Phase II Stopping Rules That Employ Response Rates and Early Progression

2008 ◽  
Vol 26 (22) ◽  
pp. 3715-3720 ◽  
Author(s):  
John R. Goffin ◽  
Dongsheng Tu
Keyword(s):  
Phase Ii ◽  
Progressive Disease ◽  
Response Rate ◽  
Error Rates ◽  
Stopping Rules ◽  
Early Stopping ◽  
Phase Ii Trials ◽  
End Point ◽  
Further Development ◽  
Early Progressive Disease

Purpose Phase II oncology trials traditionally have used response rate (RR) as the primary end point, but newer targeted agents require the consideration of alternative end points. High rates of early progressive disease (EPD) suggest inadequate drug activity and may be useful in the early stopping of trials. This study used a simulation to define a set of rules to assess a combined end point of RR and EPD. Methods The simulation assumed a two-stage trial with a specified α error and power. It randomly generated the true response rate, r, of the agent under study and its true rate of early progressive disease, epd, for each run of the simulation. Two pairs of parameters were specified: (rnul, epdnul) and (ralt, epdalt). A drug was considered uninteresting for further development if r was less than or equal to rnul and epd was greater than or equal to epdnul (ie, the null hypothesis) and interesting for further development if r was greater than or equal to ralt or epd was less than or equal to epdalt (ie, the alternate hypotheses). Thresholds for the required number of patients with responses, nr and EPD, np, were generated for each set of parameters. Results Thresholds for nr and np that satisfied the specified error rates were generated. There was at least an 89% likelihood that a study would be stopped at the first stage of accrual if r and epd were uninteresting. Conclusion The simulation was able to establish stopping rules by combining the RR and the EPD that achieved the desired error rates. High rates of early stopping suggest that this design could shorten phase II trials of inactive agents.

Phase II stopping rules employing response rates and early progression

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2553-2553
Author(s):  
J. R. Goffin ◽  
D. Tu
Keyword(s):  
Drug Development ◽  
Phase Ii ◽  
Progressive Disease ◽  
Response Rate ◽  
Response Rates ◽  
Stopping Rules ◽  
Disease Rate ◽  
Early Progression ◽  
Further Development ◽  
Early Progressive Disease

2553 Background: Drug development in oncology has become increasingly resource intensive. Anything that might accelerate drug development would benefit patients and drug developers. Traditionally, tumour response rates (RR) have been used to assess the efficacy of new agents in phase II trials. High rates of early progression of disease (EPD) may also indicate lack of drug efficacy, and this endpoint has the potential to shorten trials compared to assessing RR alone. This work seeks to create a set of rules that will allow phase II drug assessment employing both RR and EPD. Previous work on this subject suffered from insufficient power, as determined by the authors [Freidlin et al, J Clin Oncol, 20:599, 2002]. Methods: Using TreeAge Pro Healthcare software, we created a computer model that would accept specified trial parameters and determine through simulations stopping rules based on observed number of responses and EPDs to achieve the desired power and alpha error for a single-armed two-stage study with 15 patients in each stage. The null hypothesis (H(nul)) specified the response rate (rr(nul)) and early progressive disease rate (epd(nul)) that would render a drug uninteresting for further development, such that: H(nul): rr LE rr(nul) & epd GE epd(nul), where rr is that actual response rate observed and epd is the actual rate of early progression. Similarly, the alternate hypothesis (H(alt)) specified the response rate (rr(alt)) and early progressive disease rate (epd(alt)) that would render a drug interesting for further development, such that: H(alt): rr GE rr(alt) or epd LE epd(alt). (LE, less than, equal to; GE, greater than, equal to) Results: Conclusions: The simulation was able to establish stopping rules for observed number of responses and EPDs to achieve the desired error rates. Variations on the rules based on other trial sample types and design parameters will be detailed. [Table: see text] No significant financial relationships to disclose.

