résultats de phase 3 mais méthodologiquement faibles infirmés ultérieurement
Phase 3 négatives ne confirmant pas les premiers résultats
Gemtuzumab ozogamicin dans les leucémies de l'enfant
Limites des critères intermédiaires
situations où ce sont les patients du groupe control qui ont eu de la chance
Ipilimumab dasn le cancer de la prostate
Exemples pour illustration diverses et variées
Wright D, Yeatts S, Silbergleit R, et al. Very Early Administration of Progesterone for Acute Traumatic Brain Injury. N Engl J Med 2014. doi:10.1056/NEJMoa1404304.
Wright DW, Kellermann AL, Hertzberg VS, et al. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med 2007; 49: 391–402, 402.e1–2.
Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care 2008; 12: R61.
A Randomized Trial of Vertebroplasty for Painful Osteoporotic Vertebral Fractures Rachelle Buchbinder, Ph.D., Richard H. Osborne, Ph.D., Peter R. Ebeling, M.D., John D. Wark, Ph.D., Peter Mitchell, M.Med., Chris Wriedt, M.B., B.S., Stephen Graves, D. Phil., Margaret P. Staples, Ph.D., and Bridie Murphy, B.Sc. N Engl J Med 2009; 361:557-568August 6, 2009DOI: 10.1056/NEJMoa0900429
Gemtuzumab ozogamicin was approved in 2000 for the treatment of pediatric leukemia on the basis of limited data, but it was withdrawn from the market in 2010 after confirmatory trials initiated in 2004 showed increased mortality and no efficacy.42
p.1258: 42. Food and Drug Administration. Mylotarg (gemtuzumab ozogamicin): market withdrawal. Silver Spring, MD: FDA, June 21, 2010 (http:
www.fda.gov/Safety/MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ucm216458.htm). -- Highlighted 24 avr. 2014
echec de l’essai de phase III PROCEED (NCT01170650) du vintafolide qui avait eu un avis positif du CHMP pour une AMM conditionnelle sur la base des résultats de phase II.
WHITEHOUSE STATION, N.J. & WEST LAFAYETTE, Ind., May 2, 2014 – Merck, known as MSD outside the United States and Canada (NYSE: MRK), and Endocyte, Inc. (NASDAQ: ECYT), today announced that the Data Safety Monitoring Board (DSMB) of the PROCEED trial has completed a pre specified, interim futility analysis and the DSMB recommended that the trial be stopped because vintafolide did not demonstrate efficacy on the pre-specified outcome of Progression-Free Survival (PFS) in patients with platinum-resistant ovarian cancer. The DSMB did not identify any safety concerns for the patients enrolled in the trial. Based on the DSMB recommendation and while further review of the data are conducted, the Companies have taken steps to notify investigators that screening and randomization of participants in the trial will be suspended. PROCEED is a Phase 3 randomized, double-blind clinical trial, evaluating vintafolide in combination with pegylated liposomal doxorubicin (PLD) compared to PLD plus placebo for the treatment of folate receptor-positive, platinum-resistant, ovarian cancer. The primary endpoint of the trial was PFS as measured by RECIST v 1.1 (Response Evaluation Criteria In Solid Tumor) criteria in patients with all target tumor lesions positive as assessed by etarfolatide imaging agent.
