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1.  Complement-binding Donor-specific Anti-HLA Antibodies and Risk of Primary Graft Failure in Hematopoietic Stem Cell Transplantation 
Detection of donor-specific anti-HLA antibodies (DSA) has been associated with graft rejection in all forms of transplantation. The mechanism by which DSA increase the risk of graft failure remains unclear. We hypothesized that complement-binding DSA are associated with engraftment failure in hematopoietic stem-cell transplantation and analyzed 122 haploidentical transplant recipients tested prospectively for DSA. Retrospective C1q testing was done on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had DSA, 19 of which were females (86%). Seven patients with DSA (32%) rejected the graft. Median DSA level at transplant for patients who failed to engraft was 10,055 MFI versus 2,065 MFI for those who engrafted (p=0.007). Nine patients with DSA were C1q positive in the initial samples with median DSA level 15,279 MFI (range 1,554-28,615), compared with 7 C1q negative patients with median DSA level 2,471 MFI (665-12,254) (p=0.016). Of 9 patients, who tested positive for C1q in the initial samples, 5 patients remained C1q positive at time of transplant [all with high DSA levels (median 15,279, range 6,487-22,944)] and experienced engraftment failure, while 4 patients became C1q negative pre-transplant and all engrafted the donor cells (p=0.008). In conclusion, patients with high DSA levels (> 5,000 MFI) and complement-binding antibodies (C1q positive) appear to be at much higher risk of primary graft failure. C1q should be assessed in patients with DSA prior to hematopoietic stem-cell transplantation. Reduction of DSA to non-complement binding levels might prevent engraftment failure in hematopoietic stem cell transplantation.
PMCID: PMC4506716  PMID: 25985919
Donor-specific anti-HLA antibodies; complement-binding DSA; C1q; graft rejection; hematopoietic stem cell transplantation; desensitization; buffy coat
2.  Using Data Augmentation to Facilitate Conduct of Phase I–II Clinical Trials with Delayed Outcomes 
A practical impediment in adaptive clinical trials is that outcomes must be observed soon enough to apply decision rules to choose treatments for new patients. For example, if outcomes take up to six weeks to evaluate and the accrual rate is one patient per week, on average three new patients will be accrued while waiting to evaluate the outcomes of the previous three patients. The question is how to treat the new patients. This logistical problem persists throughout the trial. Various ad hoc practical solutions are used, none entirely satisfactory. We focus on this problem in phase I–II clinical trials that use binary toxicity and efficacy, defined in terms of event times, to choose doses adaptively for successive cohorts. We propose a general approach to this problem that treats late-onset outcomes as missing data, uses data augmentation to impute missing outcomes from posterior predictive distributions computed from partial follow-up times and complete outcome data, and applies the design’s decision rules using the completed data. We illustrate the method with two cancer trials conducted using a phase I–II design based on efficacy-toxicity trade-offs, including a computer stimulation study.
PMCID: PMC4217535  PMID: 25382884
Bayesian Adaptive Clinical Design; Dose-Finding; Phase I-II Clinical Trial Design; Missing Data; Data Augmentation Algorithm; Piecewise Exponential Model
3.  High Risk of Graft Failure in Patients with Anti-HLA Antibodies Undergoing Haploidentical Stem Cell Transplantation 
Transplantation  2009;88(8):1019-1024.
While donor-specific anti-HLA antibodies (DSA) have been implicated in graft rejection in solid organ transplantation, their role in hematopoietic stem cell transplantation (HSCT) remains unclear.
To address the hypothesis that the presence of DSA contributes to the development graft failure, we tested 24 consecutive patients for the presence of anti-HLA antibodies determined by a highly sensitive and specific solid-phase/single-antigen assay. The study included a total of 28 haploidentical transplants, each with 2–5 HLA allele mismatches, at a single institution, from 9/2005 to 8/2008.
DSA were detected in five patients (21%). Three out of 4 (75%) patients with DSA prior to the first transplant failed to engraft, compared with 1 out of 20 (5%) without DSA (p=0.008). All 4 patients who experienced primary graft failure had second haploidentical transplants. One patient developed a second graft failure with persistent high DSA levels, while 3 engrafted, 2 of them in the absence of DSA. No other known factors that could negatively influence engraftment were associated with the development of graft failure in these patients.
These results suggest that donor-specific anti-HLA antibodies are associated with a high rate of graft rejection in patients undergoing haploidentical stem cell transplantation. Anti-HLA sensitization should be evaluated routinely in hematopoietic stem cell transplantation with HLA mismatched donors.
