondary to MDS (60, 20%) and a complex karyotype (40, 0%). The most commonly observed TP53 mutation was a missense N310K (40%) and the most commonly observed SNP was P72R (100.0%). Patients with more than one TP53 mutation had a worse clinical course than those with only a single mutation. Conclusion Our study demonstrated that poor PS and the presence of a complex karyotype were associated with a decreased OS. TP53 mutations were relatively uncommon, occurring more frequently in male patients with an adverse karyotype. Although there was no significant difference in survival between TP53 mutated and un-mutated patients, there was a trend toward worse OS among patients with a specific SNP. These results suggest that different TP53 mutations and SNPs should not be treated the same, and that some may confer a worse prognosis than others. Larger studies are needed to validate these findings. Disclosures: No relevant conflicts of interest to declare.

BCIRG 007: Randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin first line in HER2 positive metastatic breast cancer (MBC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. LBA516-LBA516 ◽  
Author(s):  
J. F. Forbes ◽  
T. Pienkowski ◽  
V. Valero ◽  
W. Eiermann ◽  
G. Von Minckwitz ◽  
...  
Keyword(s):  
Metastatic Breast ◽  
Phase Iii ◽  
First Line ◽  
Her2 Positive ◽  
Phase Iii Trial ◽  
Efficacy Analysis ◽  
Significant Difference ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Taxane Chemotherapy

LBA516 Background: Based on preclinical synergism between docetaxel (T), carboplatin (C) and trastuzumab (H), BCIRG conducted a phase III trial for women with HER2+ MBC to evaluate efficacy and safety of H in combination with T or TC. Methods: 263 patients (pts) with HER2 FISH+ MBC were randomized to TH, (H with T 100 mg/m2) or TCH, (H with T 75 mg/m2 and C AUC=6). Chemo was given q3 wks for 8 cycles with wkly H at 2 mg/kg (loading dose of 4 mg/kg), followed by H q3 wks at 6 mg/kg until progression. Pts were stratified by centre and prior (neo) adjuvant taxane chemotherapy. Primary endpoint was TTP with 80% power (0.05 significance) to detect a 50% improvement in median TTP between the 2 arms. Secondary endpoints include overall survival, response rate, duration of response (DR), clinical benefit (CB) and safety. Results: 131 pts were treated in each arm. Pt characteristics were well balanced in both groups. Importantly, only 52% of pts received C at the protocol specified dose (RDI > 0.9). Efficacy analysis was conducted at 204 events. There was no significant difference between TH and TCH in median TTP (11.1 vs 10.4 mos, p = 0.57), ORR (73% in both arms), DR (10.7 vs 9.4 mos) and CB (67% in both arms). The most common gr 3/4 toxicities were: infection (44% vs 30%), neutropenic infection (22% vs 12%), thrombocytopenia (2% vs 15%), febrile neutropenia (12% vs 13%) asthenia (5% vs 12%), anemia (5% vs 11%), and diarrhea (2% vs 9%). Two pts died (1.5%) due to sepsis in TCH. Absolute LVEF decline > 15% were seen in 5.5% vs 6.7% of pts. One pt (0.8%) had a symptomatic CHF in TH arm Conclusions: The already effective TH regimen does not benefit from the addition of C, when the T dose in TH is 100 mg/m2 and 75 mg/m2 in TCH, in women with HER2+ MBC. No significant financial relationships to disclose.

A phase III study of Æ-941 with induction chemotherapy (IC) and concomitant chemoradiotherapy (CRT) for stage III non- small cell lung cancer (NSCLC) (NCI T99–0046, RTOG 02–70, MDA 99–303)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7527-7527 ◽  
Author(s):  
C. Lu ◽  
J. J. Lee ◽  
R. Komaki ◽  
R. S. Herbst ◽  
W. K. Evans ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Performance Status ◽  
Stage Iiib ◽  
Phase Iii ◽  
Stage Iii ◽  
Type I ◽  
Eligibility Criteria ◽  
Unresectable Stage ◽  
Significant Difference ◽  
Stage Iii Nsclc

7527 Background: Æ-941 is a shark cartilage extract with antiangiogenic properties. We conducted a placebo-controlled trial testing Æ-941, with IC and CRT, in unresectable stage III NSCLC. Methods: Eligibility criteria included performance status (PS) < 2, weight loss < 10%. Subjects received one of two treatment regimens depending on site of enrollment: carboplatin (C) (AUC 6) and paclitaxel (P) (200 mg/m2) × 2 cycles followed by CRT (60 Gy/30 fractions) with weekly C (AUC 2) and P (45 mg/m2) × 6 doses or cisplatin (CDDP) (75 mg/m2, d1) and vinorelbine (V) (30 mg/m2, d1 and 8) × 2 cycles followed by CRT (60 Gy/30 fractions) with CDDP (75 mg/m2, day 1) and V (15 mg/m2, d1 and 8) × 2 cycles. Subjects were randomized to receive Æ-941 (Arm A) or placebo (Arm B), 120 mL orally twice daily, at the start of IC and continuing after CRT as maintenance therapy. Randomization was stratified for stage, gender, and type of chemotherapy. The primary endpoint was overall survival (OS), with a planned sample size of 756 subjects providing 80% power to detect a 25% difference in OS, assuming a control arm median survival time (MST) of 13 months, type I error 0.05. Results: Between 6/00 and 2/06, 384 subjects were enrolled onto the trial and randomized. In 2/06 the trial was closed to new patient entry due to insufficient accrual. This final analysis is based on 379 randomized and eligible subjects (188 arm A, 191 arm B). Subject characteristics: 60% male, median age 63 years (range 37–84), 56% stage IIIB, 58% C-based chemotherapy, median follow-up 3.7 years. There was no significant difference in OS between arms A and B, with MSTs of 14.4 (95% CI 12.6–17.9) and 15.6 (95% CI 13.8–18.1) months, respectively (log-rank p=0.73). OS by pre-specified stratification factors: stage IIIB vs IIIA (MST 13.9 vs. 17.4 months, p=0.25), C vs. CDDP chemotherapy (MST 14.4 vs. 16.7 months, p=0.13), and male vs. female (MST 15.7 vs. 15.1 months, p=0.74). The study drug was well tolerated. Fewer subjects in arm A experienced grade 3 or higher adverse events (66% vs. 77%, p=0.018). Conclusions: The addition of Æ−941 to IC and CRT does not improve OS in patients with unresectable stage III NSCLC. No significant financial relationships to disclose.

