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.

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.

Predictive value of phase II clinical trials in pancreatic cancer: Rethinking the road to progress.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4036-4036 ◽  
Author(s):  
Daniel M. Halperin ◽  
J. Jack Lee ◽  
James C. Yao
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Predictive Value ◽  
Error Rates ◽  
Phase Iii ◽  
Type I ◽  
Type Ii ◽  
Type Ii Error ◽  
Phase Ii Trials ◽  
Fda Approval

4036 Background: Few new therapies for pancreatic adenocarcinoma (PC) have been approved by the Food and Drug Administration (FDA) or recommended by the National Comprehensive Cancer Network (NCCN), reflecting frequent failures in phase III trials. We hypothesize that the high failure rate in large trials is due to a low predictive value for “positive” phase II studies. Methods: Given a median time from initiation of clinical trials to FDA approval of 6.3 years, we conducted a systematic search of the clinicaltrials.gov database for phase II interventional trials of antineoplastic therapy in PC initiated from 1999-2004. We reviewed drug labels and NCCN guidelines for FDA approval and guideline recommendations. Results: We identified 70 phase II trials that met our inclusion criteria. Forty-five evaluated compounds without preexisting FDA approval, 23 evaluated drugs approved in other diseases, and 2 evaluated cellular therapies. With a median follow-up of 12.5 years, none of these drugs gained FDA approval in PC. Four trials, all combining chemotherapy with radiation, eventually resulted in NCCN recommendations. Forty-two of the trials have been published. Of 16 studies providing pre-specified type I error rates, these rates were ≥0.1 in 8 studies, 0.05 in 6 studies and <0.025 in 2 studies. Of 21 studies specifying type II error rates, 7 used >0.1, 10 used 0.1, and 4 used <0.1. Published studies reported a median enrollment of 47 subjects. Fourteen trials reported utilizing a randomized design. Conclusions: The low rate of phase II trials resulting in eventual regulatory approval of therapies for PC reflects the challenge of conquering a tough disease as well as deficiencies in the statistical designs. New strategies are necessary to quantify and improve odds of success in drug development. Statistical parameters of individual or coupled phase II trials should be tailored to achieve the desired predictive value prior to initiating pivotal phase III studies. Positive predictive value of a phase II study assuming a 1%, 2%, or 5% prior probability of success and 10% type II error rate. [Table: see text]

Trabectedin (T) in relapsed advanced ovarian cancer (ROC): A pooled analysis of three phase II studies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5579-5579 ◽  
Author(s):  
S. McMeekin ◽  
J. M. del Campo ◽  
N. Colombo ◽  
C. Krasner ◽  
A. Roszak ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Dose Intensity ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Phase Ii Trials ◽  
Phase Ii Studies

