Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma.

To elucidate the deregulated functional modules that drive clear cell renal cell carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC and paired normal adjacent tissue samples. Genomic analyses identified a distinct molecular subgroup associated with genomic instability. Integration of proteogenomic measurements uniquely identified protein dysregulation of cellular mechanisms impacted by genomic alterations, including oxidative phosphorylation-related metabolism, protein translation processes, and phospho-signaling modules. To assess the degree of immune infiltration in individual tumors, we identified microenvironment cell signatures that delineated four immune-based ccRCC subtypes characterized by distinct cellular pathways. This study reports a large-scale proteogenomic analysis of ccRCC to discern the functional impact of genomic alterations and provides evidence for rational treatment selection stemming from ccRCC pathobiology.

Dose optimization for cancer treatments with considerations for late-onset toxicities.

Given that novel anticancer therapies have different toxicity profiles and mechanisms of action, it is important to reconsider the current approaches for dose selection. In an effort to move away from considering the maximum tolerated dose as the optimal dose, the Food and Drug Administration Project Optimus points to the need of incorporating long-term toxicity evaluation, given that many of these novel agents lead to late-onset or cumulative toxicities and there are no guidelines on how to handle them. Numerous methods have been proposed to handle late-onset toxicities in dose-finding clinical trials. A summary and comparison of these methods are provided. Moreover, using PI3K inhibitors as a case study, we show how late-onset toxicity can be integrated into the dose-optimization strategy using current available approaches. We illustrate a re-design of this trial to compare the approach to those that only consider early toxicity outcomes and disregard late-onset toxicities. We also provide proposals going forward for dose optimization in early development of novel anticancer agents with considerations for late-onset toxicities.

Unbiased Proteomic and Phosphoproteomic Analysis Identifies Response Signatures and Novel Susceptibilities After Combined MEK and mTOR Inhibition in BRAFV600E Mutant Glioma.

The mitogen-activated protein kinase pathway is one of the most frequently altered pathways in cancer. It is involved in the control of cell proliferation, invasion, and metabolism, and can cause resistance to therapy. A number of aggressive malignancies, including melanoma, colon cancer, and glioma, are driven by a constitutively activating missense mutation (V600E) in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) component of the pathway. Mitogen-activated protein kinase kinase (MEK) inhibition is initially effective in targeting these cancers, but reflexive activation of mammalian target of rapamycin (mTOR) signaling contributes to frequent therapy resistance. We have previously demonstrated that combination treatment with the MEK inhibitor trametinib and the dual mammalian target of rapamycin complex 1/2 inhibitor TAK228 improves survival and decreases vascularization in a BRAFV600E mutant glioma model. To elucidate the mechanism of action of this combination therapy and understand the ensuing tumor response, we performed comprehensive unbiased proteomic and phosphoproteomic characterization of BRAFV600E mutant glioma xenografts after short-course treatment with trametinib and TAK228. We identified 13,313 proteins and 30,928 localized phosphosites, of which 12,526 proteins and 17,444 phosphosites were quantified across all samples (data available via ProteomeXchange; identifier PXD022329). We identified distinct response signatures for each monotherapy and combination therapy and validated that combination treatment inhibited activation of the mitogen-activated protein kinase and mTOR pathways. Combination therapy also increased apoptotic signaling, suppressed angiogenesis signaling, and broadly suppressed the activity of the cyclin-dependent kinases. In response to combination therapy, both epidermal growth factor receptor and class 1 histone deacetylase proteins were activated. This study reports a detailed (phospho)proteomic analysis of the response of BRAFV600E mutant glioma to combined MEK and mTOR pathway inhibition and identifies new targets for the development of rational combination therapies for BRAF-driven tumors.

Incorporating patient-reported outcomes in dose-finding clinical trials with continuous patient enrollment.

