Therapeutic cancer vaccines: Why so few randomised phase III studies reflect the initial optimism of phase II studies

Vaccine ◽  
2011 ◽  
Vol 29 (47) ◽  
pp. 8501-8505 ◽  
Author(s):  
Angus G. Dalgleish
Keyword(s):  
Phase Ii ◽  
Cancer Vaccines ◽  
Phase Iii ◽  
Phase Ii Studies ◽  
Therapeutic Cancer Vaccines ◽  
Phase Iii Studies

Comparison of Outcomes of Phase II Studies and Subsequent Randomized Control Studies Using Identical Chemotherapeutic Regimens

2005 ◽  
Vol 23 (28) ◽  
pp. 6982-6991 ◽  
Author(s):  
Mohammad I. Zia ◽  
Lillian L. Siu ◽  
Greg R. Pond ◽  
Eric X. Chen
Keyword(s):  
Phase Ii ◽  
English Language ◽  
Response Rates ◽  
Phase Iii ◽  
Positive Phase ◽  
Phase Ii Studies ◽  
Solid Malignancies ◽  
Study Characteristics ◽  
Phase Iii Study ◽  
Phase Iii Studies

Purpose To determine whether promising results from phase II studies could be reproduced in phase III studies, and to examine which characteristics of phase II studies might be of predictive value for subsequent phase III studies. Methods We searched for all phase III studies of chemotherapy in advanced solid malignancies, published in the English language literature from July 1998 to June 2003. Each phase III study was reviewed to identify preceding phase II studies. Phase II and phase III studies included in this analysis must have used identical regimens. Data were extracted from both phase II and phase III studies. Results Of 181 phase III studies identified, 43 used therapeutic regimens identical to those in 49 preceding phase II studies. Twelve phase III studies (28%) were “positive.” The vast majority (81%) of phase III studies have lower response rates than preceding phase II studies, with a mean difference of 12.9% among all studies analyzed. None of the phase II study characteristics evaluated significantly predicted for “positive” phase III studies, but the sample size of phase II studies demonstrated a trend toward being predictive (P = .083). Conclusion Promising results from phase II studies frequently do not translate into “positive” phase III studies. Response rates in most phase III studies are lower than those in preceding phase II studies.

Safety summary of panitumumab (pmab) in combination with chemotherapy (ctx) from four clinical trials in patients (pts) with metastatic colorectal cancer (mCRC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15005-e15005
Author(s):  
T. J. Price ◽  
M. Peeters ◽  
J. Douillard ◽  
E. Mitchell ◽  
A. Cohn ◽  
...  
Keyword(s):  
Phase Ii ◽  
Safety Data ◽  
Data Monitoring Committee ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Two Phase ◽  
Phase Ii Studies ◽  
Study Results ◽  
Phase Iii Trials ◽  
Phase Iii Studies

e15005 Background: Pmab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody approved in the US and EU (wild-type KRAS) as monotherapy for pts with mCRC. Safety data from 4 studies (Siena et al ASCO 2008; Peeters et al ASCO 2008; Cohn et al ASCO 2008; Mitchell et al WORLD GI 2008) of pmab in combination with ctx are summarized. Methods: Two studies are single-arm, phase II trials and two are randomized, phase III trials with pooled, blinded safety data that include ctx-controls. All studies were multicenter. Common pt eligibility criteria included: diagnosis of mCRC with measurable disease per modified RECIST criteria, age ≥ 18 years, and adequate hematologic, renal, hepatic, and metabolic function. All studies required pts to receive FOLFOX, FOLFIRI, or irinotecan ctx in combination with pmab. Pts received pmab 6.0 mg/kg Q2W with FOLFOX Q2W or FOLFIRI Q2W, or pmab 9.0 mg/kg Q3W with irinotecan Q3W. Results from planned interim analyses are available for 3 studies, and results from the final analysis are available for one study. Results: Among the 4-study safety data, 1213 pts received pmab + ctx; 703 pts received pmab + FOLFIRI, 455 pts received pmab + FOLFOX, and 55 pts received pmab + irinotecan. Approximately 1,200 pts were enrolled in each phase III study, and data are available from 1,003 pts who received pmab + ctx and 997 pts who received ctx alone. All pts in the phase III studies, regardless of treatment group, were included in the pooled, blinded interim analysis sets monitored by the data monitoring committee for each study. Safety results for the two phase II studies of pmab + ctx and two phase III studies of pmab ± ctx are summarized (Table). Conclusions: Phase II data are consistent with expectations, and phase III trials are ongoing. A consistent safety profile was observed across studies. [Table: see text] [Table: see text]

