Oxaliplatin, Fludarabine, Cytarabine, and Rituximab in Patients With Richter's Transformation and Leukemias: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Oxaliplatin, Fludarabine, Cytarabine, and Rituximab in Patients With Richter's Transformation and Leukemias (NCT00472849), a non-randomized phase 1, phase 2 study. The primary outcome is Maximum Total Tolerated Dose (MTD) of Daily Combination Fludarabine 30 mg/m^2 and Cytarabine 500 mg/m^2 Among 3 Dose Levels (Dose Level 1: 2 Days, Dose Level 2: 3 Days or Dose Level 3: 4 Days).

2. Clinical Question

3. Trial Design

This was a completed, non-randomized Phase I-II study sponsored by M.D. Anderson Cancer Center. The registry reports an enrollment of 92, a start date of 2007-05, and a primary completion date of 2012-02. The study status is completed. No masking was used, and the model is identified as single group.

The Phase I portion was designed to find a tolerable schedule for fludarabine and cytarabine administered with fixed doses of oxaliplatin and rituximab. The three dose levels differed in the number of treatment days: days 2-3, days 2-4, or days 2-5. The maximum tolerated dose rule was based on dose-limiting toxicities (DLTs): a level qualified when fewer than 2/3 or 2/6 participants experienced DLTs. The registry describes the fludarabine and cytarabine treatment days as increasing together.

The Phase I arm is titled OFAR (Phase I), and the Phase II arm is titled OFAR MTD (Phase II). The Phase II description gives an OFAR schedule using the maximum tolerated dose. The registry also describes treatment cycles and criteria for proceeding to a subsequent cycle, with a maximum of 6 cycles. These regimen details describe the treatment plan; they do not establish which dose level was ultimately selected or how participants responded.

The two arm labels do not make this a controlled comparison. The registry explicitly warns that the arms are not a like-for-like control comparison. No random assignment is reported. The safety information lists 12 participants at risk in the Phase I group and 78 in the Phase II group; these group counts should not be interpreted as a randomized allocation or as evidence of comparative treatment effects.

The registry lists overall response, defined through complete remission, nodular partial remission, and partial remission, as a secondary outcome. It reports 2 outcome measures and 0 analyses. Results for response and the primary dose-finding outcome are not reported in the registry record.

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.

Before assignment: Of the 92 participants enrolled on this study, two participants were excluded as having failed screening and never received study medication.

Overall Study

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.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Total Tolerated Dose (MTD) of Daily Combination Fludarabine 30 mg/m^2 and Cytarabine 500 mg/m^2 Among 3 Dose Levels (Dose Level 1: 2 Days, Dose Level 2: 3 Days or Dose Level 3: 4 Days), measured over Up to 36 weeks (6 cycles each 4-6 weeks).

The primary outcome concerns the maximum tolerated dose (MTD) of daily fludarabine 30 mg/m^2 and cytarabine 500 mg/m^2 among three schedule levels. The levels varied by the number of days on which the drugs were given together: days 2-3, days 2-4, or days 2-5. The primary outcome is therefore a dose-schedule selection question, rather than a comparison of clinical benefit between treatment groups. The registry lists the outcome unit as mg/m^2.

The stated DLT rule defines the MTD as a dose level at which fewer than 2/3 or 2/6 participants experience dose-limiting toxicities. In general, dose-finding studies use such rules to limit escalation when observed toxicity reaches a prespecified boundary, while identifying a schedule that can be taken forward for further study. The record describes the rule but does not report how many DLTs occurred at each level, which level met the rule, or the resulting MTD.

The timeframe is up to 36 weeks (6 cycles each 4-6 weeks). The registry notes that participants could receive a subsequent cycle with an additional day of fludarabine and cytarabine, subject to toxicity conditions, and that a maximum of 6 cycles were administered. Those details provide context for treatment exposure; they do not supply the primary endpoint result. The registry does not report the numerical outcome for the MTD endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design determines which statistical interpretations are appropriate. This study is identified as non-randomized, unmasked, and single group. The registry's Phase I and Phase II labels describe stages of the study, not randomly assigned arms. In general, randomization helps balance measured and unmeasured characteristics between groups, making a treatment contrast easier to interpret. Without randomization, and without a suitable control group, differences between groups can reflect differences in participants, treatment schedules, follow-up, or other factors rather than a treatment effect.

How does the dose-finding rule work?

The primary endpoint uses a threshold rule based on dose-limiting toxicities. Three candidate schedules were specified, with fludarabine and cytarabine days increasing together. Under the registry's definition, the maximum tolerated dose is the dose level at which fewer than 2/3 or 2/6 participants experience DLTs. In general, a rule of this kind provides a decision criterion for selecting a schedule in a dose-finding study. It is not the same as estimating a treatment effect against a control, nor does it establish how much benefit a schedule provides.

The registry explains the intended rule but does not provide the observed DLT counts by dose level, the number treated at each level, or the schedule selected. Those missing results prevent a reader from checking how the rule was applied or assessing uncertainty around the dose selection. A stated decision rule alone is not an observed endpoint result.