Dose-finding clinical trials in oncology estimate the maximum tolerated dose (MTD), based on toxicity obtained from the clinician's perspective. While the collection of patient-reported outcomes (PROs) has been advocated to better inform treatment tolerability, there is a lack of guidance and methods on how to use PROs for dose assignments and recommendations. The PRO continual reassessment method (PRO-CRM) has been proposed to formally incorporate PROs into dose-finding trials. In this paper, we propose two extensions of the PRO-CRM, which allow continuous enrollment of patients and longer toxicity observation windows to capture late-onset or cumulative toxicities by using a weighted likelihood to include the partial toxicity follow-up information. The TITE-PRO-CRM uses both the PRO and the clinician's information during the trial for dose assignment decisions and at the end of the trial to estimate the MTD. The TITE-CRM + PRO uses clinician's information solely to inform dose assignments during the trial and incorporates PRO at the end of the trial for the estimation of the MTD. Simulation studies show that the TITE-PRO-CRM performs similarly to the PRO-CRM in terms of dose recommendation and assignments during the trial while almost halving trial duration in case of an accrual of two patients per observation window. The TITE-CRM + PRO slightly underperforms compared to the TITE-PRO-CRM, but similar performance can be attained by requiring larger sample sizes. We also show that the performance of the proposed methods is robust to higher accrual rates, different toxicity hazards, and correlated time-to-clinician toxicity and time-to-patient toxicity data.

Surv-CRM-12: A Bayesian phase I/II survival CRM for right-censored toxicity endpoints with competing disease progression.

The growing interest in new classes of anti-cancer agents, such as molecularly-targeted therapies and immunotherapies with modes of action different from those of cytotoxic chemotherapies, has changed the dose-finding paradigm. In this setting, the observation of late-onset toxicity endpoints may be precluded by treatment and trial discontinuation due to disease progression, defining a competing event to toxicity. Trial designs where dose-finding is modeled in the framework of a survival competing risks model appear particularly well-suited. We aim to provide a phase I/II dose-finding design that allows dose-limiting toxicity (DLT) outcomes to be delayed or unobserved due to competing progression within the possibly long observation window. The proposed design named the Survival-continual reassessment method-12, uses survival models for right-censored DLT and progression endpoints. In this competing risks framework, cause-specific hazards for DLT and progression-free of DLT were considered, with model parameters estimated using Bayesian inference. It aims to identify the optimal dose (OD), by minimizing the cumulative incidence of disease progression, given an acceptable toxicity threshold. In a simulation study, design operating characteristics were evaluated and compared to the TITE-BOIN-ET design and a nonparametric benchmark approach. The performance of the proposed method was consistent with the complexity of scenarios as assessed by the nonparametric benchmark. We found that the proposed design presents satisfying operating characteristics in selecting the OD and safety.

Diffuse optical tomography breast imaging measurements are modifiable with pre-surgical targeted and endocrine therapies among women with early stage breast cancer.

PURPOSE: Diffuse optical tomography breast imaging system (DOTBIS) non-invasively measures tissue concentration of hemoglobin, which is a potential biomarker of short-term response to neoadjuvant chemotherapy. We evaluated whether DOTBIS-derived measurements are modifiable with targeted therapies, including AKT inhibition and endocrine therapy. METHODS: We conducted a proof of principle study in seven postmenopausal women with stage I-III breast cancer who were enrolled in pre-surgical studies of the AKT inhibitor MK-2206 (n = 4) or the aromatase inhibitors exemestane (n = 2) and letrozole (n = 1). We performed DOTBIS at baseline (before initiation of therapy) and post-therapy in the affected breast (tumor volume) and contralateral, unaffected breast, and measured tissue concentrations (in µM) of total hemoglobin (ctTHb), oxyhemoglobin (ctO2Hb), and deoxyhemoglobin (ctHHb), as well as water fraction (%). RESULTS: We found consistent decreases in DOTBIS-measured hemoglobin concentrations in tumor volume, with median percent changes for ctTHb, ctHHb, ctO2Hb, and water fraction for the entire cohort of - 27.1% (interquartile range [IQR] 37.5%), - 49.8% (IQR 29.3%), - 33.5% (IQR 47.4%), and - 3.6% (IQR 10.6%), respectively. In the contralateral breast, median percent changes for ctTHb, ctHHb, ctO2Hb, and water fraction were + 1.8% (IQR 26.7%), - 8.6% (IQR 29.3%), + 6.2% (IQR 29.5%), and + 1.9% (IQR 30.7%), respectively. CONCLUSION: We demonstrated that DOTBIS-derived measurements are modifiable with pre-surgical AKT inhibition and endocrine therapy, supporting further investigation of DOTBIS as a potential imaging assessment of response to neoadjuvant targeted therapies in early stage breast cancer.

Seamless phase I/II design for novel anticancer agents with competing disease progression.