scholarly journals Exploring Essential Issues for Improving Therapeutic Cancer Vaccine Trial Design

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2908
Author(s):  
Constantin N. Baxevanis ◽  
Sotirios P. Fortis ◽  
Alexandros Ardavanis ◽  
Sonia A. Perez
Keyword(s):  
Clinical Trial ◽  
Cancer Immunotherapy ◽  
Phase Ii ◽  
Cancer Vaccines ◽  
Trial Design ◽  
Vaccine Trial ◽  
Phase Iii ◽  
Special Focus ◽  
Therapeutic Cancer Vaccines ◽  
The Impact

Therapeutic cancer vaccines have been at the forefront of cancer immunotherapy for more than 20 years, with promising results in phase I and—in some cases—phase II clinical trials, but with failures in large phase III studies. After dozens of clinical studies, only Dendreon’s dendritic cell vaccine Sipuleucel-T has succeeded in receiving US FDA approval for the treatment of metastatic castrate-resistant prostate cancer. Although scientists working on cancer immunotherapy feel that this is an essential breakthrough for the field, they still expect that new vaccine regimens will yield better clinical benefits compared to the four months prolonged median overall survival (OS) Sipuleucel-T demonstrated in the IMPACT phase III clinical trial. Clinical development of cancer vaccines has been unsuccessful due to failures either in randomized phase II or—even worse—phase III trials. Thus, rigorous re-evaluation of these trials is urgently required in order to redefine aspects and optimize the benefits offered by therapeutic cancer vaccines. The scope of this review is to provide to the reader our thoughts on the key challenges in maximizing the therapeutic potentials of cancer vaccines, with a special focus on issues that touch upon clinical trial design.

Phase II Window of Idarubicin in Children With Extraocular Retinoblastoma

1999 ◽  
Vol 17 (6) ◽  
pp. 1847-1847 ◽  
Author(s):  
Guillermo L. Chantada ◽  
Adriana Fandiño ◽  
Gabriel Mato ◽  
Sandra Casak
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Progressive Disease ◽  
Bone Marrow Involvement ◽  
Complete Response ◽  
Phase Iii ◽  
Starting Dose ◽  
Hematopoietic Toxicity ◽  
Grade 3 ◽  
Phase Iii Studies

PURPOSE: The aim of this study was to evaluate in an upfront phase II study the response to idarubicin in children with extraocular retinoblastoma. PATIENTS AND METHODS: The starting dose of idarubicin was 15 mg/m2/d (days 1 and 2) weeks 0 and 3. After an interim evaluation, the dose was reduced to 10 mg/m2/d (days 1 and 2) weeks 0 and 3 because of hematopoietic toxicity. Response was evaluated at week 6. RESULTS: At the Hospital JP Garrahan (Buenos Aires, Argentina), 10 patients (five bilateral) were entered onto the study from 1995 to 1998. A total of 19 cycles were administered. Extraocular sites included orbit (n = 10), bone marrow (n = 3), bone (n = 1), lymph node (n = 1), and CNS (n = 1). The response rate was 60% (95% confidence interval, 30% to 90%). One complete response was achieved, in addition to five partial responses, two cases of stable disease, and two cases of progressive disease. All patients with bone marrow involvement achieved complete clearance of tumor cells. The patient with CNS disease had progressive disease. All patients had severe hematopoietic toxicity (grade 4 neutropenia and grade 3/4 thrombocytopenia after most cycles). Other toxicities included grade 2 diarrhea in 30%. No echocardiographic changes were detected. CONCLUSION: Idarubicin is active in extraocular retinoblastoma. The activity of this drug should be explored in future phase III studies.