PMCID: PMC4324621  PMID: 19855248
Donor-specific anti-HLA antibodies; primary graft failure; haploidentical stem cell transplantation
4.  Once Daily IV Busulfan and Fludarabine (IV Bu-Flu) Compares Favorably with IV Busulfan and Cyclophosphamide (IV BuCy2) as Pretransplant Conditioning Therapy in AML/MDS 
We postulated that fludarabine (Flu) instead of cyclophosphamide (Cy) combined with IV busulfan (Bu) as preconditioning for allogeneic hematopoietic stem cell transplantation (HSCT) would improve safety and retain antileukemic efficacy. 67 patients received BuCy2 and subsequently 148 patients received Bu-Flu. We used a Bayesian method to compare outcomes between these non-randomized patients. The groups had comparable pretreatment characteristics, except that Bu-Flu patients were older (46 vs. 39 years, p< 0.01), more often had unrelated donors (47.3% vs. 20.9%, p< 0.0003), and had shorter median follow-up (39.7 vs. 74.6 months). To account for improved supportive care and other unidentified factors that may affect outcome (“period” effects), 78 AML patients receiving Melphalan-Flu (“MF”), treated in parallel during this time (1997 to 2004) were used to estimate the period effect; The MF patients’ outcomes worsened during this period. Therefore, the period effect is unlikely to explain the greatly improved outcome with Bu-Flu. Patients transplanted with Bu-Flu in CR1 had a 3-year overall survival and event-free-survival (EFS) of 78% and 74%, respectively, while CR1 patients younger than age 41 had a 3-year EFS of 89%. These results support replacing BuCy±ATG with Bu-Flu±rabbit-ATG, and warrant a prospective comparison between allogeneic HSCT and conventional induction/consolidation chemotherapy for AML in CR1.
PMCID: PMC4230823  PMID: 18489993
IV Busulfan; Fludarabine; Cyclophosphamide; AML; MDS; Allogeneic Stem Cell Transplantation
5.  A Randomized Phase II Trial of Fludarabine/Melphalan 100 versus Fludarabine/Melphalan 140 followed by Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Multiple Myeloma 
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for multiple myeloma (MM); however, due to high-treatment related mortality (TRM) its role is not well defined.
Patients with newly diagnosed, relapsed, or primary refractory myeloma were enrolled in a randomized phase II trial of two reduced intensity conditioning regimens, fludarabine 120 mg/m2+ melphalan 100 mg/m2(FM100) versus fludarabine 120 mg/m2+ melphalan 140 mg/m2(FM140) before allo-HCT from related or unrelated donors.
Fifty patients underwent allo-HCT using FM100 (N=23) or FM140 (N=27) conditioning between April 2002 and 2011. There were no significant differences between FM100 and FM140 in time to neutrophil engraftment (p=0.21), acute grade II-IV GVHD (p=1.0), chronic GVHD (p=0.24), response rate (p=1.0), TRM (13% versus 15%, p=1.0), median progression-free survival (PFS), 11.7 versus 8.4 months, p=0.12, and median overall survival (OS), 35.1 versus19.7 months, p=0.38. Cumulative incidence of disease progression in FM100 and FM140 was 43% and 70%, respectively (p=0.08). Recurrent disease was the most common cause of death for both FM100 (26%) and FM140 (44%), p=0.24. On multivariate analysis, disease status at allo-HCT, complete response or very good partial response (VGPR) was significantly associated with longer PFS (15.6 versus 9.6 months in patients with < VGPR, p=0.05). OS was similar across all variables.
We conclude that FM 100 and FM140 may result in similar patient outcomes after allo-HCT for MM.
PMCID: PMC4157818  PMID: 23872222
Myeloma; Allogeneic transplantation; Reduced intensity conditioning; Fludarabine; Melphalan
6.  A Phase II Trial of Gemcitabine plus Capecitabine in Metastatic Renal Cell Cancer Previously Treated with Immunotherapy and Targeted Agents 
The Journal of urology  2008;180(3):867-872.
To assess the clinical activity and safety of gemcitabine (G) plus capecitabine (X) in metastatic renal cell cancer (mRCC) patients previously treated with immunotherapy.
In this phase II trial, patients received G 1000 mg/m2 intravenously on days 1, 8 and 15, plus X 830 mg/m2 orally twice daily on days 1-21 of 28-day cycles. The primary endpoint was progression-free survival (PFS) time. Secondary endpoints included overall survival (OS) time, objective response rate (ORR), and toxicity.