5579 Introduction: Trabectedin is a DNA minor groove binding drug with a distinct MoA under development in sarcoma, prostate, breast and ROC. We have performed a pooled analysis of efficacy and tolerability of all phase II trials with T as 2nd - 3rd line in ROC. Methods: Three Trabectedin schedules were investigated: two every 3weeks (q3w; A: 1.3 mg/m2 3-h or B: 1.5 mg/m2 24-h) and one weekly (C: 0.58 mg/m2 3-h ×3 q4w). Endpoints were response rate (RR), time to progression (TTP), response duration (RD) and safety. 294 patients from 3 phase II (one randomized A vs B) trials were included: 108 were resistant (R) and 186 sensitive (S) to last platinum, based on progression-free interval <6 months or longer.Results: Overall RR and median TTP were 8% and 2.1mo in R and 34% and 5.8 mo in S patients. Median RD was 5.8 m. Schedules A & B q3w showed significant better RR (33% vs 16%, p=<0.0001) and median TTP (5.8 vs 2.8 m, p=0.0001) than the weekly schedule C. No efficacy difference was seen between 3-h and 24-h q3wk. In patients with = 2 prior platinum-based regimens, RR (R:7% and S:37%) and median TTP (R: 2.5 m and S:6.3 m) were similar than patients with only 1 prior platinum [RR (R:9%; S:33%) and TTP (R: 2 m; S: 5.5 m)]. 1,404 cycles were delivered [median A: 5(1–23), B: 5(1–19), C: 3(1–22)], with similar dose intensity (mg/m2/wk) across regimens (0.38, 0.42, 0.39). Most common drug-related AEs of any grade by cycle were (A, B, C) fatigue: 38, 35, 63% and vomiting: 16, 27, 21%. Grade 3/4 lab abnormalities were non-cumulative neutropenia: 21, 28, 1% and ALT increase: 32, 26, 3%. Low incidence of febrile neutropenia, neurotoxicity, stomatitis and alopecia was seen regardless of schedule. Conclusions: Trabectedin as single agent has shown clinical activity in both R and, particularly in S ROC. Activity was fully retained in patients with =2 prior platinum lines. Trabectedin q3w schedules (with no difference between 3 and 24-h) showed higher efficacy than T weekly. Toxicities were manageable and non-cumulative. Trabectedin is a promising new drug for the treatment of ROC and is under evaluation in a phase III trial. No significant financial relationships to disclose.

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]

Efficacy and safety of panobinostat (LBH-589), a histone-deacetylase inhibitor (HDACi), in patients (pts) with advanced, previously treated soft tissue sarcoma (STS) and sex cord tumors (SCT): A study from the French Sarcoma Group.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10027-10027 ◽  
Author(s):  
Philippe Alexandre Cassier ◽  
Anne Lefranc ◽  
Nicolas Penel ◽  
Christine Chevreau ◽  
Binh Bui Nguyen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Type I Error ◽  
Treatment Options ◽  
Median Number ◽  
Type I ◽  
Phase Ii Trials ◽  
Open Label ◽  
End Point ◽  
Best Response ◽  
Grade 3

10027 Background: Treatment options are limited for pts with advanced pretreated STS. HDACi have shown activity in preclinical models of STS and SCT Methods: Pts with advanced pretreated STS and SCT were enrolled in this open label, single arm, multicenter phase II study. Panobinostat was given orally, 40 mg thrice per week. The primary end-point was 3-month progression-free rate according to RECIST 1.1 using central review. Fleming-A’Hern single-stage design for phase II trials was used, and assuming a type I error alpha of 5% with 90% power, 15/47 pts were needed to be progression free at 3 months to reject a rate of 20%. Results: Fifty three pts were enrolled between January 2010 and January 2011. Median age was 59 (range 21-79) years, and 22 (42%) pts were males, 13 had translocation-related sarcoma (TRS) and 4 had SCT. All but 5 pts had metastatic disease. The most common sites were the lung and the liver. All but one pt had documented disease progression prior to study entry. The median number of prior lines of therapy was 2 (range 1-7). Panobinostat dose was lowered to 20 mg thrice a week after 11 pts were enrolled based on the recommendation of an independent safety committee. Fifty-two pts were evaluable for toxicity (1 pt never received treatment), 48 pts (92%) reported at least one adverse event (AE) and 22 (42%) reported at least one treatment-related grade 3 or 4 AE. The most common grade 3/4 AEs were thrombocytopenia, fatigue and anemia. Fifty pts were evaluable for the primary end-point, of these, 12 pts (24%, 95%CI[13-38%]) were progression-free at 3 months, including 4/13 pts (31%, 95%CI[9-61%]) with TRS and 2/4 pts (50%, 95%CI[7-93%]) with SCT. No CR was seen, two patients (4%) with SCT had a PR and 19 pts (37%) had SD as their best response. Seven pts were progression-free at 6 months: 2 pts with SCT, 2 with TRS, 1 with liposarcoma, 1 with malignant solitary fibrous tumor and 1 with leiomyosarcoma. Conclusions: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited although some patients had prolonged SD. Activity in pts with SCT warrants further investigation.