Application of a New Multinomial Phase II Stopping Rule Using Response and Early Progression

2001 ◽  
Vol 19 (3) ◽  
pp. 785-791 ◽  
Author(s):  
S. Dent ◽  
B. Zee ◽  
J. Dancey ◽  
A. Hanauske ◽  
J. Wanders ◽  
...  
Keyword(s):  
Phase Ii ◽  
Anticancer Agents ◽  
Objective Response ◽  
Stopping Rule ◽  
Stopping Rules ◽  
Early Stopping ◽  
Phase Ii Trials ◽  
European Organization ◽  
Study Results ◽  
Early Progression

PURPOSE: A multinomial stopping rule had previously been developed that incorporated both objective response and early progression into decisions to stop or continue phase II trials of anticancer agents. The purpose of this study was to apply the multinomial rule to two independent sets of phase II data to assess its utility in appropriately recommending early trial closure as compared with other stopping rules. MATERIALS AND METHODS: Data from completed phase II trials of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and European Organization for Research and Treatment of Cancer Early Clinical Studies Group (ECSG) formed the basis of the study. Based on observed results for each trial, the recommendation of the multinomial stopping rule was applied, as was the recommendation of the actual stopping rule used (Fleming or Gehan). The appropriateness of the recommendations was evaluated based on interpretation of final study results. RESULTS: The standard and multinomial rules disagreed on early stopping in one of 16 NCIC CTG trials and in seven of 23 ECSG trials. In all cases, the standard rule advised continuing to the second stage whereas the multinomial rule advised stopping early because of excessive numbers of patients experiencing early disease progression. Final trial results indicated that the multinomial recommendation was appropriate, because in no study did final results lead to conclusions of activity. CONCLUSION: In this series of trials, the multinomial stopping rule performed more efficiently than the Fleming or Gehan rules in advising early stopping of trials. These results encourage continued exploration of this approach for phase II trials of cytotoxic and noncytotoxic anticancer agents.

scholarly journals Imatinib Mesylate in Advanced Dermatofibrosarcoma Protuberans: Pooled Analysis of Two Phase II Clinical Trials

2010 ◽  
Vol 28 (10) ◽  
pp. 1772-1779 ◽  
Author(s):  
Piotr Rutkowski ◽  
Martine Van Glabbeke ◽  
Cathryn J. Rankin ◽  
Wlodzimierz Ruka ◽  
Brian P. Rubin ◽  
...  
Keyword(s):  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Locally Advanced ◽  
Dermatofibrosarcoma Protuberans ◽  
Phase Ii Trials ◽  
Two Phase ◽  
End Point ◽  
Best Response

Purpose Dermatofibrosarcoma protuberans (DFSP) is a dermal sarcoma typically carrying a translocation between chromosomes 17 and 22 that generates functional platelet-derived growth factor B (PDGFB). Patients and Methods Two distinct phase II trials of imatinib (400 to 800 mg daily) in patients with locally advanced or metastatic DFSP were conducted and closed prematurely, one in Europe (European Organisation for Research and Treatment of Cancer [EORTC]) with 14-week progression-free rate as the primary end point and the other in North America (Southwest Oncology Group [SWOG]) with confirmed objective response rate as the primary end point. In the EORTC trial, confirmation of PDGFB rearrangement was required, and surgery was undertaken after 14 weeks if feasible. The SWOG study confirmed t(17;22) after enrollment. Results Sixteen and eight patients were enrolled onto the EORTC and SWOG trials, respectively. Tumor size ranged from 1.2 to 49 cm. DFSP was located on head/neck, trunk, and limb in seven, 11, and six patients, respectively, and was classic, pigmented, and fibrosarcomatous DFSP in 13, one, and nine patients, respectively. Metastases were present in seven patients (lung involvement was present six patients). Eleven patients (4%) had partial response as best response, and four patients had progressive disease as best response. Median time to progression (TTP) was 1.7 years. Imatinib was stopped in 11 patients because of progression, one patient because of toxicity, and two patients after complete resection of disease. Median overall survival (OS) time has not been reached; 1-year OS rate was 87.5%. Conclusion Imatinib is active in DFSP harboring t(17;22) including fibrosarcomatous DFSP, with objective response rate approaching 50%. Response rates and TTP did not differ between patients taking 400 mg daily versus 400 mg twice a day.