Of 84 patients enrolled, 83 were evaluable for response and toxicity. Sixty-five patients had intermediate- or poor-risk prognosis. Median PFS and OS times were 4.6 months (95% CI, 3.7-7.3) and 17.9 months (95% CI, 13.2-23.6), respectively. There were one complete response and six partial responses [ORR 8.4% (95% CI, 3.5-16.6)]. Two patients remain in unmaintained remission close to 3 years from initiation of GX. By multivariate analyses, >3 disease sites was significantly associated with shorter PFS time, and patients with thrombocytosis, >3 disease sites or anemia had a significantly increased risk of death. Adverse events, occurring at least once in >5% of patients, included grade ≥3 neutropenia (83%), grade ≥2 hand-foot syndrome (13%), grade ≥3 thrombocytopenia (12%), grade ≥3 thromboembolic events (8%), grade ≥3 fatigue (8%), and grade ≥2 mucositis (6%).
At the doses and schedule tested, GX demonstrated a modest clinical activity in mRCC after cytokine failure and produced significant neutropenia. A modified GX regimen may be evaluated in patients with mRCC after failure of approved targeted therapies.
PMCID: PMC4167838  PMID: 18635226
chemotherapy; metastatic renal cell carcinoma; targeted therapies; angiogenesis inhibition
7.  Using Joint Utilities of the Times to Response and Toxicity to Adaptively Optimize Schedule-Dose Regimes 
Biometrics  2013;69(3):673-682.
A Bayesian two-stage phase I-II design is proposed for optimizing administration schedule and dose of an experimental agent based on the times to response and toxicity in the case where schedules are non-nested and qualitatively different. Sequentially adaptive decisions are based on the joint utility of the two event times. A utility function is constructed by partitioning the two-dimensional positive real quadrant of possible event time pairs into rectangles, eliciting a numerical utility for each rectangle, and fitting a smooth parametric function to the elicited values. We assume that each event time follows a gamma distribution with shape and scale parameters both modeled as functions of schedule and dose. A copula is assumed to obtain a bivariate distribution. To ensure an ethical trial, adaptive safety and efficacy acceptability conditions are imposed on the (schedule, dose) regimes. In stage 1 of the design, patients are randomized fairly among schedules and, within each schedule, a dose is chosen using a hybrid algorithm that either maximizes posterior mean utility or randomizes among acceptable doses. In stage 2, fair randomization among schedules is replaced by the hybrid algorithm. A modified version of this algorithm is used for nested schedules. Extensions of the model and utility function to accommodate death discontinuation of follow up are described. The method is illustrated by an autologous stem cell transplantation trial in multiple myeloma, including a simulation study.
PMCID: PMC3963428  PMID: 23957592
Adaptive decision making; Bayesian design; Phase I/II clinical trial; Stem cell transplantation; Utility
8.  Increasing Chimerism Following Allogeneic Stem Cell Transplantation is Associated with Longer Survival Time 
Donor chimerism following allogeneic stem cell transplantation (allo-SCT) commonly is used to predict overall survival (OS) and disease-free survival (DFS) time. Because chimerism is observed at one or more times after allo-SCT, and not at baseline, if chimerism is in fact associated with OS or DFS then the occurrence of either disease progression or death informatively censors (terminates) the observed chimerism process. This violates the assumptions underlying standard statistical regression methods for survival analysis, which may lead to biased conclusions. To assess association between the longitudinal post-allo-SCT donor chimerism process and OS or DFS, we analyzed data from 195 patients with acute myelogenous leukemia (n=157) or myelodysplastic syndrome (n=38) who achieved complete remission after allo-SCT following a reduced-toxicity conditioning regimen of fludarabine/intravenous busulfan. Median follow-up was 31 months (range, 1.1–105 months). Fitted joint longitudinal-survival time models showed that a binary indicator of complete (100%) donor chimerism, and increasing percent donor T-cells, both were significantly associated with longer OS, while decreasing percent donor T-cells was highly significantly associated with shorter OS. Our analyses illustrate the usefulness of modeling repeated post-allo-SCT chimerism measurements as individual longitudinal processes jointly with OS and DFS in order to estimate their relationships.
PMCID: PMC4099297  PMID: 24727332
Chimerism; Allogeneic stem cell transplantation; AML; MDS
9.  Discussion on “A Hybrid Selection and Testing Procedure with Curtailment for Comparative Clinical Trials” by Elena M. Buzaianu and Pinyuen Chen 
Sequential analysis  2009;28(1):41-43.
Buzaianu and Chen apply strong curtailment to modify the two-stage select-and-test clinical trial design proposed by Thall et al. (1988). The modification reduces the expected sample size while maintaining overall power but requires continuous monitoring in stage 1. I will review the history of this type of design and discuss practical issues related to the use of strong curtailment that arise in trial conduct.