Molecularly targeted agents and immunotherapies have prolonged administration and complicated toxicity and efficacy profiles requiring longer toxicity observation windows and the inclusion of efficacy information to identify the optimal dose. Methods have been proposed to either jointly model toxicity and efficacy, or for prolonged observation windows. However, it is inappropriate to address these issues individually in the setting of dose-finding because longer toxicity windows increase the risk of patients experiencing disease progression and discontinuing the trial, with progression defining a competing event to toxicity, and progression-free survival being a commonly used efficacy endpoint. No method has been proposed to address this issue in a competing risk framework. We propose a seamless phase I/II design, namely the competing risks continual reassessment method (CR-CRM). Given an observation window, the objective is to recommend doses that minimize the progression probability, among a set of tolerable doses in terms of toxicity risk. In toxicity-centered stage of the design, doses are assigned based on toxicity alone, and in optimization stage of the design, doses are assigned integrating both toxicity and progression information. Design operating characteristics were examined in a simulation study compared with benchmark performances, including sensitivity to time-varying hazards and correlated events. The method performs well in selecting doses with acceptable toxicity risk and minimum progression risk across a wide range of scenarios.

A simulation study of approaches for handling disease progression in dose-finding clinical trials.

In traditional dose-finding studies, dose-limiting toxicity (DLT) is determined within a fixed time observation window where DLT is often defined as a binary outcome. In the setting of oncology dose-finding trials, often patients in advanced stage of diseases are enrolled. Therefore, disease progression may occur within the DLT observation window leading to treatment discontinuation and rendering the patient unevaluable for DLT assessment. As a result, additional patients have to be enrolled, increasing the sample size. We propose and compare several practical approaches for handling disease progression which occurs within the DLT observation window, while in the framework of the time-to-event continual reassessment method (TITE-CRM) which allows using partial observations. The approaches differ on the way they define an evaluable patient and in the way incomplete observations are included. The practical approaches, which we call strategies A, B and C, are illustrated and contrasted in the context of a single simulated trial, and compared via simulations under various scenarios of dose-progression relationship, in the setting of advanced soft-tissue sarcoma.

Dose-finding designs for cumulative toxicities using multiple constraints.

This article addresses the concern regarding late-onset dose-limiting toxicities (DLT), moderate toxicities below the threshold of a DLT and cumulative toxicities that may lead to a DLT, which are mostly disregarded or handled in an ad hoc manner when determining the maximum tolerated dose (MTD) in dose-finding cancer clinical trials. An extension of the Time-to-Event Continual Reassessment Method (TITE-CRM) which allows for the specification of toxicity constraints on both DLT and moderate toxicities, and can account for partial information is proposed. The method is illustrated in the context of an Erlotinib dose-finding trial with low DLT rates, but a significant number of moderate toxicities leading to treatment discontinuation in later cycles. Based on simulations, our method performs well at selecting the dose level that satisfies both the DLT and moderate-toxicity constraints. Moreover, it has similar probability of correct selection compared to the TITE-CRM when the true MTD based on DLT only and the true MTD based on grade 2 or higher toxicities alone coincide, but reduces the probability of recommending a dose above the MTD.

A Phase I Trial of Intravesical Cabazitaxel, Gemcitabine and Cisplatin for the Treatment of Nonmuscle Invasive bacillus Calmette-Guérin Unresponsive or Recurrent/Relapsing Urothelial Carcinoma of the Bladder.

PURPOSE: For patients with bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer, multi-agent intravesical trials have been limited. In this study we investigate the safety of intravesical cabazitaxel, gemcitabine and cisplatin in the salvage setting. MATERIALS AND METHODS: This was a dose escalation, drug escalation trial for patients with bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer who declined or were ineligible for radical cystectomy. All patients underwent a 6-week induction regimen of sequentially administered cabazitaxel, gemcitabine and cisplatin. Complete response was defined as no cancer on post-induction transurethral bladder tumor resection and negative urine cytology, while partial response allowed for positive cytology. Responders continued with maintenance cabazitaxel and gemcitabine monthly for the first year and bimonthly for the second year. RESULTS: A total of 18 patients were enrolled. Mean age was 71 years, median followup was 27.8 months (range 16.3 to 46.9) and mean number of previous rounds of intravesical therapies before trial enrollment was 3.7. Nine patients (50%) had received intravesical chemotherapy after bacillus Calmette-Guérin and 7 (39%) were previously treated in a phase I clinical trial setting. At enrollment 6 (33%) subjects had T1 disease and 13 (72%) had carcinoma in situ. There were no dose limiting toxicities. Initial partial and complete response rates were 94% and 89%, respectively. At 1 year recurrence-free survival was 0.83 (range 0.57 to 0.94) and at 2 years estimated recurrence-free survival was 0.64 (0.32 to 0.84). CONCLUSIONS: In this high risk and highly pretreated cohort of bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer cases combination intravesical cabazitaxel, gemcitabine and cisplatin was a well tolerated and potentially effective regimen.

