Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial

Key Points

Question  Does the addition of nab-paclitaxel to gemcitabine-cisplatin therapy prolong progression-free survival among patients with advanced biliary tract cancers when compared with that for historical controls treated with gemcitabine-cisplatin alone?

Findings  In this phase 2 trial that included 60 patients, administration of nab-paclitaxel plus gemcitabine-cisplatin resulted in median progression-free survival of 11.8 months and median overall survival of 19.2 months in an intention-to-treat analysis. The partial response rate was 45%; the disease control rate was 84%.

Meaning  Administration of nab-paclitaxel plus gemcitabine-cisplatin may prolong survival vs administration of gemcitabine-cisplatin alone for the treatment of advanced biliary tract cancers.

Importance  Administration of gemcitabine-cisplatin, the current standard therapy for advanced biliary tract cancers, results in median progression-free survival and overall survival of 8.0 and 11.7 months, respectively. New treatments offering improved survival outcomes are therefore needed.

Objective  To evaluate the association between progression-free survival and the addition of nanoparticle albumin-bound (nab)–paclitaxel to gemcitabine-cisplatin for the treatment of patients with advanced biliary tract cancer.

Design, Setting, and Participants  This open-label, single-arm, phase 2 clinical trial conducted at the University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix, Arizona, enrolled 62 patients with advanced biliary tract cancers between April 14, 2015, and April 24, 2017.

Interventions  Patients initially received gemcitabine, 1000 mg/m², cisplatin, 25 mg/m², and nab-paclitaxel, 125 mg/m², on days 1 and 8 of 21-day cycles. Owing to hematologic adverse events among the first 32 patients enrolled, these starting doses were reduced to 800, 25, and 100 mg/m², respectively, for the remaining 28 patients.

Main Outcomes and Measures  The primary trial end point was investigator-assessed progression-free survival in the intention-to-treat population.

Results  Of 60 patients who started treatment, the mean (SD) age was 58.4 (11.0) years, 38 (63%) had intrahepatic cholangiocarcinoma, 9 (15%) had extrahepatic cholangiocarcinoma, 13 (22%) had gallbladder cancer, 47 (78%) had metastatic disease, and 13 (22%) had locally advanced disease. Median follow-up was 12.2 (95% CI, 9.4-19.4) months, and median progression-free survival was 11.8 (95% CI, 6.0 to 15.6) months. The partial response rate was 45%, and the disease control rate was 84%. Median overall survival was 19.2 months (95% CI, 13.2 months to not estimable). Patients in the safety population (n = 57) received a median of 6 (interquartile range, 3-11) cycles of treatment; 26 patients (46%) remained on their starting dose throughout the trial. Grade 3 or higher adverse events occurred in 58% of patients, and 9 patients (16%) withdrew owing to adverse events. Neutropenia was the most common grade 3 or higher adverse event, occurring in 19 patients (33%) overall. Post hoc analyses showed that treatment efficacy was not significantly associated with starting dose, tumor type, or disease status and that tolerability was improved with reduced- vs high-dose treatment.

Conclusions and Relevance  Treatment with nab-paclitaxel plus gemcitabine-cisplatin prolonged median progression-free survival and overall survival vs those reported for historical controls treated with gemcitabine-cisplatin alone. These findings will be tested in a phase 3 randomized clinical trial.

Trial Registration  ClinicalTrials.gov identifier: NCT02392637

Biliary tract cancers (BTCs), which include intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC), often evade diagnosis until they have reached an advanced stage, when potentially curative surgical resection is no longer an option.¹ Consequently, the prognosis for most patients is poor: median overall survival (OS) with gemcitabine-cisplatin, the current first-line standard-of-care treatment of advanced BTCs (aBTCs), is less than 1 year.^1-4

An albumin-bound form of paclitaxel, nab-paclitaxel (Abraxane), is approved in combination with gemcitabine as a first-line treatment of metastatic pancreatic adenocarcinoma in the United States.⁵ Preclinical study data suggest that nab-paclitaxel enhances gemcitabine delivery to pancreatic tumors by depleting the surrounding stroma.⁶ This raises the possibility of similar effects in other stroma-rich cancers, including BTCs.^7-9 A phase 1/2 trial reported a high response rate (RR) with gemcitabine-cisplatin plus nab-paclitaxel administration in advanced pancreatic cancer,⁶ and several small studies have shown some activity of taxanes in newly diagnosed and refractory aBTCs.^10-12 Given these indications of minor efficacy, we designed the present phase 2 trial to investigate the association between progression-free survival (PFS) and the addition of nab-paclitaxel to gemcitabine-cisplatin for the treatment of patients with aBTC.

