This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Oxaliplatin, Fludarabine, Cytarabine and Rituximab in Richter's Syndrome, Refractory CLL and PLL (NCT00452374), a non-randomized phase 1, phase 2 study. The primary outcome is Maximum Tolerated Dose (MTD) Oxaliplatin.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00452374 |
| Phase | Phase 1, Phase 2 |
| Condition | Leukemia |
| Allocation | Non-Randomized |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 48 |
| Arms in the primary outcome | n/a |
| Lead sponsor | M.D. Anderson Cancer Center |
| Results posted | Yes |
2. Clinical Question
Population
Patients with Richter’s transformation, prolymphocytic leukemia, or refractory or relapsed B-cell chronic lymphocytic leukemia were eligible for the study. The registry lists 48 participants enrolled overall. It reports that 19 participants were in the Phase I maximum-tolerated-dose group and included in that endpoint’s analysis.
Intervention
The study evaluated oxaliplatin combined with fludarabine, cytarabine and rituximab. The listed starting oxaliplatin dose was 17.5 mg/m^2/day intravenously for 4 days. Fludarabine 30 mg/m^2 and cytarabine 1 g/m^2 were given intravenously for two days. Rituximab 375 mg/m^2 was given on Day 3 of Cycle 1, then on Day 1 of following cycles.
Comparator
There was no separate comparator group. The study is recorded as non-randomized and single-group, with no masking. Consequently, the design does not make a randomized, like-for-like comparison between this combination and another treatment or control.
Primary question
The primary endpoint asked for the maximum tolerated dose of oxaliplatin in the combination, using dose-limiting toxicity as the basis for defining that dose. The study also aimed to assess complete and partial response rates and safety and toxicity. A numerical MTD result and a numerical response result are not reported in the registry record, so the posted information does not establish the answer to those efficacy or dose-finding questions.
3. Trial Design
This was a Phase I-II, non-randomized, single-group study with no masking. The registry lists M.D. Anderson Cancer Center as sponsor, an enrollment of 48, and a completed status. The recorded study start is 2004-11 and the primary completion is 2011-01. The population comprised patients with Richter’s transformation, prolymphocytic leukemia, or refractory or relapsed B-cell chronic lymphocytic leukemia.
All participants were assigned to the listed combination of oxaliplatin, fludarabine, cytarabine and rituximab; there was no control arm. The treatment description specifies a starting oxaliplatin dose and the listed administration schedule for the combination. It does not report the full sequence of dose levels, any rules for moving between dose levels, or individual treatment exposure.
The Phase I objective was to determine the maximum tolerated dose and dose-limiting toxicity of oxaliplatin in the combination. The registry says that 19 of the 48 enrolled participants were in the Phase I maximum-tolerated-dose group and included in that analysis. The Phase II objectives included assessing complete and partial response rates and safety and toxicity. Secondary aims included duration of response, failure-free survival, overall survival, infection incidence, immune measures and oxaliplatin pharmacodynamics. The registry record does not report numerical results for these additional aims.
Because this was a single-group study, its design can describe outcomes observed among participants receiving the combination, but it does not provide a randomized estimate of how those outcomes compare with a different treatment. The registry record does not report a detailed statistical analysis plan, sample-size justification, or further description of the study’s allocation procedures.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Overall Study
| Stage | Oxaliplatin, Fludarabine, Cytarabine + Rituximab |
|---|---|
| STARTED | 48 |
| COMPLETED | 48 |
| NOT COMPLETED | 0 |
Analysis population for the primary outcome, as defined in the registry: Of the 48 study participants, 19 were enrolled in the Phase I MTD group and included in the MTD analysis.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
| Characteristic | Unit | Oxaliplatin, Fludarabine, Cytarabine + Rituximab |
|---|---|---|
| Participants analysed | 48 | |
| Age Continuous | years | 61 (37 to 78) |
| Sex: Female, Male: Female | Participants | 14 |
| Sex: Female, Male: Male | Participants | 34 |
| Region of Enrollment: United States | participants | 48 |
6. Primary Endpoint
The registry lists the primary outcome as Maximum Tolerated Dose (MTD) Oxaliplatin, measured over From treatment onset to end of each cycle of treatment (every 21 days).