PMCID: PMC2900801  PMID: 20622929
Clinical trials; Generalized power; Phase II-III design
10.  Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer 
Clinical features characteristic of small-cell prostate carcinoma (SCPC), (““anaplastic””) often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined “anaplastic” clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low PSA levels relative to tumor burden or short response to androgen deprivation therapy.
Experimental Design
A 120-patient phase II trial of frontline carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity.
Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after 4 cycles of CD and EP, respectively. Median overall survival (OS) was 16 months (95% CI, 13.6-19.0 months). Of the 7 “anaplastic” criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase (LDH) strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy.
Our findings support the hypothesis that patients with “anaplastic” prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with CRPC and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population.
PMCID: PMC3699964  PMID: 23649003
Small-cell; neuroendocrine; castration-resistant; prostate carcinoma; platinum chemotherapy
11.  Quantifying the Survival Benefit for Allogeneic Stem Cell Transplantation in Relapsed Acute Myeloid Leukemia 
Allogeneic hematopoietic stem cell transplantation (HSCT) is the recommended therapy for patients with relapsed AML despite little evidence showing a survival benefit for patients who undergo HSCT vs. chemotherapy alone.
Because a prospective randomized trial addressing this issue is unlikely to be conducted we retrospectively reviewed all patients given 1st salvage therapy for AML at M.D. Anderson Cancer Center from 1995–2004, focusing on patients given HSCT or chemotherapy without HSCT (a) as second salvage after 1st salvage failed to produce CR or (b) in 1st salvage-induced CR. Median survival in group (a) was 5.1 months for HSCT (n=84) vs. 2.3 months for chemotherapy (n=200, p=0.004) and, in group (b), was 11.7 months for HSCT (n=46) vs. 5.6 months for chemotherapy (n=66, p<0. 001). HSCT was associated with a survival benefit in each of 8 subgroups defined by age 36 weeks). Our data suggest that HSCT is preferable to chemotherapy alone in these poor prognosis patients with particular benefit noted in patients <50.
PMCID: PMC4067765  PMID: 19822303
Relapsed acute myeloid leukemia; Hematopoietic stem cell transplant; Overall survival
12.  Reduced-toxicity conditioning therapy with allogeneic stem cell transplantation for acute leukemia 
Current opinion in oncology  2009;21(0 1):S11-S15.
We hypothesized that standardized systemic drug delivery would improve treatment safety and provide better leukemia control. We therefore developed an intravenous busulfan formulation and combined it with fludarabine instead of cyclophosphamide in preparation for allogeneic stem cell transplantation (alloSCT). We used a Bayesian method to compare the outcomes of 67 acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients who received intravenous busulfan–cyclophosphamide (BuCy2) with 148 subsequent AML/MDS patients who received busulfan–fludarabine (Bu-Flu). The groups had comparable pretreatment characteristics, except that the Bu-Flu patients were older, more often had unrelated donors and had a shorter follow-up. A greatly improved outcome in the Bu-Flu group is unlikely to be explained by improved supportive care during this time period. Overall, the data support replacing BuCy2 with or without antithymocyte globulin (ATG) with Bu-Flu with or without rabbit-ATG for AML or MDS. We further suggest that the high level of safety and fast recovery from conditioning therapy-related side effects after the Bu-Flu regimen makes it a suitable platform technology for testing additional adjuncts for improved posttransplant immune recovery and long-term disease control in patients who are at high risk of rapidly recurrent disease after alloSCT. The extremely low one-year treatment-related mortality as well as high overall and event-free survival of patients in the Bu-Flu group indicate that it is time to revisit the value of alloSCT compared with conventional maintenance chemotherapy for patients in first complete remission of AML/MDS.
PMCID: PMC4037323  PMID: 19561406
acute myeloid leukemia; allogeneic stem cell transplantation; cyclophosphamide; fludarabine; intravenous busulfan; myelodysplastic syndrome; reduced-toxicity conditioning therapy
13.  A Randomized Phase II Trial of a Preparative Regimen of Bortezomib, High Dose Melphalan, Arsenic Trioxide and Ascorbic Acid 
Cancer  2011;118(9):2507-2515.
Bortezomib is active for newly diagnosed and relapsed multiple myeloma, and has synergistic activity with melphalan. We conducted a randomized trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA) and melphalan.