Incorporating patient-reported outcomes in dose-finding clinical trials.

Oncology dose-finding clinical trials determine the maximum tolerated dose (MTD) based on toxicity outcomes captured by clinicians. With the availability of more rigorous instruments for measuring toxicity directly from patients, there is a growing interest to incorporate patient-reported outcomes (PRO) in clinical trials to inform patient tolerability. This is particularly important for dose-finding trials to ensure the identification of a well-tolerated dose. In this paper, we propose three extensions of the continual reassessment method (CRM), termed PRO-CRMs, that incorporate both clinician and patient outcomes. The first method is a marginal modeling approach whereby clinician and patient toxicity outcomes are modeled separately. The other two methods impose a constraint using a joint outcome defined based on both clinician and patient toxicities and model them either jointly or marginally. Simulation studies show that while all three PRO-CRMs select well-tolerated doses based on clinician's and patient's perspectives, the methods using a joint outcome perform better and have similar performance. We also show that the proposed PRO-CRMs are consistent under robust model assumptions.

Dose-finding design and benchmark for a right censored endpoint.

Dose-finding trials aim to determine a safe dose to be tested in larger trials for efficacy. In oncology, designs generally assume conventional monotonic increasing dose-toxicity relationships, mostly with binary outcomes (e.g., dose-limiting toxicity or not), measured in the first cycle of therapy or for a fixed number of cycles. However, with new anti-cancer agents such as molecularly targeted therapies and immunotherapies, late-onset toxicities have become more frequent. Designs with prolonged observation windows and censored endpoints analyzed using survival models, appear particularly suited to these settings. Moreover, in this setting, the observation of the late-onset toxicity endpoint could be precluded by trial discontinuation due to death, progression, patient withdrawal, or physician discretion, defining a competing event to toxicity. We propose extensions of the Continual Reassessment Method (CRM) dose-finding design using survival working models for right-censored endpoints and for handling treatment discontinuation in the toxicity observation window, namely the Survival-CRM (Surv-CRM) and the informative survival-CRM (iSurv-CRM). We also developed a benchmark approach for its evaluation. In a simulation study, we compared the performance of the Surv-CRM and iSurv-CRM, to those of the Time-to-event (TITE)-CRM and the nonparametric benchmark. The performance of the proposed methods was consistent with the complexity of scenarios as assessed by the nonparametric benchmark. Without treatment discontinuations, the Surv-CRM provides proportions of correct dose selection close to those of the TITE-CRM with fewer observed toxicities and patients assigned to overtoxic dose levels. In the presence of treatment discontinuation, the iSurv-CRM outperforms the TITE-CRM in identifying the correct dose level.

A real-world study of cardiac events in > 3700 patients with HER2-positive early breast cancer treated with trastuzumab: final analysis of the OHERA study.

PURPOSE: Cardiac dysfunction risk associated with intravenous trastuzumab (H IV) treatment may differ in real-world practice versus randomized trials. We investigated cardiac events in patients with HER2-positive early breast cancer (EBC) treated with H IV as adjuvant therapy in routine practice. METHODS: The observational study of cardiac events in patients with HER2-positive EBC treated with Herceptin (OHERA; NCT01152606) enrolled patients with stage I-IIIb disease eligible for H IV in the adjuvant setting per the European Summary of Product Characteristics (SmPC). Primary outcomes were symptomatic congestive heart failure incidence (CHF; New York Heart Association class II-IV) and cardiac death. Patient visits/assessments were per local practice. RESULTS: 3733 Patients received ≥ 1 H IV dose per local practice; 88.9% received H IV for > 300 days (median follow-up: ~ 5 years). Prior to disease recurrence (if any), symptomatic CHF occurred in 106 patients (2.8%); 6 (0.2%) cardiac deaths occurred (5 in patients with cardiac disease history). Median time to symptomatic CHF onset was 5.7 months (95% CI 5.3-6.5); 77/106 (72.6%) patients with symptomatic CHF achieved resolution. CHF incidence was higher in patients ≥ 65 years, and those with pre-existing cardiac conditions, hypertension, or left ventricular ejection fraction ≤ 55% at baseline. CONCLUSIONS: OHERA is the largest prospective observational study to investigate the cardiac safety of H IV as adjuvant EBC therapy in a real-world setting. Symptomatic CHF and cardiac event incidences were consistent with randomized trials in this setting and baseline risk factors identified in the H IV European SmPC.