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | mg/m^2 |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the maximum tolerated dose of oxaliplatin, expressed in mg/m^2. The registry defines this as the dose level at which 2/3 or 2/6 participants experience a dose-limiting toxicity. A qualifying toxicity is an oxaliplatin-related, at least Grade 3, non-hematological toxicity involving a major organ system: brain, heart, kidney, liver or lung. The stated grading reference is National Cancer Institute Version 3.0.
This endpoint is used in dose-finding because it links the dose under evaluation to the occurrence of specified toxicities. In general, a maximum-tolerated-dose rule is a protocol-defined way to identify a dose level that meets a prespecified toxicity criterion; it is not itself a measure of response, survival or comparative benefit. The registry describes the definition and the timeframe, from treatment onset to the end of each 21-day cycle, but does not report the numerical MTD found.
The registry identifies 19 Phase I participants in the MTD analysis, rather than all 48 enrolled participants. It does not report the dose-level results, the number of dose-limiting toxicities at each level, or the final selected MTD. Accordingly, the endpoint’s definition can be interpreted, but its observed value and the evidence supporting that value cannot be assessed from the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted record describes a dose-finding and response-assessment study of oxaliplatin, fludarabine, cytarabine and rituximab in a population spanning Richter’s transformation, prolymphocytic leukemia, and refractory or relapsed B-cell chronic lymphocytic leukemia. It specifies the primary MTD endpoint and its toxicity rule. It also reports that 19 participants were included in the MTD analysis out of 48 enrolled overall. However, the numerical MTD result is not reported in the registry record.
The registry lists a secondary outcome for the number of participants with a complete response or partial response, but does not provide a response count or rate in the registry record recorded for this study. The stated objectives also include safety, duration of response, failure-free survival and overall survival. Numerical results for these efficacy and time-to-event outcomes are not reported in the registry record. Therefore, readers cannot use the posted information to quantify response frequency, response duration, survival, or uncertainty around those outcomes.
The study’s single-group design matters to interpretation. Outcomes observed in a group receiving a combination do not, by themselves, estimate the difference between that combination and an alternative. Without a randomized comparator, differences in patient characteristics, disease type, prior treatment or other factors cannot be separated from treatment effects through a like-for-like trial contrast. The record does not report an adjusted comparative analysis.
The serious adverse event information gives the listed group’s at-risk denominator as 48 and says 28 participants were affected by serious adverse events. The most frequently listed serious terms include infection at 22.9%, neutropenic fever at 18.8%, fever at 10.4%, and death at 8.3%. These figures describe safety reporting in the enrolled study group. They do not establish which events were caused by a particular drug, and the percentages should not be read as comparative risk estimates. The separate death count is not reported in the registry record.
In general, a point estimate describes the observed value, while an interval estimate communicates uncertainty around an estimate. The posted information does not report confidence intervals for the MTD, response, or safety results. It therefore offers limited information about precision in addition to the missing efficacy outcome values. No conclusion about comparative effectiveness or treatment benefit follows from the registry entries alone.
9. Statistical Methods Explained
What does the design permit?
The study is classified as Phase I-II, non-randomized, unmasked and single-group. In general, randomization helps balance measured and unmeasured participant characteristics across treatment groups, on average. Since there is no randomized comparator in this study, the record cannot support a randomized between-group treatment-effect estimate. A single-group study can still document outcomes and toxicity among the participants who received the regimen, but those observations do not answer what would have happened to comparable participants under another treatment.
The registry does not describe a control group, masking procedures beyond recording none, or an allocation process beyond classifying the study as non-randomized. It also does not report an adjusted comparison. Any interpretation should therefore remain descriptive rather than comparative.