http:
www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002571/smops/Positive/humansmop000666.jsp&mid=WC0b01ac058001d127
http:
www.medscape.com/viewarticle/829066?nlid=62607_2201 ALTTO demonstrated that adding lapatinib (Tykerb/Tyverb) to standard trastuzumab (Herceptin) therapy after surgery does not improve survival in women with HER2-positive early breast cancer
Darapladib No Benefit in ACS Patients: SOLID-TIMI 52 http:
www.medscape.com/viewarticle/830726
Darpladib STABILITY http:
www.medscape.com/viewarticle/822992
Justification de l'absence de cross-over
http:
www.biospace.com/newssubjectall_results.aspx?CatagoryId=39520
Tivozanib Fails to Show Overall Survival Difference in Metastatic RCC News | September 16, 2013 | Renal Cell Carcinoma, Genitourinary Cancers, Kidney CancerBy Leah Lawrence The results of the phase III study comparing Aveo’s tivozanib to sorafenib for the treatment of metastatic renal cell carcinoma, which were the basis for the US Food and Drug Administration’s (FDA) rejection of the company’s new drug application earlier this year, were published recently in the Journal of Clinical Oncology. Although the results indicated that tivozanib improved progression-free survival compared to sorafenib, it failed to show an improvement in overall survival. Robert J. Motzer, MD, of the Memorial Sloan-Kettering Cancer Center, and colleagues conducted a study of the potent and selective tyrosine kinase inhibitor of VEGF receptor 1, 2 and 3 in comparison to the drug sorafenib. They enrolled 517 patients and randomly assigned them to tivozanib (n = 260) or sorafenib (n = 257). Patients assigned to sorafenib were given the option to cross-over to receive tivozanib at progression; of the 162 patients in this arm who elected to receive a second targeted-agent at progression, 156 received tivozanib (61%). The median progression-free survival was 11.9 months with tivozanib compared with 9.1 months with sorafenib (P = .042). In addition, patients on tivozanib had an improved overall response rate (33.1%) compared with sorafenib (23.3%; P = .014). However, the tivozanib only showed a trend towards improved overall survival compared with sorafenib. Forty-two percent of patients in the intention-to-treat population died. The median overall survival was 29.3 months for tivozanib compared with 28.8 months for sorafenib (P = .105). Adverse events, although different with each of the study drugs, were comparable. In an editorial that accompanied the trial results, Marc B. Garnick, MD, of Beth Israel Deaconess Medical Center, Boston, wrote that based on the results of this study many projected that tivozanib would be approved for the treatment of metastatic RCC; however, according to Garnick the study design compromised the “sanctity of overall survival” with its allowing patients on the sorafenib arm to cross-over to tivozanib at progression. “In particular, differences in overall survival in favor of the sorafenib arm could not be adequately assessed because this study represents, in essence, a sequential trial of two agents (sorafenib [then] tivozanib) compared with one agent (tivozanib),” Garnick wrote. “Although the overall survival results might be attributed to a design that compares sequential therapy with monotherapy, other equally plausible explanations were put forth by the FDA review team, including that sorafenib may be more effective than tivozanib in improving overall survival, that tivozanib has greater delayed toxicity, or that tivozanib has unrecognized toxicity that contributed to the lower survival in ways that are difficult to appreciate.” And, in fact, Garnick wrote that researchers may never know. Instead, he suggested that researchers learn a lesson from this situation mainly that any approval based on a trial with a primary endpoint of progression-free survival must not have any study design weaknesses. - See more at: http:
www.cancernetwork.com/renal-cell-carcinoma/tivozanib-fails-show-overall-survival-difference-metastatic-rcc#sthash.r4pHY48c.dpuf
Amgen Inc said its experimental ovarian cancer drug did not show statistically significant improvement in overall survival rate in a late-stage trial.
Patients given the drug, trebananib, along with a chemotherapy agent paclitaxel, experienced overall survival of 19.3 months, compared with 18.3 months for the placebo group.
Statistically significant improvement in overall survival was the secondary goal of the trial.
The trial, TRINOVA-1, is the first of three late-stage studies to evaluate safety and effectiveness of the drug in ovarian cancer patients.
The company in 2013 reported results on the main goal of trial, where patients survived longer without the disease getting worse when compared with a placebo.
Jefferies analysts in a note published on Oct. 20 said oncologists expect the drug to have little or no benefits in terms of overall survival. "Thus, FDA approval is unlikely in our view," they wrote.
Everolimus Fails to Improve Overall Survival in Advanced HCC Fran Lowry July 01, 2014 Everolimus (Afinitor) does not improve overall survival in patients with advanced hepatocellular carcinoma (HCC) whose disease had progressed on treatment with sorafenib (Nexavar), researchers report.
The disappointing result — from the first Everolimus for Liver Cancer Evaluation (EVOLVE-1) randomized clinical trial — represents the sixth failed phase 3 trial in liver cancer over the past 7 years, said Andrew X. Zhu, MD, PhD, from the Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston.