Glioblastoma (GBM) in elderly patients: A randomized phase III trial comparing survival in patients treated with 6-week radiotherapy (RT) versus hypofractionated RT over 2 weeks versus temozolomide single-agent chemotherapy (TMZ).

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA2002-LBA2002 ◽  
Author(s):  
A. Malmstrom ◽  
B. H. Grønberg ◽  
R. Stupp ◽  
C. Marosi ◽  
D. Frappaz ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Survival Data ◽  
Treatment Time ◽  
Performance Status ◽  
Treatment Options ◽  
Single Agent ◽  
Tumor Resection ◽  
Phase Iii ◽  
Primary Study ◽  
Significant Difference

LBA2002 Background: Despite treatment advances, survival of elderly GBM patients (pts) is usually < 12 months. Hypofractionated RT is advocated in order to shorten treatment time, and chemotherapy has been proposed as an alternative to RT. In a randomized trial we compared two different RT schedules with single-agent TMZ chemotherapy. Methods: Newly diagnosed GBM pts age ≥ 60 years with PS 0-2, were randomized to either standard RT (60 Gy in 2 Gy fractions over 6 weeks) or hypofractionated RT (34 Gy in 3,4 Gy fractions over 2 weeks) or 6 cycles of chemotherapy with TMZ (200 mg/m2 day 1-5 every 28 days). Follow-up including quality of life, symptom checklist, and steroid dosing was completed at 6 weeks, 3 months, and 6 months after start of treatment. The primary study end point was overall survival (OS). Results: A total of 342 pts were included. 291 pts were randomized between the 3 treatment options, 51 pts between hypofractionated RT and TMZ. Median age was 70 years (range 60-88), 59% were male and 72% had undergone tumor resection, the remaining 28% had a diagnostic biopsy only. Performance status was 0-1 for 75% of pts. Survival data are available for 334 pts (98%), with 11 pts (3%) being alive. There was no significant difference in OS between the three treatment arms, with median survival being 8 months for TMZ, 7.5 months for hypofractionated RT and 6 months for 6 weeks RT (p=0.14). Conclusions: Elderly patients with GBM have a short survival. Time-consuming therapy that does not offer longer survival should therefore be avoided. Our study showed no advantage of standard 6 weeks RT compared to hypofractionated RT over 2 weeks or 6 cycles of TMZ chemotherapy. These results indicate that standard RT should no longer be offered to the elderly pt population with GBM. Exclusive TMZ chemotherapy may be an alternative to RT. Subgroup analyses and determination of molecular markers is ongoing. Whether outcome could be improved by concomitant chemoradiotherapy is subject of ongoing clinical trials. [Table: see text]

A phase III trial of nab-paclitaxel versus dacarbazine in chemotherapy-naive patients with metastatic melanoma: A subanalysis based on BRAF status.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9030-9030 ◽  
Author(s):  
Evan Hersh ◽  
Michele Del Vecchio ◽  
Michael Paul Brown ◽  
Richard Kefford ◽  
Carmen Loquai ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Braf Mutation ◽  
Performance Status ◽  
Braf Inhibitor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Ecog Performance Status ◽  
Mutation Status ◽  
Phase Iii Trial

9030 Background: Activating mutations of BRAF V600 can be found in 40%-50% of melanomas and are related to poor prognosis. In a phase 3 trial for the treatment of metastatic melanoma (MM) in chemotherapy-naive patients, nab-paclitaxel (nab-P) vs dacarbazine (DTIC) demonstrated a significant improvement in the primary endpoint of progression-free survival (PFS), assessed by independent radiological review (IRR), and a trend toward prolonged overall survival (OS) at the interim survival analysis. The study also explored the effect of BRAF status on the efficacy parameters. Methods: Chemotherapy-naive patients with stage IV melanoma (M1c stage 65%; elevated LDH 28%) and ECOG performance status 0-1 were randomized to nab-P 150 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n = 264) or DTIC 1000 mg/m2 on day 1 of each 21-day cycle (n = 265) independent of BRAF status. Prespecified subgroup analyses of final PFS and interim OS in subgroups by BRAF status (V600E mutant, wild-type, or unknown) were performed. Results: BRAF mutation status was balanced between the treatment arms, with 36% and 38% of patients with known BRAF mutation status in the nab-P and DTIC arms, respectively. Patient characteristics were also balanced within BRAF subgroups. As shown in the Table, advantage in the nab-P arm vs DTIC arm was observed for both PFS and interim OS regardless of BRAFmutation status. Poststudy BRAF inhibitor treatment was also balanced. Conclusions: In this phase III trial, treatment effect was independent of BRAF mutation status, benefiting all patients who received nab-P vs DTIC. Therefore nab-P should be considered in the armamentarium for all chemotherapy-naive patients with MM. Clinical trial information: NCT00864253. [Table: see text]

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