Eligibility criteria included at least 18 years of age; histologically or cytologically confirmed IHCC, EHCC, or GBC; metastatic or locally advanced unresectable disease documented on diagnostic imaging studies; Eastern Cooperative Oncology Group performance status score less than or equal to 1; and adequate hematologic (absolute neutrophil count at least 1.5 × 10³/μL [to convert to ×10⁹ per liter, multiply by 0.001], platelets ≥100 × 10³/μL [to convert to ×10⁹ per liter, multiply by 1.0], and hemoglobin >9.0 g/dL [to convert to grams per liter, multiply by 10.0]), hepatic (total bilirubin ≤1.5 mg/dL [to convert to micromoles per liter, multiply by 17.104]; aspartate aminotransferase and alanine aminotransferase ≤5 × upper limit of reference standard), and renal (creatinine ≤1.5 mg/dL [to convert to micromoles per liter, multiply by 88.4]) function. Exclusion criteria included prior chemotherapy (prior adjuvant chemotherapy was permitted if received >6 months before initiating trial medication); grade 2 or higher peripheral neuropathy as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0; any concurrent severe or uncontrolled medical condition that could compromise trial participation; and known central nervous system disease other than treated brain metastasis. All procedures were conducted in accordance with the Declaration of Helsinki¹³ and the International Conference on Harmonization Guidelines for Good Clinical Practice. The protocol was approved by the institutional review boards at the University of Texas MD Anderson Cancer Center, Houston, Texas, and the Mayo Clinic, Phoenix, Arizona. All patients provided written informed consent prior to enrollment.

This was an open-label, single-arm, phase 2 clinical trial conducted at the University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix. Patients enrolled between April 14, 2015, and April 24, 2017, received sequential intravenous nab-paclitaxel, cisplatin, and gemcitabine (30-, 60-, and 30-minute infusions, respectively) on days 1 and 8 every 21 days. Within 30 minutes prior to receiving the trial medication, all patients also received precisplatin hydration comprising sodium chloride injection (0.9%, 1000 mL) with mannitol, 18.5 g, and magnesium sulfate, 2 g (intravenous infusion for 2 hours); and palonosetron, 0.25 mg, fosaprepitant, 150 mg, and dexamethasone, 12 mg. After treatment, patients received a sodium chloride solution (0.9%, 1000 mL) intravenously (3-hour infusion).

Initially, patients received starting doses of gemcitabine, 1000 mg/m², cisplatin, 25 mg/m², and nab-paclitaxel, 125 mg/m² (high-dose group; n = 32); however, in response to the incidence of grade 3/4 hematologic adverse events (AEs), these doses were reduced to 800 mg/m², 25 mg/m², and 100 mg/m², respectively, in later enrollees (reduced-dose group; n = 28). Treatment continued until disease progression, defined according to Response Evaluation Criteria In Solid Tumors, version 1.1,¹⁴ or unacceptable toxicity. Dose modifications and interruptions, and treatment with growth factor in accordance with American Society of Clinical Oncology guidelines,¹⁵ were permitted for AE management. The dose reduction schedule is given in eTable 1 in the Supplement.

The primary trial end point was investigator-assessed (R.S., M.J., A.K., G.V., R.W., K.R., R.R., D.A., T.B.-S., and M.B.) PFS, defined as the time from treatment initiation until either disease progression or death due to any cause, whichever occurred first. Secondary end points included response (complete response plus partial response), disease control (response plus stable disease) and AE rates, and OS. Survival outcomes were measured from the first dose of trial medication. Exploratory end points included correlations of the tumor marker carbohydrate antigen (CA) 19-9 response (>50% decrease from baseline) with tumor response, PFS, and OS.