Dr. Andrew Zhu
"Hepatocellular carcinoma is a huge challenge to treat. Patients with advanced HCC have a median overall survival of less than 1 year, largely because of the absence of effective therapies. It's really humbling," Dr. Zhu told Medscape Medical News.
"Since the initial sorafenib approval in 2007 by the FDA, we have made tremendous efforts to find additional target drugs for this disease," he explained. "The negative result from this study shows 3 things: that we have not selected the right drug to be tested in the right populations, that we have not designed the right trial to answer the question, and that we need to reconsider the direction about how to move the field forward."
The negative findings were published in the July 2 issue of JAMA.
There are no effective systemic therapies for the treatment of advanced HCC, aside from sorafenib. But its benefits are mostly transient and modest, and the cancer eventually progresses, the researchers note.
In preclinical models, everolimus prevented tumor progression and improved survival. The aim of EVOLVE-1 was to determine the efficacy and safety of everolimus 7.5 mg per day in patients with advanced HCC who were refractory to or intolerant of sorafenib.
The study, conducted in 17 countries from May 2010 to March 2012, involved adults with advanced HCC whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Of the 546 participants, 362 were randomized to receive everolimus and 184 were randomized to receive placebo.
Both groups also received best supportive care. Treatment continued until disease progression or intolerable toxicity.
There was no significant difference in median overall survival between the everolimus and placebo groups (7.6 vs 7.3 months). There were 303 deaths in the everolimus group and 151 in the placebo group (83.7% vs 82.1%; hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.86 - 1.27; P = .68).
Median time to progression with everolimus was 3.0 months and with placebo 2.6 months (HR, 0.93; 95% CI, 0.75 - 1.15).
The disease control rate — the percentage of patients with a best overall response (complete or partial) or stable disease — was 56.1% with everolimus and 45.1% with placebo.
Patients with hepatitis B virus, who made up 26.2% of the study sample, had the best prolonged overall survival with everolimus, but the reasons for this are not clear, Dr. Zhu explained.
"The results from EVOLVE-1 extend the list of failed phase 3 studies in advanced HCC, highlighting the challenge of developing effective therapies for this cancer," he said.
"I think the early phase 1/phase 2 data with everolimus in advanced HCC were perhaps somewhat weak, in the sense that we only performed a single-arm trial. We do not have a randomized trial to tell us the extent to which the efficacy observed was really due to the drug-induced benefit or just because of some selection bias in patients," he added.
The first-line use of the multikinase inhibitors sunitinib, brivanib, and linifanib in HCC has not shown efficacy. And no benefit was seen when erlotinib was added to sorafenib.
"The cancer is very heterogeneous, both clinically and biologically. As well, the underlying cirrhosis that exists in most patients with HCC adds to the complexity of treatment," Dr. Zhu said.
A Very Complex Cancer
The point about tumor heterogeneity was emphasized in a recent study (Gut. 2014;63:844-855).
In HCC, "not only might each patient have their own private cancer, but each tumor site may be genetically unique," Jordi Bruix, MD, from Hospital Clinic de Barcelona in Spain, told Medscape at the time.
Dr. Bruix explained that the molecular pathogenesis of HCC is extremely complex and heterogeneous. He noted that several trials have failed to improve the benefits of established therapies, but emphasized the need for more work.
"Studies assessing the sequential or combined application of those already known to be beneficial are needed," he said. "Also, new concepts are provided in regards to selecting and stratifying patients for second-line studies, which may help explain the failure of prior studies."
The study was sponsored by Novartis Pharmaceuticals, manufacturer of everolimus. Dr. Zhu reports financial relationships with sanofi-aventis, Exelixis, Eisai, and Daichi Sankyo.
JAMA. 2014;312:57-67. Abstract
Ipilimumab fails to show overall survival benefit in mCRPC after chemotherapy
According to a media release issued by Bristol-Myers Squibb this morning, the company’s recombinant, human, monoclonal antibody ipilimumab (Yervoy) — which acts by blocking the effects of cytotoxic T- lymphocyte antigen-4 (CTLA-4) — has shown no overall survival benefit in treatment of men with chemotherapy-refractory, metastatic, castration-resistant prostate cancer (mCRPC).