Phase II trials of cetuximab (CX) plus cisplatin (CDDP), 5-fluorouracil (5-FU) and radiation (RT) in immunocompetent (ECOG 3205) and HIV-positive (AMC045) patients with squamous cell carcinoma of the anal canal (SCAC): Safety and preliminary efficacy results.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4030-4030 ◽  
Author(s):  
Madhur Garg ◽  
Jeanette Y Lee ◽  
Lisa A. Kachnic ◽  
Paul J. Catalano ◽  
David H. Henry ◽  
...  
Keyword(s):  
Phase Ii ◽  
Task Force ◽  
Stopping Rules ◽  
Hiv Positive ◽  
Type I ◽  
Phase Ii Trials ◽  
Efficacy Data ◽  
Safety And Efficacy ◽  
Phase Ii Studies ◽  
Egfr Expression

4030 Background: Epidermal growth factor receptor (EGFR) expression and HPV infection are common in SCAC. We therefore initiated 2 phase II studies to evaluate the safety and efficacy of the EGFR inhibitor CX given concurrently with CDDP/5-FU/RT in HIV-positive (AMC045) and immunocompetent (E3205) patients with SCAC. Methods: All patients received CX (400 mg/m2 loading, then 250 mg/m2/wk IV x 6-8 wks) plus CDDP (75 mg/m2 IV q28 days x 2) and 5-FU (1000 mg/m2/day IV infusion days 1-4 q 28 days x 2) concurrently with RT (45-54 Gy) beginning with CX dose 2. Patients in E3205 also received 2 cycles of CDDP/5-FU alone prior to CX/CDDP/5-FU/RT; this was discontinued on recommendation of the NCI Anorectal Task Force after 28 patients. Both trials were powered to detect a reduction in 3-year local-regional failure (LRF) rate from 35% to 17.5% (alpha=0.10, beta=0.10), the primary end point. Other endpoints included progression free survival (PFS) and overall survival (OS). The results below include complete toxicity and preliminary efficacy data (including only the first 28 patients from E3205). Results: Expedited reporting was required for type I (any grade 5, grade 4 cardiac) or II (grade 4 RT skin, diarrhea) adverse events, with prespecified rates of >5% or >20%, respectively defined as unacceptable. Early stopping rules were not invoked for either trial. LRF rates data will be presented after more detailed case review is completed. Conclusions: CX plus CDDP/5-FU/RT is feasible in patients with SCAC, including patients with HIV infection. Preliminary safety and efficacy data appear encouraging, but accrual without neoadjuvant CDDP/5-FU continues in E3205, and additional followup of both study cohorts is required in order to determine whether pre-specified efficacy endpoints were met. [Table: see text]

A phase II trial design with direct assignment option for initial marker validation.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 34-34 ◽  
Author(s):  
Sumithra J. Mandrekar ◽  
Ming-Wen An ◽  
Daniel J. Sargent
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Type I Error ◽  
Predictive Biomarkers ◽  
Stage Ii ◽  
Phase Iii ◽  
Type I ◽  
Design Strategies ◽  
Number Of Patients ◽  
The Impact