A physical examination was performed, and vital signs, performance status, hematology, and biochemistry workups were assessed on or before days 1 and 8 of each cycle; the CA19-9 level was assessed on day 1 of each cycle. Tumor assessment (computed tomography or magnetic resonance imaging of the chest, abdomen, and pelvis) was performed every 3 cycles, at the end-of-treatment visit, and every 12 weeks during follow-up until disease progression. Response was evaluated according to Response Evaluation Criteria in Solid Tumors, version 1.1.¹⁴ All AEs, monitored from treatment initiation until 30 days after treatment, were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Following disease progression, patients were followed up every 3 months for OS.

A maximum of 60 patients were to be enrolled. A Bayes factor single-arm model was used to monitor PFS.¹⁶ Historical data indicate a median PFS of 8.0 months among patients treated with gemcitabine-cisplatin²; it was assumed that adding nab-paclitaxel to the regimen would extend this to 10 months. Therefore, using a Bayesian hypothesis test–based design, a median PFS of 8 months was assumed under the null hypothesis, and of 10 months under the alternative hypothesis. The trial would be terminated for futility if the posterior probability of the alternative hypothesis was less than 0.15. If the true median PFS was 10 months, the probability of trial termination in favor of the null hypothesis would be 11.8%, with a mean of 58 patients treated. The trial would also be terminated in the event of a greater than 90% chance of a higher than 30% rate of treatment-associated grade 4 or higher hematologic AEs or of grade 3 or higher nonhematologic AEs.

Statistical analyses were performed using Stata software, version 13.1 (StataCorp). Efficacy end points were evaluated in the intention-to-treat (ITT) population, defined as all patients who received at least 1 dose of trial medication, and in all patients who completed at least 1 cycle of treatment (the efficacy-evaluable population); here we report efficacy results for the ITT population only. Safety was evaluated in all patients who completed at least 1 cycle of the investigational regimen (the safety population). Post hoc subgroup analyses were conducted according to dose group, tumor type, and disease status (metastatic vs locally advanced). Median follow-up times were evaluated for surviving patients only; among patients who underwent surgery, follow-up was measured until the time of surgery. The Kaplan-Meier method was used to estimate PFS and OS, with surviving patients censored at the time of surgery or at last known follow-up. For exploratory purposes, the following tests were used for comparisons between dose groups: the log-rank test for PFS and OS; Fisher exact test for best treatment response, AEs, and categorical demographic characteristics; and the unpaired t test (if normally distributed) or Mann-Whitney test for continuous demographic characteristics. Changes in CA19-9 were measured from baseline to best response, and their statistical significance was determined by the Wilcoxon matched-pairs test. The Mann-Whitney test was used for post hoc between-group comparisons of change in CA19-9 and the number of treatment cycles received. A significance level of .05 was used for all statistical tests.

Of 62 patients who were enrolled, 60 started treatment (32 in the initial high-dose group, and the remaining 28 in the reduced-dose group) and thus comprised the ITT population. The Table summarizes the demographic and baseline characteristics of the ITT population; patient disposition is outlined in Figure 1.

The mean (SD) age of the ITT population was 58.4 (11.0) years, the most common tumor type was IHCC (38 of 60 patients; 63%), and 47 of 60 patients (78%) had metastatic disease. The high- and reduced-dose groups were comparable in terms of most characteristics; however, there was a greater proportion of patients with locally advanced disease in the reduced-dose vs the high-dose group (10 of 28 [36%] vs 3 of 32 [9%]). In addition, GBC was more prevalent among the reduced-dose vs the high-dose group (9 of 28 patients [32%] vs 4 of 32 patients [13%]).

Fifty-seven patients (31 high dose, 26 low dose) received at least 1 treatment cycle and thus comprised the safety population. Three patients discontinued after receiving less than 1 cycle of treatment owing to AEs (grade 2 nausea, fatigue, and dysgeusia, and grade 3 dehydration in 1 patient receiving high-dose treatment) and early death unrelated to treatment (2 patients).

The median follow-up time for surviving patients in the ITT population was 12.2 (95% CI, 9.4-19.4) months. Three patients were lost to follow-up after prematurely discontinuing the trial medication; follow-up in the remaining 57 patients is depicted in eFigure 1 in the Supplement.