A comparison of nurses' and physicians' perception of cancer treatment burden based on reported adverse events.

BACKGROUND: Cancer treatments are associated with a multitude of adverse events (AEs). While both nurses and physicians are involved in patient care delivery and AE assessment, very few studies have examined the differences between nurses' and physicians' reporting and perception of AEs. An approach was recently proposed to assess treatment burden based on reported AEs from the physician's perspective. In this paper, we use this approach to evaluate nurses' perception of burden, and compare nurses' and physicians' assessment of the overall and relative burden of AEs. METHODS: AE records for 334 cancer patients from a randomized clinical trial conducted by the SWOG Cancer Research Network were evaluated by 14 nurses at Columbia University Medical Center. Two nurses were randomly selected to assign a burden score from 0 to 10 based on their impression of the global burden of the captured AEs. These nurses did not interact directly with the patients. Scores were compared to previously obtained physicians scores using paired T-test and Kappa statistic. Severity scores for individual AEs were obtained using mixed-effects models with nurses assessments, and were qualitatively compared to physicians'. RESULTS: Given the same AEs, nurses' and physicians' perception of the burden of AEs differed. While nurses generally perceived the overall burden of AEs to be only slightly worse compared to physicians (mean average VAS score of 5.44 versus 5.14), there was poor agreement in the perception of AEs that were in mild to severe range. The percent agreement for a moderate or worse AE was 64% with a Kappa of 0.34. Nurses also assigned higher severity scores to symptomatic AEs compared to physicians (p < 0.05), such as gastrointestinal (4.77 versus 4.14), hemorrhage (5.07 versus 4.14), and pain (5.17 versus 4.14). CONCLUSIONS: These differences in the perception of burden of AEs can lead to different treatment decisions and symptom management strategies. Thus, having provider consistency, training, or a collaborative approach in follow-up care between nurses and physicians is important to ensure continuity in care delivery. Moreover, estimating overall burden from both physicians' and nurses' perspective, and comparing them may be useful for deciding when collaborations are warranted.

Estimating global treatment toxicity burden from adverse-event data.

BACKGROUND: A summary measure that reflects the global toxicity burden of a treatment is essential for comparing therapies. Current toxicity summaries are ad hoc and do not distinguish among the severities and types of toxicities. Here a clinically feasible method for estimating the toxicity burden, based on a prospective evaluation of the toxicity profile of a randomized clinical trial of 746 prostate cancer patients conducted by SWOG, is proposed. METHODS: For 308 patients who experienced severe toxicities, 2 physicians randomly selected from 14 physicians evaluated each toxicity profile and assigned a visual analogue scale score (0-10) based on their impression of the global burden of toxicities. With mixed-effects models, severity scores and a 10-point toxicity burden score (TBS) were derived from 27 predictors accounting for severe (grade 3) and life-threatening (grade 4) toxicities for each organ class of the Common Terminology Criteria for Adverse Events. RESULTS: For most organ classes, grade 3 toxicities had a TBS of 4.14 (95% confidence interval [CI], 3.65-4.63), but infections, cardiovascular events, and pulmonary events had a higher TBS with differences of 0.87 (95% CI, 0.53-1.21), 0.88 (95% CI, 0.51-1.25), and 0.73 (95% CI, 0.22-1.24), respectively. Moreover, most grade 4 events had a higher TBS than grade 3 events, except for hemorrhaging, pain, metabolic events, and musculoskeletal events. The intrarater and interrater correlations were 0.91 and 0.59, respectively. CONCLUSIONS: The burden of toxicity grades differs with toxicity types. A TBS provides a toxicity burden summary that incorporates physicians' perspectives and differentiates between severe and life-threatening toxicities and organ classes. Cancer 2018;124:858-64. © 2017 American Cancer Society.