What can the safety counts tell readers?

The serious and other adverse event entries report counts of participants affected and counts at risk for each listed group. These are descriptive summaries. In general, a count of participants with at least one event differs from a count of all events: one participant may experience more than one event, and a participant may contribute to multiple event categories. The registry does not explain whether or how event terms overlap, and it does not provide exposure-adjusted rates or timing details. The counts should therefore be read as recorded, without deriving totals or treating term frequencies as mutually exclusive.

The registry also lists selected serious adverse event terms with percentages. Since the reported information does not identify the denominators or group attribution for those percentages, they cannot safely be translated into participant counts or used to compare the Phase I and Phase II groups. General statistical practice requires a clear denominator and population definition to interpret a percentage.

What does the record say about statistical analyses?

The registry reports 0 analyses. It does not report an analysis population, an approach to missing outcome data, a statistical model, confidence intervals, hypothesis tests, or an inferential comparison for the primary or secondary outcomes. These items are not reported in the registry record. The absence of a posted analysis does not show that no analysis occurred outside the record; it means the record does not give information needed to assess one.

A confidence interval, in general, describes the precision of an estimate under the assumptions of the method used. No confidence interval for the MTD or response outcome is reported. Likewise, no p-value for an efficacy comparison is reported, and the non-randomized design would not support treating the Phase I and Phase II groups as a randomized treatment contrast.

How should planning illustrations be understood?

The sample-size assumptions are described as a planning illustration computed from an observed effect, not as the trial's own design. The stated assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. Time-to-event illustrations use the total number of events, while other illustrations give participants per arm. These are planning conventions, not observed trial outcomes or evidence of the trial's power.

In general, a sample-size illustration depends on its assumptions about the effect, variability, allocation, and statistical method. A planning illustration does not establish that the original study was designed using those assumptions. In this case, the record identifies a single-group, non-randomized design, so equal allocation between two arms in a generic illustration should not be confused with the actual study design. The registry does not report a sample-size justification for the trial.

Over-dispersion is a general concern when count data vary more than a chosen statistical model expects; if present and ignored, uncertainty estimates may be too narrow. The record does not report a count model or over-dispersion assessment, and no such analysis can be inferred from the registry entries. Similarly, no interim analysis plan or stopping-boundary details beyond the MTD rule are reported in the registry record.

Because the numerical results and analysis details are not posted, the central statistical task for readers is to separate design information from results. The regimen, endpoint definition, DLT criterion, and safety counts are reported. A selected MTD, a response estimate, estimates of precision, or an adjusted comparison are not reported.

10. Multiplicity, Missing Data and Analysis Populations

The record lists a primary dose-finding outcome and a secondary overall response outcome. It does not report a statistical testing plan, a hierarchy for interpreting outcomes, or a correction for multiple testing. These details are not reported in the registry record. Without an inferential analysis, there is no basis for describing the probability of a false-positive result across outcomes or for interpreting a family of p-values.

The registry reports 0 analyses and does not describe how missing outcome information was handled. An analysis population, exclusions from outcome analyses, and the handling of participants who did not complete treatment are not reported in the registry record. The enrolled number is 92, while the safety entries separately list groups of 12 and 78 at risk. The record does not explain the relationship between the enrollment entry and these safety group counts, so they should not be treated as a reconciled analysis population.

In general, missing data can affect an estimate when the chance that an outcome is unobserved is related to the outcome or to participants' characteristics. Methods such as complete-case analysis or imputation require explicit assumptions and a clear definition of who was included. No missing-data method or assumption is reported, so none should be attributed to the study.

The registry also does not report whether any interim analyses were planned or conducted. The MTD decision rule is described, but additional monitoring procedures or statistical stopping rules are not. These gaps limit evaluation of how outcomes were selected, analyzed, and reported; they do not establish that particular procedures were or were not used outside the registry record.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neutropenic fever (25.0%), infection (16.7%), diarrhea (16.7%), dehydration (8.3%), death (8.3%).

The registry reports serious and other adverse event summaries for the two named groups. For OFAR (Phase I), 8 of 12 participants at risk were affected by serious adverse events, and 8 of 12 were affected by other adverse events. For OFAR MTD (Phase II), 15 of 78 were affected by serious adverse events, and 71 of 78 were affected by other adverse events. These are participant counts, not counts of every event that occurred.

The listed serious adverse event terms include Neutropenic Fever (25.0%), Infection (16.7%), Diarrhea (16.7%), Dehydration (8.3%), Death (8.3%), and Dyspnea (8.3%). The registry does not specify the denominator or group attribution for these percentages in the reported information. They should not be converted into event counts or assumed to describe either group alone.

In general, a participant-level adverse-event summary indicates whether participants were affected, while event-level summaries may count multiple events for one participant. The registry does not report enough detail to establish how these term entries overlap, when events occurred, or how long participants were observed. Since the groups are not randomized control groups, their safety counts should not be interpreted as a causal comparison. No medical conclusion follows from these entries alone.