scholarly journals A Review of Docetaxel: Its Use in the Treatment of Gastric Cancer

2010 ◽  
Vol 2 ◽  
pp. CMT.S5191
Author(s):  
Alessandro Inno ◽  
Michele Basso ◽  
Alessandra Cassano ◽  
Carlo Barone
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Poor Performance ◽  
Phase Iii ◽  
Poor Performance Status ◽  
Phase Ii Studies ◽  
Combination Regimens

Docetaxel, a member of the taxane family, promotes cell death by binding β-tubulin and has demonstrated activity against several human malignancies, both as a single agent and in combination therapy. It has been approved in Europe and the US as front-line treatment for advanced gastric cancer in combination with cisplatin and fluorouracil (DCF regimen). This approval was based on the results of a pivotal study (V325) which demonstrated that the addition of docetaxel to the reference regimen of cisplatin and fluorouracil improves overall survival and progression-free survival with a better quality of life despite increased toxicity (mainly haematological). Modifications of DCF regimen have been successfully investigated as a means of making the treatment more tolerable and suitable also for elderly patients or patients with poor performance status. Emerging data from several phase II studies suggest that other docetaxel-based combination regimens with anthracyclines or irinotecan have interesting activity with acceptable toxicity profiles, but the true efficacy of these regimens needs to be assessed in large randomized phase III studies. Thus, the best docetaxel-containing regimen has yet to be identified. Docetaxel also represents a good candidate for combination with novel molecular target agents. In light of the high response rates observed in phase II-III studies, a docetaxel-based chemotherapy regimen might also be considered a treatment option as perioperative or adjuvant therapy in potentially curable gastric cancer and further studies with or without biological agents are eagerly awaited in this setting.

Evolution of statistical methodology and design of phase II/III clinical trials in non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7108-7108 ◽  
Author(s):  
R. K. Bagai ◽  
A. Dowlati
Keyword(s):  
Clinical Trials ◽  
Survival Time ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Iii ◽  
Type I ◽  
Phase Ii Trials ◽  
Improvement In Survival ◽  
Phase Ii And Iii ◽  
Phase Iii Studies

7108 Background: A significant heterogeneity exists in the design and reporting of phase II and III therapeutic clinical trials in NSCLC. This has led to difficulty in interpretation of these trials leading to over- or underestimation of therapeutic efficacy. We set out to investigate the statistical methodology and design reporting of chemotherapeutic trials in NSCLC published in the Journal of Clinical Oncology (JCO) over 20 years. Methods: We identified all phase II and III NSCLC chemotherapy trials published in the JCO from January 1983 to August 2005. All manuscripts were reviewed to evaluate components of statistical design that were reported, including: sample size calculation, power, type I error, single or multiple drug trials, relative response sought in phase II trials and improvement in survival time or response rate sought in phase III trials. Results: One hundred forty eight trials were identified. 52% of studies were phase III and 48% were phase II. The majority (78%) were conducted in advanced stage NSCLC. Sample size calculations were reported for only 58% of phase III studies and 31% of phase II studies. Power was reported in 66% of phase III studies and 13% of phase II trials. Type I error was reported in 47% of phase III studies and 17% in phase II studies. 60% of phase III trials defined endpoints (percentage improvement in survival time, improvement in survival time in months or increase in response rate). 41% of phase II trails defined the target response rate, ranging from response rates of 15% to 70%. The frequency of adequate reporting of statistical design was shown to increase from 31% in 1990–1995 to 64% in 2000–2005 ( table ). Conclusions: Significant heterogeneity exists in trial design and reporting of phase II and III trials in NSCLC. This impacts the ability to adequately interpret these studies. More widespread application of statistical methods in planning and reporting of lung cancer clinical trials are necessary to increase reliability of data. [Table: see text] No significant financial relationships to disclose.