Among 60 patients enrolled between October 2006 and September 2007, 58 received autologous transplantation with a preparative regimen of melphalan 200 mg/m2 IV, AA 1000 mg/day IV × 7 days and ATO 0.25 mg/kg IV × 7 days. Patients were randomized to receive no bortezomib (group 1), bortezomib 1 mg/m2 × 3 doses (group 2), and bortezomib 1.5 mg/m2 × 3 doses (group 3). Primary endpoints were complete response (CR), grade 4 toxicity, and 90-day treatment-related mortality (TRM). Secondary endpoints were progression-free (PFS) and overall survival (OS).
Median follow-up in all surviving patients was 36 months (range 20–43). CR rates in groups 1, 2 and 3 were 20%, 10% and 10%. Grade 3–4 non-hematologic toxicities and TRM were comparable. Median OS has not been reached in the groups, while median PFS was 17.8, 17.4 and 20.7 months, respectively. PFS and OS were significantly shorter in patients with high-risk cytogenetics (p0.016 and 0.0001) and relapsed disease (p=0.0001 and 0.0001) regardless of the treatment group.
Adding bortezomib to a preparative regimen of ATO, AA and high dose melphalan is safe and well tolerated in patients with multiple myeloma. There was no significant improvement in CR rate, PFS or OS in the bortezomib groups.
PMCID: PMC4015116  PMID: 21887685
Autologous transplant; Myeloma; Bortezomib; Arsenic Trioxide; Melphalan
14.  Adenoviral Infections in Adult Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Single Center Experience 
Bone marrow transplantation  2013;48(9):1218-1223.
Disseminated adenoviral infection (AI) is associated with profound immunosuppression and poor outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). A better understanding of AI in allo-HCT recipients can serve a basis to develop more effective management strategies. We evaluated all adult patients who received allo-HCT at M.D. Anderson Cancer Center between 1999 and 2008. Among the 2879 allo-HCT patients, 73 (2.5%) were diagnosed with AI. Enteritis (26%) and pneumonia (24%) were the most common clinical manifestations; pneumonia was the most common cause of adenovirus-associated death. A multivariable Bayesian logistic regression showed that, when the joint effects of all covariates were accounted for, a cord blood transplant, absolute lymphocyte count (ALC) ≤ 200/mm3, and male gender were associated with a higher probability of disseminated AI. The overall survival was significantly worse for patients with AI that was disseminated rather than localized (median of 5 months versus 28 months, respectively, p<0.001) and for patients with ALC ≤ 200/mm3 (p<0.001). Disseminated AI, in patients who received allo-HCT, is a significant cause of morbidity and mortality. Strategies for early diagnosis and intervention are essential, especially for high-risk patients.
PMCID: PMC4010139  PMID: 23503529
adenovirus; adult; allogeneic stem cell transplant; outcome; absolute lymphocyte count
15.  Propensity score based comparison of long term outcomes with 3D conformal radiotherapy (3DCRT) versus Intensity Modulated Radiation Therapy (IMRT) in the treatment of esophageal cancer 
Although 3DCRT is the worldwide standard for the treatment of esophageal cancers, IMRT improves dose conformality and reduces radiation exposure to normal tissues. We hypothesized that the dosimetric advantages of IMRT should translate to substantive benefits in clinical outcomes compared to 3DCRT.
Methods and Materials
Analysis was performed on 676 nonrandomized patients (3DCRT=413, IMRT=263) with stage Ib-IVa (AJCC 2002) esophageal cancers treated with chemoradiation at a single institution from 1998–2008. An inverse probability of treatment weighting (IPW) and inclusion of propensity score (treatment probability) as a covariate were used to compare overall survival (OS) time, time to local failure, and time to distant metastasis, while accounting for effects of other clinically relevant covariates. Propensity scores were estimated using logistic regression.
A fitted multivariate inverse probability weighted (IPW)-adjusted Cox model showed that OS time was significantly associated with several well-known prognostic factors, along with radiation modality (IMRT vs 3DCRT, HR=0.72, p<0.001). Compared to IMRT, 3DCRT patients had a significantly greater risk of dying (72.6% vs 52.9%, IPW log rank test: p<0.0001) and for local-regional recurrence (LRR) (p=0.0038). There was no difference in cancer-specific mortality (Gray’s test, p=0.86), or distant metastasis (p=0.99) between the two groups. An increased cumulative incidence of cardiac deaths was seen in the 3DCRT group (p=0.049), but most deaths were undocumented (5 year estimate: 11.7% in 3DCRT vs 5.4% in IMRT, Gray’s test, p=0.0029).
Overall survival, locoregional control, and non-cancer related deaths were significantly better for IMRT compared to 3DCRT. Although these results need confirmation, IMRT should be considered for the treatment of esophageal cancer.