12. What the Result Does, and Does Not, Mean

The registry record establishes the study's purpose and design: a non-randomized Phase I-II investigation of an OFAR regimen, with a Phase I dose-finding question and a Phase II schedule described at the MTD. It also gives the threshold used to define the MTD and reports selected safety counts. These details help explain what investigators set out to assess, but they do not provide the primary endpoint result.

The record does not state which fludarabine and cytarabine schedule was selected, the DLT counts supporting that selection, or the numerical MTD outcome. It also does not report response results, despite listing overall response as a secondary outcome. Thus, the registry information does not quantify efficacy or allow readers to assess the precision of an efficacy estimate.

The safety entries show participants affected in each group and list serious adverse event terms. They do not establish that one schedule is safer than another: the study was not randomized, the arm descriptions differ by study phase, and the registry does not provide enough context for a like-for-like contrast. Nor do these summaries establish the cause of an event or its relationship to an individual drug.

In general, a study's design and endpoint definition explain how evidence was intended to be generated, while outcome data and analysis methods are needed to judge what was observed and how uncertain it is. Here, the design and endpoint are described, but the primary and secondary outcome results and inferential analyses are not reported in the registry record. That distinction matters: missing posted results should not be recast as a positive or negative finding.

The registry therefore supports a limited statistical reading. It describes a dose-escalation objective, a DLT-based decision rule, and safety summaries, but not the outcome values needed to evaluate dose selection or response. The record cannot establish a comparative treatment effect, because there is no randomized comparator and no reported response analysis.

13. Why This Trial Matters Statistically

This study illustrates a distinct statistical problem from the usual randomized treatment comparison. Its primary aim was to select a tolerable schedule of fludarabine and cytarabine in combination with fixed doses of oxaliplatin and rituximab. The key inferential task is therefore dose selection under a toxicity rule, not estimation of a contrast against a control group.

The distinction between a rule and its result is important. The registry states how the MTD was defined, including the candidate schedules and the DLT threshold. But without the DLT observations by level and the selected schedule, the reader cannot evaluate the dose-finding outcome. Reporting the decision criterion alone does not show whether the criterion was met.

The record also demonstrates why design labels should not be mistaken for comparator structure. Although it names Phase I and Phase II groups, it identifies the study as non-randomized and single group and warns that the arms are not a like-for-like control comparison. Descriptive differences between safety entries cannot substitute for a randomized estimate of treatment effect.

Finally, the record separates safety reporting from efficacy reporting. It gives affected-participant counts and selected serious event terms, while listing overall response as a secondary outcome without reporting its result. This limits what can be learned from the registry entry. For biostatisticians and clinical researchers, the case underscores the importance of making outcome values, analysis populations, uncertainty estimates, and missing-data methods available alongside protocol definitions.

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.

Several limitations follow directly from the registry information. The primary dose-finding outcome is defined, but its numerical result is not reported. The registry does not give DLT counts by dose level, the number treated at each level, or the schedule selected. Consequently, the stated MTD rule cannot be checked against observed data from the record.

The secondary outcome is described as the number of participants with complete remission, nodular partial remission, and partial remission, but the registry does not report those counts or an analysis. The record also reports 0 analyses, with no confidence intervals, p-values, or model results for the listed outcomes. The precision of any outcome estimate is therefore not available.

The study is non-randomized and has no like-for-like control comparison. Phase I and Phase II groups should not be interpreted as randomized treatment arms. The registry does not report enough detail to determine how the listed enrollment relates to the safety group counts, how participants were included in outcome analyses, or how missing data were handled.

For safety, the registry gives participants affected and participants at risk, plus selected serious adverse event terms with percentages. It does not clarify the denominators or group attribution for those term percentages, event timing, exposure duration, or overlap between terms. The reported summaries cannot support exposure-adjusted comparisons or causal attribution.

More broadly, the registry record does not report a sample-size justification, an interim analysis plan, or statistical methods beyond the dose-limiting toxicity rule and the assumptions for planning illustrations. This limits assessment of the study's statistical planning and reporting, without implying that unreported procedures were absent from work outside the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Oxaliplatin, Fludarabine, Cytarabine, and Rituximab in Patients With Richter's Transformation and Leukemias — NCT00472849.
• Registry record last updated 2013-11-26; status last verified 2013-11.
• Results first posted 2013-11-26.
• 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.

18. Record Summary

NCT00472849 is a completed, non-randomized Phase I-II study sponsored by M.D. Anderson Cancer Center. The registry reports an enrollment of 92, a start date of 2007-05, and a primary completion date of 2012-02. The study examined oxaliplatin, fludarabine, cytarabine, and rituximab in patients with Richter's transformation and leukemias.

The primary outcome was the maximum tolerated schedule of fludarabine and cytarabine among three dose levels, using a stated DLT rule. Overall response was listed as a secondary outcome. The registry reports safety group counts and selected serious adverse event terms, but gives 0 analyses and does not report the numerical primary outcome or response result.

The record identifies the study as single group and cautions that Phase I and Phase II are not a like-for-like control comparison. It does not provide the outcome and analysis details needed to quantify dose selection, response, or comparative effects.