Design Issues of Randomized Phase II Trials and a Proposal for Phase II Screening Trials

2005 ◽  
Vol 23 (28) ◽  
pp. 7199-7206 ◽  
Author(s):  
Lawrence V. Rubinstein ◽  
Edward L. Korn ◽  
Boris Freidlin ◽  
Sally Hunsberger ◽  
S. Percy Ivy ◽  
...  
Keyword(s):  
Phase Ii ◽  
False Positive ◽  
Standard Treatment ◽  
False Negative ◽  
Error Rates ◽  
Targeted Treatment ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Treatment Control ◽  
Randomized Phase Ii

Future progress in improving cancer therapy can be expedited by better prioritization of new treatments for phase III evaluation. Historically, phase II trials have been key components in the prioritization process. There has been a long-standing interest in using phase II trials with randomization against a standard-treatment control arm or an additional experimental arm to provide greater assurance than afforded by comparison to historic controls that the new agent or regimen is promising and warrants further evaluation. Relevant trial designs that have been developed and utilized include phase II selection designs, randomized phase II designs that include a reference standard-treatment control arm, and phase II/III designs. We present our own explorations into the possibilities of developing “phase II screening trials,” in which preliminary and nondefinitive randomized comparisons of experimental regimens to standard treatments are made (preferably using an intermediate end point) by carefully adjusting the false-positive error rates (α or type I error) and false-negative error rates (β or type II error), so that the targeted treatment benefit may be appropriate while the sample size remains restricted. If the ability to conduct a definitive phase III trial can be protected, and if investigators feel that by judicious choice of false-positive probability and false-negative probability and magnitude of targeted treatment effect they can appropriately balance the conflicting demands of screening out useless regimens versus reliably detecting useful ones, the phase II screening trial design may be appropriate to apply.

scholarly journals Phase II Study of Lenvatinib in Patients With Progressive, Recurrent or Metastatic Adenoid Cystic Carcinoma

2019 ◽  
Vol 37 (18) ◽  
pp. 1529-1537 ◽  
Author(s):  
Vatche Tchekmedyian ◽  
Eric J. Sherman ◽  
Lara Dunn ◽  
Crystal Tran ◽  
Shrujal Baxi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Adenoid Cystic Carcinoma ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Overall Response ◽  
End Point ◽  
Adenoid Cystic

PURPOSE Recurrent or metastatic adenoid cystic carcinoma (R/M ACC) is a malignant neoplasm of predominantly salivary gland origin for which effective therapies are lacking. We conducted a phase II trial evaluating the multitargeted tyrosine kinase inhibitor lenvatinib in patients with R/M ACC. PATIENTS AND METHODS This study was conducted with a two-stage minimax design. Patients with histologically confirmed R/M ACC of any primary site with radiographic and/or symptomatic progression were eligible. Any prior therapy was allowed except previous lenvatinib. Patients received lenvatinib 24 mg orally per day. The primary end point was overall response rate. Secondary end points were progression-free survival and safety. An exploratory analysis of how MYB expression and genomic alterations relate to outcomes was conducted. RESULTS Thirty-three patients were enrolled; 32 were evaluable for the primary end point. Five patients (15.6%) had a confirmed partial response, 24 patients (75%) had stable disease, two patients (6.3%) discontinued treatment as a result of toxicity before the first scan, and one patient (3.1%) had progression of disease as best response. Median progression-free survival time was 17.5 months (95% CI, 7.2 months to not reached), although only eight progression events were observed. Patients otherwise were removed for toxicity (n = 5), as a result of withdrawal of consent (n = 9), or at the treating physician’s discretion (n = 6). Twenty-three patients required at least one dose modification, and 18 of 32 patients discontinued lenvatinib for drug-related issues. The most common grade 3 or 4 adverse events were hypertension (n = 9; 28.1%) and oral pain (n = 3; 9.4%). Three grade 4 adverse events were observed (myocardial infarction, n = 1; posterior reversible encephalopathy syndrome, n = 1; and intracranial hemorrhage, n = 1). CONCLUSION This trial met the prespecified overall response rate primary end point, demonstrating antitumor activity with lenvatinib in R/M ACC patients. Toxicity was comparable to previous studies, requiring monitoring and management.

Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer.

1993 ◽  
Vol 11 (8) ◽  
pp. 1566-1572 ◽  
Author(s):  
H I Scher ◽  
W K Kelly
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Progressive Disease ◽  
Initial Therapy ◽  
Phase Ii Trials ◽  
Gnrh Analog ◽  
Combined Androgen Blockade ◽  
Hormone Refractory ◽  
Flutamide Withdrawal ◽  
Androgen Blockade

PURPOSE To evaluate the effect of discontinuation of the antiandrogen, flutamide, in patients with metastatic prostate cancer who are progressing on hormonal therapy. PATIENTS AND METHODS Thirty-six patients with progressive disease on hormonal treatment that included flutamide had discontinuation of the antiandrogen. Thirty-five (95%) had progressive increases in prostate-specific antigen (PSA) levels, despite castrate levels of testosterone. Twenty-five patients (69%) were treated with combined androgen blockade (orchiectomy or gonadotropin-releasing hormone [GnRH] analog plus flutamide) as initial therapy and 11 (31%) were started on monotherapy alone. Patients who had not undergone a previous orchiectomy were continued on the GnRH analog. Patients were monitored clinically and with serial PSA measurements, radionuclide scans, and radiographs as indicated to assess response. RESULTS Considering the 35 patients with increasing PSA values, 10 (29%) showed a significant decline (> or = 80% in seven, and > or = 50% in three) in PSA from baseline. All 10 had received combined androgen blockade as initial therapy. The duration of decline was short (median, 5+ months; range, 2 to 10+), but was associated with improvement in clinical symptoms, while one patient had a partial response in an epidural mass with parallel decline in PSA. None of the patients started on single hormone therapies responded. CONCLUSION Discontinuation of flutamide was associated with a significant decrease in PSA values in 10 of 25 patients (40%; 95% confidence interval, 21% to 59%) and clinical improvement in a subset of patients who had an initial response, but later progressive disease on combined androgen blockade. A trial of flutamide withdrawal should be considered in patients progressing on total androgen blockade before the initiation of more toxic therapies. It is likely that flutamide withdrawal has contributed to the observed responses in phase II trials of both second-line hormonal therapies and new cytotoxic agents. Future phase II trials in hormone-refractory prostatic cancer must control for this observation, and insure that progression off flutamide is documented before initiation of alternative treatment.

Final Results of a Phase I/II Study of the Combination of the Hypomethylating Agent 5-aza-2′-Deoxycytidine (DAC) and the Histone Deacetylase Inhibitor Valproic Acid (VPA) in Patients with Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 408-408 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Hagop Kantarjian ◽  
Blanca Sanchez-Gonzalez ◽  
Hui Yang ◽  
Gary Rosner ◽  
...  
Keyword(s):  
Phase I ◽  
Histone Acetylation ◽  
Phase Ii ◽  
Response Rate ◽  
Stopping Rules ◽  
Clinical Activity ◽  
Dna Hypomethylation ◽  
Global Methylation ◽  
Platelet Recovery ◽  
Number Of Patients