REACT: A phase II study of rindopepimut (CDX-110) plus bevacizumab (BV) in relapsed glioblastoma (GB).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS2103-TPS2103 ◽  
Author(s):  
David A. Reardon ◽  
James J. Vredenburgh ◽  
Annick Desjardins ◽  
Ronald G. Steis ◽  
Erin M. Dunbar ◽  
...  
Keyword(s):  
Immune Responses ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Peptide Sequence ◽  
Phase Iii ◽  
Open Label ◽  
Term Survival ◽  
Gm Csf ◽  
Phase Ii Studies

TPS2103 Background: EGFRvIII is a constitutively active tumorigenic deletion mutation of EGFR. It is expressed in ~30% of primary GB where it is linked to poor long-term survival (Pelloski 2007). The investigational vaccine rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin (KLH), delivered intradermally (500ug with 150ug GM-CSF as an adjuvant). Remarkably consistent and promising results across 3 phase II studies in newly diagnosed, resected EGFRvIII+ GB (Lai 2011) represent a statistically significant improvement over a historical control cohort matched for major eligibility criteria (median overall survival [OS] = 24.4 - 24.6 vs. 15.2 months from diagnosis [m] and median progression-free survival [PFS] = 12.3 - 15.3 vs. 6.4 m). ACT IV, a phase III trial in this population, is ongoing. The immunosuppressive influence of residual/advanced GB presents a challenge to activation of efficacious antitumor immune responses. Anecdotal evidence (compassionate use cases, Sampson 2008) suggests that rindopepimut may induce specific immune responses and regression in multifocal and bulky residual tumors. Rindopepimut with BV, which inhibits VEGF and its immunosuppressive properties (including impaired maturation of dendritic cells and disruption of tumoral T cell infiltration [Johnson 2007, Shrimali 2010]) may further optimize EGFRvIII-specific immune response and antitumor activity. Methods: ReACT is a Phase II study of rindopepimut plus BV in patients (pts) with 1st or 2nd relapse of EGFRvIII+ GB. BV-naïve pts will be enrolled to Group 1 (n=70: randomized 1:1 to BV plus either rindopepimut/GM-CSF or control injection [low-dose KLH]) while BV-refractory patients will enter Group 2 (n=25: to receive BV plus open-label rindopepimut/GM-CSF). Concurrent with BV (10 mg/kg, q 2 wks), blinded treatment or open-label vaccine is given in priming phase (days 1, 15 and 29), then monthly until PD. Tumor response is assessed every 8 weeks, and patients are followed for survival after PD. Objectives are PFS at 6 months (primary), objective response rate, PFS, OS, safety, immunogenicity and elimination of EGFRvIII. ReACT opened to accrual in December 2011 (NCT01498328).

Meta-analysis and systematic review of the cardiotoxicity of TAS-102.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16053-e16053 ◽  
Author(s):  
Carlos Alberto Lopez ◽  
Elham Azimi-Nekoo ◽  
Su Yun Chung ◽  
James Newman ◽  
Janice Shen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Systematic Review ◽  
Phase I ◽  
Phase Ii ◽  
Literature Search ◽  
Meta Analysis ◽  
Phase Iii ◽  
Cardiac Events ◽  
Phase Ii Studies ◽  
Increased Risk