PMCID: PMC3923623  PMID: 22867894
IMRT; 3D-conformal radiation therapy; chemoradiation; esophageal cancer; propensity score
17.  Evaluating Joint Effects of Induction-Salvage Treatment Regimes on Overall Survival in Acute Leukemia 
Typical oncology practice often includes not only an initial, frontline treatment, but also subsequent treatments given if the initial treatment fails. The physician chooses a treatment at each stage based on the patient’s baseline covariates and history of previous treatments and outcomes. Such sequentially adaptive medical decision-making processes are known as dynamic treatment regimes, treatment policies, or multi-stage adaptive treatment strategies. Conventional analyses in terms of frontline treatments that ignore subsequent treatments may be misleading, because they actually are an evaluation of more than front-line treatment effects on outcome. We are motivated by data from a randomized trial of four combination chemotherapies given as frontline treatments to patients with acute leukemia. Most patients in the trial also received a second-line treatment, chosen adaptively and subjectively rather than by randomization, either because the initial treatment was ineffective or the patient’s cancer later recurred. We evaluate effects on overall survival time of the 16 two-stage strategies that actually were used. Our methods include a likelihood-based regression approach in which the transition times of all possible multi-stage outcome paths are modeled, and estimating equations with inverse probability of treatment weighting to correct for bias. While the two approaches give different numerical estimates of mean survival time, they lead to the same substantive conclusions when comparing the two-stage regimes.
PMCID: PMC3762505  PMID: 24014891
Causal inference; Clinical trial; Dynamic treatment regime; Treatment policy
18.  Prior Effective Sample Size in Conditionally Independent Hierarchical Models 
Bayesian analysis (Online)  2012;7(3):10.1214/12-BA720.
Prior effective sample size (ESS) of a Bayesian parametric model was defined by Morita, et al. (2008, Biometrics, 64, 595–602). Starting with an ε-information prior defined to have the same means and correlations as the prior but to be vague in a suitable sense, the ESS is the required sample size to obtain a hypothetical posterior very close to the prior. In this paper, we present two alternative definitions for the prior ESS that are suitable for a conditionally independent hierarchical model. The two definitions focus on either the first level prior or second level prior. The proposed methods are applied to important examples to verify that each of the two types of prior ESS matches the intuitively obvious answer where it exists. We illustrate the method with applications to several motivating examples, including a single-arm clinical trial to evaluate treatment response probabilities across different disease subtypes, a dose-finding trial based on toxicity in this setting, and a multicenter randomized trial of treatments for affective disorders.
PMCID: PMC3810292  PMID: 24175005
Bayesian hierarchical model; Conditionally independent hierarchical model; Computationally intensive methods; Effective sample size; Epsilon-information prior
19.  Clofarabine±Fludarabine with Once Daily IV Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and MDS 
While a combination of IV busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for AML/MDS, recurrent leukemia post transplantation remains a problem. To enhance the conditioning regimen’s antileukemic effect we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Busulfan (Bu) in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu. We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation (allo-SCT); Patients were adaptively randomized as follows: Arm I - Clo:Flu 10:30 mg/m2, Arm II - 20:20 mg/m2, Arm III - 30:10 mg/m2, and Arm IV - single-agent Clo at 40 mg/m2. The nucleoside analog(s) were/was infused over one hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily AUC of 6,000 μMol-min +/− 10%. Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days. There were 32 males and 19 females with a median age of 45 years (range: 6-59). Nine patients had CML (BC: 2, second AP: 3, and tyrosine-kinase inhibitor refractory first CP: 4). Forty two patients had AML: 14 were induction failures, 8 in first chemotherapy-refractory relapse, 7 in untreated relapse, 3 in second or subsequent relapse, 4 were in second CR and 3 in second CR without platelet recovery (CRp), 2 were in high-risk CR1. Finally, 1 patient was in first CRp. Graft vs host disease- (GVHD) prophylaxis was tacrolimus and mini-MTX, and those who had an unrelated or one Ag-mismmatched donor received low-dose rabbit-ATG (Thymoglobulin™). RESULTS: All patients engrafted. Forty-one patients had active leukemia at the time of transplant, and 35 achieved CR (85%). Twenty of the 42 AML patients and 5 of 9 CML patients are alive with a projected median overall survival of 23 months. Marrow and blood (T-cell) chimerism studies at day +100 revealed that both in the lower dose Clo groups (groups 1+2) and the higher dose Clo groups (groups 3+4) the patients had a median of 100% donor (T-cell)-derived DNA. There has been no secondary graft failure. In the first 100 days one patient died of pneumonia, and one of liver GVHD. We conclude that 1) Clo±Flu with IV Bu as pretranslant conditioning is safe in high-risk myeloid leukemia patients, 2) Clofarabine is sufficiently immunosuppressive to support allo-SCT in myeloid leukemia, and 3) the median overall survival (OS) of 23 months in this high-risk patient population is encouraging. Additional studies to evaluate the antileukemic efficacy of Clo±Flu with IV Bu as pretransplant conditioning therapy are warranted.