Progression-free survival data were available for 58 patients, 34 of whom had disease progression or died. Demographic and baseline characteristics of the 2 patients without PFS data are summarized in eTable 2 in the Supplement. Median PFS was 11.8 (95% CI, 6.0-15.6) months (Figure 2A); the 12-month PFS rate was 45% (95% CI, 30%-60%). Post hoc subgroup analyses showed that median PFS was 11.4 months (95% CI, 6.0-15.6 months) among patients who received high-dose treatment and 14.9 months (95% CI, 3.8 months to not estimable [NE]) among patients in the reduced-dose group (P = .62) (eFigure 2A in the Supplement); the number of deaths/progressions was 24 in the high-dose group and 10 in the reduced-dose group. Neither tumor type (eFigure 2B in the Supplement) nor disease stage (eFigure 2C in the Supplement) was significantly associated with PFS. Median PFS was 12.9 months (95% CI, 8.5-16.1 months) among patients with IHCC, 6.0 months (95% CI, 0.7 months to NE) among patients with EHCC, and 4.1 months (95% CI, 2.1-14.9 months) among patients with GBC (P = .22); and 11.4 months (95% CI, 5.7-14.9 months) vs 16.1 months (95% CI, 3.8 months to NE) among patients with metastatic vs locally advanced disease (P = .50).

Overall survival data were available for 57 patients. The demographic and baseline characteristics of the 3 patients without OS data are given in eTable 3 in the Supplement. Median OS was 19.2 months (95% CI, 13.2 months to NE) (Figure 2B); the 12-month OS rate was 66% (95% CI, 51%-78%). On post hoc analysis, median OS among high-dose recipients was 19.5 months (95% CI, 10.0 months to NE), with 15 patients having died, and 15.7 months (95% CI, 8.7 months to NE) among reduced-dose recipients, with 10 patients having died (P = .39) (eFigure 3A in the Supplement). Overall survival did not differ significantly by tumor type (eFigure 3B in the Supplement) or disease stage (eFigure 3C in the Supplement). Median OS was NE (95% CI, 13.6 months to NE) among patients with IHCC, 13.2 months (95% CI, 1.8 months to NE) among patients with EHCC, and 15.7 months (95% CI, 3.8 months to NE) among patients with GBC (P = .13). For patients with metastatic disease, median OS was 18.8 months (95% CI, 10.0 months to NE) vs NE (95% CI, 4.6 months to NE) for patients with locally advanced disease (P = .60).

Treatment response data were available for 51 patients; demographic and baseline characteristics of the 9 patients with missing data are provided in eTable 4 in the Supplement. Best responses are given in eTable 5 in the Supplement. Figure 3 shows changes in tumor size from baseline to best response among the 50 patients with measurements at both time points. No complete response was achieved. The partial response rate was 45%, and the disease control rate was 84%. Post hoc analyses showed that response rates were not significantly associated with dose group, tumor type, or disease stage. Twelve patients (20%; 5 in the high-dose group and 7 in the reduced-dose group) were converted from unresectable to resectable disease, and they subsequently underwent surgery. The causes of unresectability (as determined by specialists [R.S., M.J., A.K., G.V., R.W., K.R., R.R., D.A., T.B.-S., and M.B.] at the 2 high-volume cancer centers) in these 12 patients are given in eTable 6 in the Supplement. Two patients with metastatic disease (1 in each dose group) achieved a pathologic complete response after surgery.

Baseline and best response CA19-9 levels were available for 53 patients. The median change in CA19-9 levels from baseline to best response was –25 U/mL (95% CI, –95 to –1 U/mL; P < .001); the median value decreased from 93 to 27 U/mL (to convert units per milliliter to 10³ units per liter, multiply by 1.0). Post hoc analyses found a median change among high-dose recipients of –34 U/mL (95% CI, –129 to 0 U/mL; P = .002) vs –16 U/mL (95% CI, –280 to 0 U/mL; P = .01) among reduced-dose recipients; median values decreased among high-dose recipients from 93 to 27 U/mL and among reduced-dose recipients from 79 to 41 U/mL. The difference between dose groups was not significant (P = .86).