How is the primary endpoint defined?
The primary endpoint is a dose level, not a response proportion or survival time. Its rule identifies the MTD as the level where 2/3 or 2/6 participants experience a qualifying dose-limiting toxicity. The qualifying event must be oxaliplatin-related, at least Grade 3, non-hematological, and involve a major organ system named in the registry. The assessment period runs from treatment onset to the end of each 21-day cycle.
In general, a dose-finding endpoint is interpreted through the stated toxicity definition and the observed toxicity at each evaluated dose. The threshold is part of the endpoint definition, not a result. The registry record does not report the observed dose-by-dose toxicity data, the number of dose levels evaluated, or the selected MTD. Thus, the definition alone cannot establish what dose the study identified.
What can a confidence interval contribute?
General explanation: a confidence interval gives a range of values compatible with the observed data under a specified statistical method. For a response proportion, it can convey how imprecisely the proportion is estimated; for a comparative estimate, it can communicate uncertainty around a contrast. Its interpretation depends on the analysis and assumptions used. No confidence interval for the MTD, response outcomes, or safety outcomes is reported in the registry record. Because the numerical response result itself is also not reported, neither its magnitude nor its precision can be evaluated from this record.
What is the role of the sample-size illustrations?
General explanation: sample-size planning depends on the outcome, the effect the study is intended to detect, variability or event rates, the chosen significance level, desired power, and design assumptions. A planning calculation is not an observed result and does not establish that a study had adequate power for its actual effect. The registry record does not report the trial’s sample-size justification or a statistical plan for such calculations. It also does not report a comparative effect estimate on which to base a study-specific planning interpretation. The absence of these details means the rationale for the enrollment target cannot be assessed from the registry record.
General explanation: when planning a comparison of two groups, equal allocation and a normal approximation are possible assumptions, but their use must be distinguished from the design and analysis actually conducted. This study has one group and no randomized comparator. Any hypothetical two-arm planning illustration would not transform its observed data into a controlled comparison, and such an illustration would not be observed power.
Why can over-dispersion matter?
General explanation: count outcomes are sometimes analyzed using models that assume a particular relationship between the mean and variance. Over-dispersion occurs when the observed variability is greater than that assumption allows. If unaccounted for, standard errors can be too small and intervals or tests can appear more precise than warranted. Whether over-dispersion is relevant depends on the outcome and analysis model. The registry record does not report a count model or an analysis of count outcomes, so no claim can be made that such a method was used or needed in this trial.
Which analysis details are documented?
The MTD analysis population is described as 19 participants from the 48 enrolled. The registry also lists a complete-or-partial-response outcome and gives the study’s objectives, but the numerical response result and the analysis methods are not reported in the registry record. The record does not state how missing outcome data were handled, whether analyses followed intention-to-treat or another population definition, how repeated measures were handled, whether interim analyses occurred, or which statistical tests or models were used. Those procedures should not be inferred from a Phase I-II label or from the endpoint definition.
10. Multiplicity, Missing Data and Analysis Populations
The study lists multiple objectives: determining an MTD and dose-limiting toxicity, assessing complete and partial response, characterizing safety, and evaluating secondary outcomes such as response duration, failure-free survival, overall survival, infections, immune parameters and pharmacodynamic measures. When several outcomes are examined, general statistical practice recognizes that the chance of at least one apparently notable result can increase if many tests are conducted. Methods for addressing multiplicity depend on which outcomes are confirmatory, how they are tested, and the analysis plan.
The registry record does not report a multiplicity adjustment, a hierarchy of outcome testing, or a detailed statistical analysis plan. It also does not report interim analyses. None of these procedures should be assumed to have been used or not used beyond what is explicitly recorded.
