Randomized Phase II Designs

Rubinstein, Larry; Crowley, John; Ivy, Percy; LeBlanc, Michael; Sargent, Daniel J.

doi:10.1158/1078-0432.ccr-08-2031

Cited by 125 publications

(101 citation statements)

References 37 publications

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“…We used what some have referred to as a "selection" or "pick the winner" randomized phase 2 trial design, wherein each arm is regarded as experimental and the efficacy of each arm is evaluated independently and compared with historical data with standard therapy. 27 We sought to determine whether either experimental arm was associated with a CR rate of at least 75%, substantially higher than the approximately 50% CR rate typically observed for standard regimens, including CHOP or R-CHOP therapy in a previous AMC trial (AMC 010) performed in the HAART era. 8 Although this design does not allow a direct efficacy comparison between the 2 arms, it does facilitate a direct comparison of toxicity in the 2 arms.…”

Section: Discussionmentioning

confidence: 99%

Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma

Sparano

Lee

Kaplan

et al. 2010

Blood

233

185

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Rituximab plus intravenous bolus chemotherapy is a standard treatment for immunocompetent patients with B-cell nonHodgkin lymphoma (NHL). Some studies have suggested that rituximab is associated with excessive toxicity in HIVassociated NHL, and that infusional chemotherapy may be more effective. We performed a randomized phase 2 trial of rituximab (375 mg/m 2 ) given either concurrently before each infusional etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH) chemotherapy cycle or sequentially (weekly for 6 weeks) after completion of all chemotherapy in HIV-associated NHL. EPOCH consisted of a 96-hour intravenous infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by intravenous bolus cyclophosphamide given every 21 days for 4 to 6 cycles. In the concurrent arm, 35 of 48 evaluable patients (73%; 95% confidence interval, 58%-85%) had a complete response. In the sequential arm, 29 of 53 evaluable patients (55%; 95% confidence interval, 41%-68%) had a complete response. The primary efficacy endpoint was met for the concurrent arm only. Toxicity was comparable in the 2 arms, although patients with a baseline CD4 count less than 50/L had a high infectious death rate in the concurrent arm. We conclude that concurrent rituximab plus infusional EPOCH is an effective regimen for HIV-associated lymphoma. This study is registered at http://clinicaltrials.gov as NCT00049036. (Blood. 2010;115(15): 3008-3016)

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Section: Discussionmentioning

confidence: 99%

Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma

Sparano

Lee

Kaplan

et al. 2010

Blood

233

185

View full text Add to dashboard Cite

show abstract

“…Because a usual randomized study, designed to detect a small difference in outcomes between the two arms, would have needed a large number of patients (not compatible with a phase II study nor a rare disease), no formal statistical comparison between the two arms was planned. 19,20 The decision rules were the same for our reference (etoposide-carboplatin) and the new arm (vincristinecarboplatin), and were defined according to the singlestage Fleming design. 21,22 The number of eyes to include in each arm is 33 (17 to 33 patients).…”

Section: Methodsmentioning

confidence: 99%

Conservative treatment of retinoblastoma: a prospective phase II randomized trial of neoadjuvant chemotherapy followed by local treatments and chemothermotherapy

Rouic

Aerts

Hajage

et al. 2015

Eye

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Purpose Intraocular retinoblastoma treatments often combine chemotherapy and focal treatments. A first prospective protocol of conservative treatments in our institution showed the efficacy of the use of two courses of chemoreduction with etoposide and carboplatin, followed by chemothermotherapy using carboplatin as a single agent and diode laser. In order to decrease the possible longterm toxicity of chemotherapy due to etoposide, a randomized neoadjuvant phase II protocol was conducted using vincristinecarboplatin vs etoposide-carboplatin. Patients and methods The study was proposed when initial tumor characteristics did not allow front-line local treatments. Patients included in this phase II noncomparative randomized study of neoadjuvant chemotherapy received vincristin-carboplatin (new arm) vs etoposide-carboplatin (our reference arm). They were subsequently treated by local treatments and chemothermotherapy. Primary end point was the need for secondary enucleation or external beam radiotherapy (EBRT) not exceeding 40% at 2 years. Results A total of 65 eyes in 55 children were included in the study (May 2004 to August 2009. Of these, 32 eyes (27 children) were treated in the arm etoposide-carboplatin and 33 eyes (28 children) in the arm vincristin-carboplatin. At 2 years after treatment, 23/33 (69.7%) eyes were treated and salvaged without EBRT or enucleation in the arm vincristin-carboplatin and 26/32 (81.2%) in the arm etoposide-carboplatin. Conclusion Even if the two treatment arms could be considered as sufficiently active according to the study decision rules, neoadjuvant chemotherapy by two cycles of vincristine-carboplatin followed by chemothermotherapy appear to offer less optimal local control than the etoposidecarboplatin combination.

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“…16,17 First, the outcomes associated with patients and the methods used to assess the outcomes will change over time due to factors, such as improved supportive care, efficacy of later-line therapies, earlier disease detection, better equipment and technology, and new versions of response assessment criteria (eg, WHO -Ͼ RECIST 1.0 -Ͼ RECIST 1.1). Second, patient baseline prognostic factors (Eastern Cooperative Oncology Group performance status, previous treatments, tolerance of adverse events, and unrecognized and therefore unaccountable factors) will inevitably fluctuate between trials, so that the patient population in the new trial differs from the historical controls.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Error Rates in Single-Arm Versus Randomized Phase II Cancer Clinical Trials

Tang

Foster

Grothey

et al. 2010

JCO

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A B S T R A C T PurposeTo improve the understanding of the appropriate design of phase II oncology clinical trials, we compared error rates in single-arm, historically controlled and randomized, concurrently controlled designs. Patients and MethodsWe simulated error rates of both designs separately from individual patient data from a large colorectal cancer phase III trials and statistical models, which take into account random and systematic variation in historical control data. ResultsIn single-arm trials, false-positive error rates (type I error) were 2 to 4 times those projected when modest drift or patient selection effects (eg, 5% absolute shift in control response rate) were included in statistical models. The power of single-arm designs simulated using actual data was highly sensitive to the fraction of patients from treatment centers with high versus low patient volumes, the presence of patient selection effects or temporal drift in response rates, and random small-sample variation in historical controls. Increasing sample size did not correct the over optimism of single-arm studies. Randomized two-arm design conformed to planned error rates. ConclusionVariability in historical control success rates, outcome drifts in patient populations over time, and/or patient selection effects can result in inaccurate false-positive and false-negative error rates in single-arm designs, but leave performance of the randomized two-arm design largely unaffected at the cost of 2 to 4 times the sample size compared with single-arm designs. Given a large enough patient pool, the randomized phase II designs provide a more accurate decision for screening agents before phase III testing.

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Randomized Phase II Designs

Cited by 125 publications

References 37 publications

Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma

Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma

Conservative treatment of retinoblastoma: a prospective phase II randomized trial of neoadjuvant chemotherapy followed by local treatments and chemothermotherapy

Comparison of Error Rates in Single-Arm Versus Randomized Phase II Cancer Clinical Trials

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