Fifty-seven patients received at least 1 cycle of treatment and were included in the exposure and safety analyses (eTable 7 in the Supplement). Patients received a median of 6 (interquartile range, 3-11) treatment cycles, with 26 patients (46%) remaining on their starting dose for the duration of treatment. Patients in the high-dose group received a median number of 8 cycles, while those in the reduced-dose group received a median of 5 cycles (P = .06), reflecting the sequential order of enrollment; 11 of 31 patients (35%) vs 15 of 26 patients (58%) in each dose group remained on their starting dose (P = .12). Grade 3 or higher AEs occurred in 33 patients overall (58%), being reported in 19 patients (61%) in the high-dose group and in 14 patients (54%) in the reduced-dose group. Neutropenia was the most common AE at grade 3 or higher, occurring in 19 of the 57 patients (33%) included in the safety population (10 [32%] in the high-dose group and 9 [35%] in the reduced-dose group, although these data are not shown in a table). Nine patients (16%; 5 in the high-dose group, 4 in the reduced-dose group) withdrew prematurely owing to AEs; 4 of 57 patients (7%) discontinued cisplatin, and 1 of 57 patients (2%) discontinued nab-paclitaxel. One grade 5 AE (sepsis in a patient in the high-dose group) occurred during the trial.

Our findings suggest that adding nab-paclitaxel to gemcitabine-cisplatin therapy results in promising efficacy among patients with aBTCs. After a median follow-up of approximately 1 year, median PFS was 11.8 months and median OS was 19.2 months (ITT analysis). These outcomes appear favorable compared with those of historical populations with aBTCs treated with first-line gemcitabine-cisplatin (median PFS and OS of 8.0 and 11.7 months, respectively).²

Twelve patients were converted from unresectable to resectable disease and underwent surgery; 2 subsequently achieved a pathologic complete response. This high resection rate suggests a synergistic association between the triplet combination and patients’ treatment responses; this will be further investigated in an ongoing neoadjuvant study that is evaluating the same regimen in borderline resectable IHCC (ClinicalTrials.gov identifier, NCT03579771). In addition to a high resection rate, we observed a reduction in CA19-9 levels from baseline to best tumor response in the majority (62%) of patients, which is important in view of the known association between CA19-9 levels and clinical outcomes in aBTCs.⁶

Post hoc subgroup analyses showed that neither survival nor response rates differed significantly with tumor site. This is consistent with the findings of a retrospective analysis of 740 patients with aBTCs, which reported no significant difference in response to gemcitabine-cisplatin between primary tumor sites.⁴

The initial treatment doses that we used—gemcitabine 1000 mg/m², cisplatin 25 mg/m², and nab-paclitaxel 125 mg/m²—were based on those administered in the respective phase 3 studies of gemcitabine plus cisplatin in BTC² and nab-paclitaxel plus gemcitabine in pancreatic cancer.¹⁷ These doses were also used successfully in a phase 1b/2 pilot trial in 25 patients with stage IV pancreatic cancer.¹⁸ Similar to our findings, that study demonstrated an impressive 71% overall RR in a notoriously chemoresistant cancer. However, we found limited tolerability of the initial dose level in aBTCs: less than half of patients completed the trial without dose modifications. The reduced dose of gemcitabine, 800 mg/m², cisplatin, 25 mg/m², and nab-paclitaxel, 100 mg/m², appeared to be better tolerated, with 58% of patients requiring no dose reductions for the duration of their treatment. Overall and individual rates of grade 3 or higher AEs did not appear to differ between the dose groups. As expected, hematologic AEs were the most common.^17,18

Although higher AE rates were observed with administration of the gemcitabine-cisplatin plus nab-paclitaxel triplet vs those for historical gemcitabine-cisplatin, these AEs were more common in the high-dose group. Increased AEs must be balanced against the survival and quality-of-life improvements that are associated with a more complex regimen. Such intensification of chemotherapy has been shown to improve quality-of-life metrics for patients with other malignant neoplasms despite AE rates—for example, with FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) for the treatment of pancreatic cancer.¹⁹

The benefits of triplet chemotherapy with gemcitabine-cisplatin plus nab-paclitaxel are underscored by the findings of a phase 2 clinical trial (protocol No. PrE0204), in which 74 patients with newly diagnosed cholangiocarcinoma received doublet therapy with gemcitabine plus nab-paclitaxel.²⁰ That study failed to meet its primary end point of improvement in PFS rate at 6 months (the 6-month PFS rate of 61% was insufficient to achieve the alternative hypothesis of 70% based on historical data); however, median OS was 12.4 months, suggesting that gemcitabine plus nab-paclitaxel may be considered an alternative to gemcitabine-cisplatin.