The record identifies 19 participants in the MTD analysis from 48 enrolled, but does not give a broader analysis-population definition for response or other outcomes. It does not report how participants who discontinued, lacked an assessment, or had incomplete follow-up were handled. Missing-data methods, imputation procedures, and sensitivity analyses are not reported in the registry record. These omissions limit assessment of whether available outcome results, if reported elsewhere, represent all enrolled participants or a selected subset. The posted record also lacks numerical response and MTD results, so the extent to which missing observations could affect those estimates cannot be evaluated.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Oxaliplatin, Fludarabine, Cytarabine + Rituximab | 28 | 48 | 58.3% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Oxaliplatin, Fludarabine, Cytarabine + Rituximab | 48 of 48 |
Most frequent serious adverse event terms
| Event term | Organ system | Oxaliplatin, Fludarabine, Cytarabine + Rituximab |
|---|---|---|
| Infection | Infections and infestations | 11 of 48 |
| Neutropenic Fever | Infections and infestations | 9 of 48 |
| Fever | General disorders | 5 of 48 |
| Death | General disorders | 4 of 48 |
| Dehydration | Gastrointestinal disorders | 1 of 48 |
| Hemolysis | Blood and lymphatic system disorders | 1 of 48 |
| Left Pleural Effusion | Respiratory, thoracic and mediastinal disorders | 1 of 48 |
| Retinal Hemorrhage | Vascular disorders | 1 of 48 |
| Gastrointestinal Hemorrhage | Vascular disorders | 1 of 48 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Oxaliplatin, Fludarabine, Cytarabine + Rituximab |
|---|---|---|
| Neutropenia | Blood and lymphatic system disorders | 48 of 48 |
| Anemia | Blood and lymphatic system disorders | 48 of 48 |
| Thrombocytopenia | Blood and lymphatic system disorders | 48 of 48 |
| Fatigue | General disorders | 20 of 48 |
| Nausea | Gastrointestinal disorders | 13 of 48 |
| Diarrhea | Gastrointestinal disorders | 8 of 48 |
| Constipation | Gastrointestinal disorders | 5 of 48 |
| Pain | General disorders | 5 of 48 |
| Mucositis | Gastrointestinal disorders | 4 of 48 |
| Dyspnea | Respiratory, thoracic and mediastinal disorders | 4 of 48 |
Serious events with the highest arm-level rate: infection (22.9%), neutropenic fever (18.8%), fever (10.4%), death (8.3%), dehydration (2.1%).
The registry lists one treatment group with 48 participants at risk for serious adverse events and 28 participants affected. The serious-event terms with the highest listed percentages are infection at 22.9%, neutropenic fever at 18.8%, fever at 10.4%, and death at 8.3%. Dehydration and hemolysis are each listed at 2.1%. These percentages are descriptions of the reported serious-event terms in this study group, not comparisons with another group.
A participant may experience more than one event, so event-term percentages should not be added to obtain a total number of affected participants. The registry lists serious events separately from other adverse events; the group’s other-adverse-event fields indicate 48 at risk and 48 affected. That does not mean every participant experienced every listed event. The registry’s separate deaths field is not reported, so the serious-event term Death at 8.3% should not be treated as a complete account of deaths without further information.
In general, an adverse event occurring during a study is not automatically evidence that the study treatment caused it. The registry record does not provide event-level attribution, timing, severity detail beyond the serious-event listing, or a comparator group for estimating excess risk. These figures should be read as safety reporting, not as a causal or comparative estimate.
12. What the Result Does, and Does Not, Mean
The record establishes that this was a Phase I-II, single-group evaluation of oxaliplatin with fludarabine, cytarabine and rituximab in patients with three specified disease categories. It documents an MTD endpoint with a defined toxicity threshold, and reports that 19 participants were included in that analysis from 48 enrolled. It also records serious adverse event information for the single treatment group.
Those details do not reveal the numerical MTD, the observed dose-limiting toxicities by dose, or the complete and partial response results. Although response and survival outcomes were among the study objectives, their numerical results are not reported in the registry record. It is therefore not possible to quantify the observed response frequency, duration of response, failure-free survival or overall survival from these registry entries. Confidence intervals and other measures of precision for these outcomes are also not reported.