e16053 Background: Fluoropyrimidines such as 5-FU and capecitabine are known to be cardiotoxic drugs. TAS-102 (trifluridine-tipiracil) is a novel oral fluoropyrimidine that was recently FDA approved to treat gastric and colon cancer. However, the incidence of cardiac related events of TAS-102 is not fully ascertained. We performed a meta-analysis and systematic review to determine the incidence of cardiotoxic events associated with TAS-102. Methods: We performed a literature search through PubMed, Embase, and Web of Science to identify any publications in any language up to December 31st, 2019 where TAS-102 (and equivalent terms such as “trifluridine-tipiracil” and “Lonsurf”) was used. These were then manually reviewed to identify any publications reporting cardiac events. Randomized controlled trials (RCTs) were included for meta-analysis to determine the incidence of cardiotoxic events, which were summarized as pooled odds ratios (OR) when compared to placebo. Non-randomized, non-controlled clinical trials (phase I and phase II studies) were included in the systematic review but excluded from the pooled OR calculation. Results: 869 publications were identified in the initial literature search, of which 17 trials (3 Phase III studies, 6 Phase II studies, and 8 phase I studies) met inclusion criteria. A total of 1,877 patients among 4 RCTs were included in the meta-analysis. Compared with placebo, TAS-102 did not increase the risk of myocardial infarction (OR 1.97 95% CI [0.22-17.89]), hypertension (OR 0.73 95% CI [0.37, 1.44]), palpitations (OR 1.51 95% CI [0.30, 7.56]), cardio-pulmonary arrest (OR 0.83 95% CI [0.11-6.32]), or syncope (OR 1.50 95% CI [0.06-37.14]). Among the 1,252 patients receiving TAS-102, the overall incidence of cardiovascular events was low, with hypertension being the most common side effect (21 events), followed by palpitations (6 events), cardiopulmonary arrest (2 events), and myocardial infarction (3 events), though there was no statistically significant increased risk compared to placebo. No deaths were reported. Conclusions: Unlike other fluoropyrimidines, TAS-102 appears to be a cardiogentle drug, with no increased risk of cardiac events compared to placebo. Since fluoropyrimidines remain the backbone of treatment for gastrointestinal malignancies, TAS-102 can offer an alternative to patients who developed cardiotoxicities from other agents. Prospective studies with consideration of cardiac risk factors are required.

scholarly journals Rational Clinical Experiment: Assessing Prior Probability and Its Impact on the Success of Phase II Clinical Trials

2015 ◽  
Vol 33 (26) ◽  
pp. 2914-2919 ◽  
Author(s):  
Daniel M. Halperin ◽  
J. Jack Lee ◽  
Cecile Gonzales Dagohoy ◽  
James C. Yao
Keyword(s):  
Phase Ii ◽  
Prior Probability ◽  
Type I Error ◽  
Drug Approval ◽  
Phase Iii ◽  
Type I ◽  
Phase Ii Trials ◽  
Predictive Values ◽  
Phase Ii Studies ◽  
Therapeutic Decisions

Purpose Despite a robust clinical trial enterprise and encouraging phase II results, the vast minority of oncologic drugs in development receive regulatory approval. In addition, clinicians occasionally make therapeutic decisions based on phase II data. Therefore, clinicians, investigators, and regulatory agencies require improved understanding of the implications of positive phase II studies. We hypothesized that prior probability of eventual drug approval was significantly different across GI cancers, with substantial ramifications for the predictive value of phase II studies. Methods We conducted a systematic search of phase II studies conducted between 1999 and 2004 and compared studies against US Food and Drug Administration and National Cancer Institute databases of approved indications for drugs tested in those studies. Results In all, 317 phase II trials were identified and followed for a median of 12.5 years. Following completion of phase III studies, eventual new drug application approval rates varied from 0% (zero of 45) in pancreatic adenocarcinoma to 34.8% (24 of 69) for colon adenocarcinoma. The proportion of drugs eventually approved was correlated with the disease under study (P < .001). The median type I error for all published trials was 0.05, and the median type II error was 0.1, with minimal variation. By using the observed median type I error for each disease, phase II studies have positive predictive values ranging from less than 1% to 90%, depending on primary site of the cancer. Conclusion Phase II trials in different GI malignancies have distinct prior probabilities of drug approval, yielding quantitatively and qualitatively different predictive values with similar statistical designs. Incorporation of prior probability into trial design may allow for more effective design and interpretation of phase II studies.

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