PMCID: PMC3760472  PMID: 20946966
Clofarabine; Fludarabine; IV Busulfan; CML; AML; MDS; Allogeneic Stem Cell Transplantation
20.  Adaptive Randomization to Improve Utility-Based Dose-Finding with Bivariate Ordinal Outcomes 
A sequentially outcome-adaptive Bayesian design is proposed for choosing the dose of an experimental therapy based on elicited utilities of a bivariate ordinal (toxicity, efficacy) outcome. Subject to posterior acceptability criteria to control the risk of severe toxicity and exclude unpromising doses, patients are randomized adaptively among the doses having posterior mean utilities near the maximum. The utility increment used to define near-optimality is non-increasing with sample size. The adaptive randomization uses each dose’s posterior probability of a set of good outcomes, defined by a lower utility cut-off. Saturated parametric models are assumed for the marginal dose-toxicity and dose-efficacy distributions, allowing the possible requirement of monotonicity in dose, and a copula is used to obtain a joint distribution. Prior means are computed by simulation using elicited outcome probabilities, and prior variances are calibrated to control prior effective sample size and obtain a design with good operating characteristics. The method is illustrated by a phase I/II trial of radiation therapy for children with brain stem gliomas.
PMCID: PMC3385658  PMID: 22651115
Adaptive design; Bayesian design; Clinical trial; Dose-finding; Epsilon-greedy algorithm; Phase I/II clinical trial; Utility
21.  A Hybrid Geometric Phase II/III Clinical Trial Design based on Treatment Failure Time and Toxicity 
The problem of comparing several experimental treatments to a standard arises frequently in medical research. Various multi-stage randomized phase II/III designs have been proposed that select one or more promising experimental treatments and compare them to the standard while controlling overall Type I and Type II error rates. This paper addresses phase II/III settings where the joint goals are to increase the average time to treatment failure and control the probability of toxicity while accounting for patient heterogeneity. We are motivated by the desire to construct a feasible design for a trial of four chemotherapy combinations for treating a family of rare pediatric brain tumors. We present a hybrid two-stage design based on two-dimensional treatment effect parameters. A targeted parameter set is constructed from elicited parameter pairs considered to be equally desirable. Bayesian regression models for failure time and the probability of toxicity as functions of treatment and prognostic covariates are used to define two-dimensional covariate-adjusted treatment effect parameter sets. Decisions at each stage of the trial are based on the ratio of posterior probabilities of the alternative and null covariate-adjusted parameter sets. Design parameters are chosen to minimize expected sample size subject to frequentist error constraints. The design is illustrated by application to the brain tumor trial design.
PMCID: PMC3249838  PMID: 22228921
Bayesian design; clinical trial; phase II/III design; treatment selection
22.  Optimizing the Concentration and Bolus of a Drug Delivered by Continuous Infusion 
Biometrics  2011;67(4):1638-1646.
We consider treatment regimes in which an agent is administered continuously at a specified concentration until either a response is achieved or a predetermined maximum infusion time is reached. Response is an event defined to characterize therapeutic efficacy. A portion of the maximum planned total amount administered is given as an initial bolus. For such regimes, the amount of the agent received by the patient depends on the time to response. An additional complication when response is evaluated periodically rather than continuously is that the response time is interval censored. We address the problem of designing a clinical trial in which such response time data and a binary indicator of toxicity are used together to jointly optimize the concentration and the size of the bolus. We propose a sequentially adaptive Bayesian design that chooses the optimal treatment for successive patients by maximizing the posterior mean utility of the joint efficacy-toxicity outcome. The methodology is illustrated by a trial in which tissue plasminogen activator is infused intra-arterially as rapid treatment for acute ischemic stroke.