Abstract The combination of DAC and VPA has synergistic antileukemia activity in vitro. Based on this, we developed a phase I/II study of this combination for patients with leukemia. The dose of DAC was fixed: 15 mg/m2 IV daily x 10. Three dose levels of VPA were studied: 20, 35 and 50 mg/kg orally daily x 10 concomitantly with DAC. The phase I portion of the study followed a classic 3+3 schema. The phase II targeted a response rate of 30%. Patients with relapsed/refractory chronic and acute leukemia with adequate renal, hepatic functions and performance status were eligible. Patients older than 60 years of age with untreated disease were eligible if they were not candidates for higher priority therapies. Fifty four patients have been registered and treated on this study that is now closed to new patient accrual. Median age was 60 years (range 5 to 80). All, but 2 patients with MDS, had AML. Median number of prior therapies was 2 (range 0–5). Thirty patients (56%) had abnormal cytogenetics. No non-hematological VPA dose limiting toxicities were observed during the phase I portion of the study. Therefore the phase II combination consisted of VPA at a dose of 50 mg/kg daily with DAC. Ten patients achieved a CR and 2 a CRP (same criteria as of CR but without complete platelet recovery), for an overall response rate of 22%. The study did not meet any of its planned stopping rules and the maximal number of patients (n=40) was accrued in the phase II portion of the study. Ten out 40 patients (25%) achieved a response in that phase. Two out 12 patients (16%) achieved a response at lower doses of VPA. Five out of 11(45%) previously untreated older patients achieved a CR. The median overall survival (OS) for the whole group was 5.3 months, and it has not been reached for those patients achieving a response. The median duration of response is 8.3 months. Complete cytogenetic responses were observed in 4 out 4 patients with informative karyotypes. A trend toward higher VPA levels was observed in responders (p=0.02). Twelve out 35 (34%) patients receiving VPA at a dose of 50 mg/kg had evidence of histone acetylation compared to 1 out 12 (8%) at lower doses. Histone acetylation was transient. The effects on global methylation were assessed using the LINE assay. Median LINE methylation pretreatment was 44% (range 35.7–57.6%) and it decline to 37.08% (p=0.000) by day 10 to return to baseline by day 28. Methylation of p15, p57, p73, MDR1 and THSB1 was measured pretreatment and serially during therapy. Pretreatment p15 methylation was observed in 36 out 46 patients (78%) with a median value of 18.4% (range 0–80) to decline to 11.7% (range 1.3–67.8), p=0.005, by day 10. Methylation of THSB2 was observed in 19 out 48 patients (39.5%) but it was not affected by the therapy. Methylation of p57KIP2, p73 and MDR1 were rare events in this population. p15 hypomethylation was associated with the the induction of p15 mRNA expression. In summary, the combination of DAC with VPA has significant clinical activity in patients with AML and MDS and effect potentially mediated by the induction of DNA hypomethylation and histone acetylation.

Intensified Chemo-Immunotherapy Including up-Front Autologous or Allogeneic Stem Cell Transplantation (SCT) for Young Patients with Newly Diagnosed Peripheral T-Cell Lymphomas: Final Results of a Phase II Multicenter Prospective Clinical Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1984-1984
Author(s):  
Paolo Corradini ◽  
Umberto Vitolo ◽  
Alessandro Rambaldi ◽  
Rosalba Miceli ◽  
Francesca Patriarca ◽  
...  
Keyword(s):  
Risk Factors ◽  
T Cell ◽  
Phase Ii ◽  
Progressive Disease ◽  
Newly Diagnosed ◽  
Risk Of Death ◽  
T Cell Lymphomas ◽  
Short Course ◽  
Early Progressive Disease ◽  
Peripheral T Cell Lymphomas