Obesity and survival in the neoadjuvant breast cancer setting: role of tumor subtype in an ethnically diverse population.

BACKGROUND: Obesity may negatively affect survival in breast cancer (BC), but studies are conflicting, and associations may vary by tumor subtypes and race/ethnicity groups. METHODS: In a retrospective review, we identified 273 women with invasive BC administered Adriamycin/Taxane-based neoadjuvant chemotherapy from 2004 to 2016 with body mass index (BMI) data at diagnosis. Obesity was defined as BMI ≥30. Associations between obesity and event-free survival (EFS), using STEEP events, and overall survival (OS), using all-cause mortality, were assessed overall and stratified by tumor subtype [[Hormone Receptor Positive (HR+)/HER2-, HER2+, and Triple-Negative Breast Cancer (TNBC])] in our diverse population. RESULTS: Median follow-up was 32.6 months (range 5.7-137.8 months). Overall, obesity was associated with worse EFS (HR 1.71, 95% CI 1.03-2.84, p = 0.04) and a trend towards worse OS (p = 0.13). In HR+/HER2- disease (n = 135), there was an interaction between obesity and hormonal therapy with respect to OS but not EFS. In those receiving tamoxifen (n = 33), obesity was associated with worse OS (HR 9.27, 95% CI 0.96-89.3, p = 0.05). In those receiving an aromatase inhibitor (n = 89), there was no association between obesity and OS. In TNBC (n = 44), obesity was associated with worse EFS (HR 2.62, 95% CI 1.03-6.66, p = 0.04) and a trend towards worse OS (p = 0.06). In HER2+ disease (n = 94), obesity was associated with a trend towards worse EFS (HR 3.37, 95% CI 0.97-11.72, p = 0.06) but not OS. Race/ethnicity was not associated with survival in any subtype, and there were no interactions with obesity on survival. CONCLUSIONS: Obesity may negatively impact survival, with differences among tumor subtypes.

Using Delayed Toxicities to Re-evaluate Tolerability in Phase 2 Trials: A Case Example using Bortezomib.

In advanced stage patients enrolled in dose-finding trials, it is difficult to assess delayed toxicities because frequently patients discontinue after one or two cycles of treatment. Patients enrolled in phase 2 trials are typically followed longer to assess efficacy. Thus, their data may be useful for evaluating long-term tolerability. We illustrate this using as example two phase 2 bortezomib trials (total N = 172) conducted by SWOG. While treatment-related severe toxicity rates based on cycle 1 were acceptable (23% and 31%), they were notably higher over extended administration (37% and 70%). This additional information should be considered when designing subsequent trials.

Modelling semi-attributable toxicity in dual-agent phase I trials with non-concurrent drug administration.

In oncology, combinations of drugs are often used to improve treatment efficacy and/or reduce harmful side effects. Dual-agent phase I clinical trials assess drug safety and aim to discover a maximum tolerated dose combination via dose-escalation; cohorts of patients are given set doses of both drugs and monitored to see if toxic reactions occur. Dose-escalation decisions for subsequent cohorts are based on the number and severity of observed toxic reactions, and an escalation rule. In a combination trial, drugs may be administered concurrently or non-concurrently over a treatment cycle. For two drugs given non-concurrently with overlapping toxicities, toxicities occurring after administration of the first drug yet before administration of the second may be attributed directly to the first drug, whereas toxicities occurring after both drugs have been given some present ambiguity; toxicities may be attributable to the first drug only, the second drug only or the synergistic combination of both. We call this mixture of attributable and non-attributable toxicity semi-attributable toxicity. Most published methods assume drugs are given concurrently, which may not be reflective of trials with non-concurrent drug administration. We incorporate semi-attributable toxicity into Bayesian modelling for dual-agent phase I trials with non-concurrent drug administration and compare the operating characteristics to an approach where this detail is not considered. Simulations based on a trial for non-concurrent administration of intravesical Cabazitaxel and Cisplatin in early-stage bladder cancer patients are presented for several scenarios and show that including semi-attributable toxicity data reduces the number of patients given overly toxic combinations. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.