PMCID: PMC3137757  PMID: 21401568
Adaptive design; Bayesian design; Clinical trial; Continuous infusion; Phase I/II clinical trial; Stroke
23.  Evaluation of Viable Dynamic Treatment Regimes in a Sequentially Randomized Trial of Advanced Prostate Cancer 
We present new statistical analyses of data arising from a clinical trial designed to compare two-stage dynamic treatment regimes (DTRs) for advanced prostate cancer. The trial protocol mandated that patients were to be initially randomized among four chemotherapies, and that those who responded poorly were to be rerandomized to one of the remaining candidate therapies. The primary aim was to compare the DTRs’ overall success rates, with success defined by the occurrence of successful responses in each of two consecutive courses of the patient’s therapy. Of the one hundred and fifty study participants, forty seven did not complete their therapy per the algorithm. However, thirty five of them did so for reasons that precluded further chemotherapy; i.e. toxicity and/or progressive disease. Consequently, rather than comparing the overall success rates of the DTRs in the unrealistic event that these patients had remained on their assigned chemotherapies, we conducted an analysis that compared viable switch rules defined by the per-protocol rules but with the additional provision that patients who developed toxicity or progressive disease switch to a non-prespecified therapeutic or palliative strategy. This modification involved consideration of bivariate per-course outcomes encoding both efficacy and toxicity. We used numerical scores elicited from the trial’s Principal Investigator to quantify the clinical desirability of each bivariate per-course outcome, and defined one endpoint as their average over all courses of treatment. Two other simpler sets of scores as well as log survival time also were used as endpoints. Estimation of each DTR-specific mean score was conducted using inverse probability weighted methods that assumed that missingness in the twelve remaining drop-outs was informative but explainable in that it only depended on past recorded data. We conducted additional worst-best case analyses to evaluate sensitivity of our findings to extreme departures from the explainable drop-out assumption.
PMCID: PMC3433243  PMID: 22956855
Causal inference; Efficiency; Informative dropout; Inverse probability weighting; Marginal structural models; Optimal regime; Simultaneous confidence intervals
24.  Defining and Ranking Effects of Individual Agents Based On Survival Times of Cancer Patients Treated with Combination Chemotherapies 
Statistics in medicine  2011;30(15):1777-1794.
An important problem in oncology is comparing chemotherapy (chemo) agents in terms of their effects on survival or progression free survival time. When the goal is to evaluate individual agents, a difficulty commonly encountered with observational data is that many patients receive a chemo combination including two or more agents. Because agents given in combination may interact, quantifying the contribution of each individual agent to the combination’s overall effect is problematic. Still, if on average combinations including a particular agent confer longer survival, then that agent may be considered superior to agents whose combinations confer shorter survival. Motivated by this idea, we propose a definition of individual agent effects based on observational survival data from patients treated with many different chemo combinations. We define an individual agent effect as the average of the effects of the chemo combinations that include the agent. Similarly, we define the effect of each pair of agents as the average of the effects of the combinations including the pair. Under a Bayesian regression model for survival time in which the chemo combination effects follow a hierarchical structure, these definitions are used as a basis for estimating the posterior effects and ranks of the individual agents, and of all pairs of agents. The methods are illustrated by a data set arising from 224 pediatric brain tumor patients treated with over 27 different chemo combinations involving seven chemo agents.
PMCID: PMC3115413  PMID: 21590700
Bayesian analysis; Brain tumors; Hierarchical model; Ranking; Survival analysis
25.  Placental Growth Factor and Soluble c-Kit Receptor Dynamics Characterize the Cytokine Signature of Imatinib in Prostate Cancer and Bone Metastases 
To assess the hypothesis that the dynamics of plasma angiogenic and inflammatory cytokines after docetaxel chemotherapy with or without the c-kit/abl/platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate for prostate cancer are associated with outcome, the kinetics of 17 plasma cytokines before versus after chemotherapy were assessed and associations with progression-free survival (PFS) examined. After adjusting for multiple tests, significantly different declines in placental growth factor (PIGF), soluble vascular endothelial growth factor receptor-1 (VEGFR1), VEGF, and soluble c-kit were observed with docetaxel plus imatinib (n = 41) compared to docetaxel alone (n = 47). Based on a piecewise linear regression model for change in concentration of each cytokine as a function of the probability of change in p-PDGFR in vivo, only the dynamics of PIGF (P < 0.0001) and soluble c-kit (P < 0.0001) differed with imatinib therapy. In a Bayesian log-normal regression model for PFS, a rise in human matrix metalloproteinase 9 after docetaxel alone associated with a longer PFS. Distinct plasma angiogenic cytokines are modified by imatinib and partitioned by in vivo p-PDGFR dynamics after docetaxel chemotherapy for metastatic prostate cancer. Plasma PIGF and soluble c-kit kinetics are candidate biomarkers of imatinib effect. The predictive value of human matrix metalloproteinase 9 kinetics for docetaxel efficacy requires prospective validation.
PMCID: PMC3163391  PMID: 21323568

Results 1-25 (36)