The randomized, double-blind Phase III clinical trial (Study 043) had been designed to compare the effects of ipilimumab to a placebo after radiation therapy in men with advanced mCRPC who had already received treatment with docetaxel.
According to the media release: •The trial enrolled a total of 799 patients. ◦399 patients were randomized to treatment with ipilimumab. ◦400 patients were randomized to treatment with a placebo.
•Median overall survival (OS) times were ◦11.2 months for patients treated with ipilimumab. ◦10 months for patients treated with a placebo.
•The difference in OS for patients in the two arms of the trial (1.2 months or about 6 weeks) was not statistically significant (hazard ratio [HR] = 0.85). •Survival rate data showed that ◦47 percent of patients treated with ipilimumab were still alive at 1 year after initiation of treatment. ◦40 percent of patients treated with a placebo were still alive at 1 year after initiation of treatment. ◦26 percent of patients treated with ipilimumab were still alive at 2 years after initiation of treatment. ◦15 percent of patients treated with a placebo were still alive at 2 years after initiation of treatment..
•Median progression-free survival data showed that ipilimumab had greater activity than a placebo (HR = 0.70) •Data on the reduction in PSA levels to less than 50 percent of the baseline levels showed that ◦13.1 percent of patients treated with ipilimumab had this degree of PSA reduction. ◦5.3 percent of patients treated with a placebo had this level of PSA reduction.
•Pre-specified subset analyses suggest that Yervoy may be more active in patients with indicators for less advanced disease. •Treatment-related adverse events were common, and most were immune-related. ◦Immune-related gastrointestinal adverse effects of Grade 3 or higher were reported in 18 percent of ipilimumab patients (as compared to 1 percent of palecbo patients). ◦Immune-related adverse effects on liver function of Grade 3 or higher were reported in 5 percent of ipilimumab patients (as compared to 1 percent of placebo patients). ◦Adverse effects on endocrine function of Grade 3 or higher were reported in 2 percent of ipilimumab patients (as compared to 1 percent of placebo patients). ◦Adverse dermatologic effects of Grade 3 or higher were reported in 1 percent of ipilimumab patients (as compared to 0 percent of placebo patients). ◦The incidence of drug-related death and GI perforation was 1 percent in patients treated with ipilimumab (as compared to 0.5 percent of placebo patients).
The company states that these data will be presented at the 2013 European Cancer Congress in an oral session on September 28 this year (abstract no. 2850).
Clearly these data will be a disappointment to the developer. However, The “New” Prostate Cancer InfoLink is not entirely surprised by this outcome. It is apparent that ipilimumab does have some activity in the treatment of at least some men with progressive forms of prostate cancer. However, it was hoping a lot to think that the demonstrated activity would translate in a real overall survival benefit in a subset of patients with very advanced forms of metastatic disease. The level of adverse effects of Grade 3 and higher is also an issue that may be particularly problematic in men who have very advanced forms of prostate cancer.
The real question is going to be whether ipilimumab has a role either earlier in the disease or in a definable subset of patients that can be identified through the use of a specific marker for CTLA-4 activity (or similar). To that point, a senior Bristol-Myers Squibb executive is quoted as follows in the media release:
While we are disappointed that the primary endpoint of overall survival was not met, we remain encouraged that results in this advanced population support the potential role of immunotherapies for prostate cancer. We are committed to continuing our development of Yervoy in prostate cancer.
This is not going to be the end of the ipilimumab story in management of prostate cancer, but it is clear that the potential value of this drug for most men with mCRPC who have failed chemotherapy is low in the extreme.
Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C, et al. Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer. N Engl J Med. 2009 Feb 11;360(7):679–91. Pubmed
Gheorghiade M, B\xc3\xb6hm M, Greene SJ, Fonarow GC, Lewis EF, Zannad F, Solomon SD, Baschiera F, Botha J, Hua TA, Gimpelewicz CR, Jaumont X, Lesogor A, Maggioni AP. Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. JAMA 2013 Mar 20;309(11):1125-35 Pubmed
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