Abstract Abstract 1984 Background: Peripheral T-cell lymphomas (PTCL) are characterized by a poor prognosis, conventional chemotherapy provides a long-term survival of approximately 25%. Few prospective data suggest that autologous SCT (autoSCT) can improve prognosis when used up-front. Allogeneic SCT (alloSCT) can obtain a durable disease control at relapse in 40% of patients (pts). Based upon these premises, we designed a phase II trial for young pts (age 18 –60 yrs) in which intensified chemo-immunotherapy was used before auto or alloSCT. Transplant type was decided according to the donor availability. Primary endpoint was CR rate at one year after the end of treatment. This was the first prospective trial employing high-dose (hd) chemo-immunotherapy and alloSCT frontline in PTCLs. Methods: 64 pts with newly diagnosed PTCL (ALK-positive ALCL cases were excluded) were included (EudraCT N° 200600423433). Histology was centrally reviewed. The intensified pre-transplant phase consisted of 2 courses of CHOP-21 regimen preceded by alemtuzumab (30 mg total dose) followed by 2 courses of Hyper-C-Hidam (hd-methotrexate, hyper-fractionated cyclophosphamide and hd-ara-C). Autologous stem cells were collected after the second Hyper-C-Hidam or after a short course of intermediate dose Ara-C. Responding pts were transplanted according to a genetic stratification based on donor availability: pts with HLA-identical, one antigen mismatched sibling, or allele matched unrelated donors (MUD) received alloSCT. Conditioning regimen was thiotepa-fludara-cyclophosphamide [Corradini et al JCO 2004]; GVHD prophylaxis was cyclosporine, short course methotrexate and 7 mg/kg of Thymoglobuline for alternative donors only. Pts without a donor received BEAM followed by autoSCT. Results: A total of 64 pts were enrolled, but 61 fulfilled all the inclusion criteria and were thus evaluable. Diagnosis included PTCL-not otherwise specified (PTCL-NOS, n=38), ALK-negative ALCL (n=12), angioimmunoblastic lymphoma (AILT, n=9), enteropathy-type T-cell lymphoma (n=2). Median age was 48 years (range, 24–60 yrs). Fifty-seven pts (93%) had advanced disease; IPI was <2: 19 pts (31%), and ≥2: 42 pts (69%); PIT was 0–1 risk factors in 40 (66%), 2–4 risk factors in 21 (34%). Of 61 pts, 56 completed alemtuzumab-CHOP whereas 5 pts had early progressive disease (PD). After induction phase, 38 pts (62%) achieved a response [n=31 CR (51%), n= 7 PR (11%)] whereas 18 (30%) had PD and 5 (8%) died of toxicity in the Hyper-C-Hidam phase. All the 18 pts with early PD died of disease at median time of 180 days since the beginning of treatment. Transplantation-eligible pts were 38 (62%): 14 underwent autoSCT and 23 alloSCT whereas one patient, in continuous CR, did not receive autoSCT for previous viral infection. Overall, at a median follow-up of 33 months, 30 pts (49%) are alive in CR and 31 died (51%) (n=8 death for toxicity, n=23 for PD). Eleven of 14 pts who received autoSCT are alive in CR (3 relapsed). Sixteen of 23 pts who received alloSCT (n=10 matched siblings; n=13 MUD) are alive in CR, 4 (17%) died of disease, and 3 died for toxicity. In a intention-to-treat analysis, the estimated 3-years disease-free survival (DFS), PFS and overall survival (OS) values for entire cohort (61 pts) were 76%, 44%, 47%, respectively. The 3-year cumulative incidence of non-relapse mortality (NRM) and relapse were 13% and 42%, respectively. In univariate analysis, involvement of liver and/or gastrointestinal tract was associated to a poor outcome [PFS: 21% versus 53% (p=0.03); OS: 27% versus 55% (p=0.07)]. At multivariable analysis by Cox model (including as variables IPI, extranodal disease, response and SCT), pts not achieving a clinical response and not receiving SCT had a 5.8 (p=0.0003)- and 8-fold (p=0.0002) risk of death as compared to pts responding and transplanted. Pts not in response or in partial response had a 20-fold (p< 0.0001)- and 3-fold (p=0.07) risk of progression as compared to pts with CR maintained for at least 6 months. Conclusions: Our findings indicate: 1) the achievement of CR is an independent predictor of longer PFS and OS, regardless of IPI or gastric/liver disease; 2) although the trial was not sized for a formal comparison, up-front autoSCT appeared not inferior to alloSCT in responding pts; 3) the use of alemtuzumab and pre-transplant hd-chemotherapy did not reduce the amount of primary refractory or early progressive disease although SCT improves survival. Disclosures: No relevant conflicts of interest to declare.

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