34 Background: Phase II clinical trials aim to identify promising experimental regimens for further testing in phase III trials. Testing targeted therapies with predictive biomarkers mandates efficient trial designs. Current biomarker-based trial designs, including the enrichment, all-comers, and adaptive designs, randomize patients to receive treatment or not throughout the entire duration of the trial. Recognizing the need for randomization yet acknowledging the possibility of promising but nonconclusive results after a preplanned interim analysis (IA), we propose a two-stage phase II design that allows for the possibility of direct assignment (i.e., stop randomization and assign all patients to the experimental arm in stage II) based on IA results. Methods: Using simulations, we compared properties of the direct assignment option design to a 1:1 randomized phase II design and assessed the impact of the timing of IA (after 33%, 50%, or 67% of accrual) and number of IA (one versus two with option for direct assignment at the first and second) over a range of response rate ratios (between 1.0 and 3.0). Results: Between 12% and 30% of the trials (out of 6,000 simulated trials) adopt direct assignment in stage II, with direct adoption depending on the treatment effect size and specified type I error rate (TIER). The direct assignment option design has minimal loss in power (<1.8%) and minimal increase in T1ER (<2.1%) compared to a 1:1 randomized design. The maximum loss in power across possible timings of IA was <1.2%. For the direct assignment option design, there was a 20%-50% increase in the number of patients treated on the experimental (vs. control) arm for the 1 IA case, and 40%-100% increase for the 2 IA case. Conclusions: Testing predictive biomarkers in clinical trials requires new design strategies. In the spectrum of phase II designs from adaptive to balanced randomized all-comers or enrichment designs, the direct assignment design provides a middle ground with desirable statistical properties that may appeal to both clinicians and patients.

Assessing pretest probability in phase II trials: One step back before two steps forward.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 312-312
Author(s):  
Daniel M. Halperin ◽  
Cecile Dagohoy Dagohoy ◽  
J. Jack Lee ◽  
James C. Yao
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Error Rates ◽  
Pretest Probability ◽  
Phase Iii ◽  
Positive Phase ◽  
Type I ◽  
Success Rates ◽  
Phase Ii Trials ◽  
Fda Approval

312 Background: With frequent phase III failures, only 5% of new oncology drugs entering clinical development gain FDA approval. We hypothesize that pivotal trial failures are directly related to the poor predictive value of “positive” phase II studies, with odds of success varying by multiple factors, including disease site. We assessed success rates from phase II to allow calculation of pretest probability of eventual approval. Methods: As the median time from trial start to FDA approval is 6.3 years, we systematically searched clinicaltrials.gov for phase II trials of GI cancer therapy from 1999-2004. We reviewed drug labels for FDA approval. Drugs without FDA approval within 12 months of clinical trial start were classified New Drug Application (NDA) eligible. Drugs with prior approval were considered supplemental NDA (sNDA) eligible. Success rates were calculated as proportion of trials with drugs eventually approved. Results: We identified 280 trials; some included multiple disease sites. Approvals are shown in the table. Trials in different diseases had distinct rates of drug approval. sNDAsuccess in colorectal tumors was driven by multiple trials of drugs later gaining approval. Conclusions: Variable rates of phase II trials resulting in eventual approval for different GI cancers reflect the landscape of distinct diseases in which we test new therapies. Posterior probability of approval after a positive phase II trial varies by prior probability. For a positive phase II study with type I and II error rates of 0.1, given pretest probability of 1%, 3%, or 10%, the odds of eventual approval are 8%, 22%, and 50% respectively. With a quantitative understanding, we can tailor phase II trial design to improve phase III success rates. [Table: see text]

NRG-BR002: A phase IIR/III trial of standard of care therapy with or without stereotactic body radiotherapy (SBRT) and/or surgical ablation for newly oligometastatic breast cancer (NCT02364557).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS1117-TPS1117 ◽  
Author(s):  
Steven J. Chmura ◽  
Kathryn A. Winter ◽  
Hania A Al-Hallaq ◽  
Virginia F. Borges ◽  
Nora T. Jaskowiak ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Systemic Therapy ◽  
Stereotactic Body Radiotherapy ◽  
Type I Error ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Type I