The study design does not include a randomized comparator. Consequently, the recorded outcomes cannot estimate a causal difference between this regimen and another treatment. The safety percentages describe reported events in the study group and do not establish that the regimen caused every event. Nor do they provide a comparative estimate of how frequently events would occur under another approach.
In general, registry objectives describe questions a study set out to address, whereas results require observed outcome values and enough methodological detail to interpret them. The objectives alone do not establish that a particular endpoint was met or that a treatment is effective or ineffective. The posted information supports a description of the design, endpoint definition and listed safety findings, but leaves the central numerical efficacy and dose-finding results unresolved.
13. Why This Trial Matters Statistically
This trial is statistically notable for combining a dose-finding question with response and safety objectives in a single-group Phase I-II design. The primary endpoint is not simply an adverse-event count: it uses a prespecified toxicity definition to identify a dose level, with a threshold based on 2/3 or 2/6 participants experiencing qualifying toxicity. Clear endpoint definitions matter because they determine which events contribute to the dose-finding decision.
The record also illustrates why analysis populations should be stated for each outcome. Although 48 participants were enrolled, the registry identifies 19 participants for the Phase I MTD analysis. A reader should not assume that the same population contributed to response, survival, or safety analyses. Those outcome populations and the handling of missing assessments are not reported in the registry record.
Its single-group design is central to statistical interpretation. A regimen can be described in terms of observed toxicity or response, but without a comparator the study does not estimate a randomized treatment contrast. The distinction between documenting an outcome and establishing a comparative effect is important when multiple diseases and objectives are part of the study.
Finally, the registry record contains endpoint definitions and some safety figures but not the numerical MTD or response results. That gap shows why a stated objective and an operational endpoint are not substitutes for an estimate, its uncertainty, and the analysis methods used to obtain it. Statistical interpretation depends on all of those elements, not on the study label alone.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The registry record does not report the numerical maximum tolerated dose, dose-limiting toxicity counts at individual dose levels, or the numerical complete and partial response result. The main dose-finding and response questions therefore cannot be answered from the posted information. Numerical outcomes for duration of response, failure-free survival and overall survival are also not reported.
The single-group, non-randomized design has no like-for-like control group. It cannot provide a randomized comparison with another regimen, and the record does not report an adjusted comparative analysis. The population includes Richter’s transformation, prolymphocytic leukemia, and refractory or relapsed B-cell chronic lymphocytic leukemia; results stratified by these conditions are not reported in the registry record.
The registry identifies 19 participants for the MTD analysis but does not report the analysis population for other outcomes. It does not describe missing-data handling, exclusions, follow-up completeness, sample-size justification, or the statistical analysis plan. Dose-level allocation and escalation details beyond the listed starting regimen are not reported. The record also lacks confidence intervals for the reported safety percentages and does not give a separate death count. These limitations constrain assessment of outcome precision, analysis choices and the completeness of the posted results.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Oxaliplatin, Fludarabine, Cytarabine and Rituximab in Richter's Syndrome, Refractory CLL and PLL — NCT00452374.
- Registry record last updated 2011-11-02; status last verified 2011-10.
- Results first posted 2011-08-29.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
The completed study is recorded as a Phase I-II, non-randomized, unmasked, single-group trial sponsored by M.D. Anderson Cancer Center. It enrolled 48 participants with Richter’s transformation, prolymphocytic leukemia, or refractory or relapsed B-cell chronic lymphocytic leukemia. The intervention combined oxaliplatin, fludarabine, cytarabine and rituximab.
The primary endpoint was the maximum tolerated dose of oxaliplatin, defined using specified dose-limiting toxicities. Nineteen participants were included in the MTD analysis. The registry also lists response and safety objectives. Numerical MTD and response results are not reported in the registry record. Serious adverse event information includes 28 affected participants among 48 at risk, with infection, neutropenic fever, fever and death among the listed terms. No randomized comparator is reported.