TPS1117 Background: This is a randomized Phase II/III trial to evaluate if stereotactic body radiotherapy (SBRT) and/or surgical resection (SR) of all metastatic sites in newly oligo-metastatic breast cancer who have received up to 12 months of first line systemic therapy without progression will significantly improve median progression free survival (PFS). If this aim is met the trial continues as a phase III to evaluate if SBRT/SR improves 5 year overall survival. Secondary aims include local control in the metastatic site, new distant metastatic rate, and technical quality. Translational primary endpoint is to determine whether < 5 CTCs is an independent prognostic marker for improved PFS and OS. Methods: Women with pathologically confirmed metastatic breast cancer to ≤ 4 sites who have been diagnosed within 365 days with metastatic disease and the primary tumor site disease is controlled. CNS metastases are ineligible. ER/PR and HER-2 neu status is required. Site radiation credentialing with a facility questionnaire and pre-treatment review of first case is required. Randomization is to standard systemic therapy with local radiotherapy/ surgery for palliation when necessary versus ablative therapy of all metastases with SBRT and/or SR. For the phase IIR portion to detect a signal for improved median PFS from 10.5 months to 19 months with 95% power and a 1-sided alpha of 0.15 and accounting for ineligible/lost patients, 128 patients will be required. For the Phase III, an additional 232 patients will be required to definitively determine if ablative therapy improves 5-year overall survival from 28% to 42.5% (HR=0.67), with 85% power and a one-sided type I error of 0.025. For the translational research assuming a two-sided probability of type I error of 0.05, the number of patients accrued in the Phase II-R and Phase III portions will provide sufficient power of at least 91% and 93% to detect whether < 5 CTC’s is prognostic for PFS and OS, respectively. Present accrual (1-31-2019): 105. Contact Information: Protocol: CTSU member web site https://www.ctsu.org . Enrollment: OPEN at https://open.ctsu.org . Support: This project is supported by NRG Oncology grants U10CA180868 and U10CA180822 from the National Cancer Institute (NCI). Translational science is supported by the Ludwig Foundation for Cancer Research. Clinical trial information: NCT02364557.

scholarly journals Inefficiencies in Phase II to Phase III Transition Impeding Successful Drug Development in Glioblastoma

2020 ◽  
Author(s):  
Adithya Balasubramanian ◽  
Ashray Gunjur ◽  
Umbreen Hafeez ◽  
Siddharth Menon ◽  
Lawrence M Cher ◽  
...  
Keyword(s):  
Drug Development ◽  
Phase Ii ◽  
Pearson Correlation ◽  
Critical Role ◽  
Phase Iii ◽  
Statistical Characteristics ◽  
Phase Ii Trials ◽  
Medline Search ◽  
Phase Ii Studies ◽  
The Impact

Abstract Background Improving outcomes of patients with glioblastoma (GBM) represents a significant challenge in neuro-oncology. We undertook a systematic review of key parameters of phase II and III trials in GBM to identify and quantify the impact of trial design on this phenomenon. Methods Studies between 2005-2019 inclusive were identified though MEDLINE search and manual bibliography searches. Phase II studies (P2T) were restricted to those referenced by the corresponding phase III trials (P3T). Clinical and statistical characteristics were extracted. For each P3T, corresponding P2T data was “optimally matched” where same drug was used in similar schedule and similar population; “suboptimally matched” if dis-similar schedule and/or treatment setting; or “lacking”. Phase II/III transition data was compared by Pearson Correlation, Fisher’s Exact or Chi-square testing. Results Of 20 P3Ts identified, 6 (30%) lacked phase II data. Of the remaining 14 P3T, 9 had 1 prior P2T, 4 had 2 P2T and 1 had 3 P2T, for a total of 20 P3T-P2T pairs (called dyads). The 13 “optimally matched” dyads showed strong concordance for mPFS (r 2=0.95, p&lt;0.01) and mOS (r 2=0.84, p&lt;0.01), whilst 7 “suboptimally matched” dyads did not (p&gt;0.05). Overall, 7 P3Ts underwent an ideal transition from P2T to P3T. “Newly diagnosed” P2Ts with mPFS&lt; 14 months and/or mOS&lt; 22 months had subsequent negative P3Ts. “Recurrent” P2Ts with mPFS&lt; 6 months and mOS&lt; 12 months also had negative P3Ts. Conclusion Our findings highlight the critical role of optimally designed phase II trials in informing drug development for GBM.

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