The present trial was limited in that it was not a randomized, controlled trial, it included a relatively low number of patients, and it was not powered to detect PFS improvement in the different BTC subtypes vs historical controls. An additional limitation was the fact that median follow-up and treatment exposure times differed between the dose groups. As a result of these limitations, our findings must be interpreted with caution.

The single-arm, noncomparative design mirrored that of prior trials in advanced pancreatic cancer and biliary cancer,^6,20 which nevertheless produced clinically meaningful results. It is important to note that the phase 3 ABC-02 clinical trial² was similarly based on the smaller phase 2 ABC-01 study of gemcitabine plus cisplatin vs gemcitabine alone.²¹ The ABC-01 clinical trial accurately predicted the final results of the subsequent ABC-02 clinical trial, with a median PFS of 8.0 months and a response rate of 28%.²¹ Although the patient population in the present study closely mirrored that of ABC-01, with a similar proportion of enrolled patients having received a diagnosis of cholangiocarcinoma vs GBC (69% vs 26% in ABC-01, with 6% of patients having ampullary cancer) and more than 75% of patients having metastatic disease at enrollment (69% in ABC-01), we acknowledge that we included a higher percentage of patients with IHCC (63%, compared with 22% in ABC-01).²¹ This latter observation is reflective of the changing trends in biliary cancer epidemiology and was also seen in the recent study of gemcitabine and nab-paclitaxel by Sahai et al (82% of patients with IHCC).²⁰ A recent retrospective analysis suggests that this subset of BTCs may be associated with improved survival vs EHCC and GBC.²² High secondary resection rates may bias survival data, which can be circumvented by randomized, prospective studies. The Southwest Oncology Group 1815 study (ClinicalTrials.gov identifier NCT03768414), a phase 3 randomized clinical trial comparing gemcitabine-cisplatin plus nab-paclitaxel with gemcitabine-cisplatin as a control arm, will address these issues.

In conclusion, the present phase 2 clinical trial met its primary end point of a PFS increase among patients with aBTCs receiving gemcitabine-cisplatin plus nab-paclitaxel compared with historical data for those receiving gemcitabine-cisplatin. The median PFS, OS, and RR achieved in the present clinical trial were higher than those reported previously.

Accepted for Publication: January 16, 2019.

Corresponding Author: Rachna T Shroff, MS, MD, Division of Hematology/Oncology, Department of Medicine, University of Arizona Cancer Center, 1515 N Campbell Ave, R 1921, Tucson, AZ 85724 (rshroff@email.arizona.edu).

Published Online: April 18, 2019. doi:10.1001/jamaoncol.2019.0270

Author Contributions: Dr Shroff had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Shroff, Javle, Xiao, Wolff, Borad.

Acquisition, analysis, or interpretation of data: Shroff, Xiao, Kaseb, Varadhachary, Wolff, Raghav, Iwasaki, Masci, Ramanathan, Ahn, Bekaii-Saab, Borad.

Drafting of the manuscript: Shroff, Javle, Kaseb, Ramanathan, Ahn, Borad.

Critical revision of the manuscript for important intellectual content: Shroff, Javle, Xiao, Kaseb, Varadhachary, Wolff, Raghav, Iwasaki, Masci, Ahn, Bekaii-Saab, Borad.

Statistical analysis: Xiao, Iwasaki.

Obtained funding: Shroff.

Administrative, technical, or material support: Kaseb, Ramanathan, Bekaii-Saab, Borad.

Supervision: Shroff, Javle, Kaseb, Ahn.

Conflict of Interest Disclosures: Dr Shroff reported receiving grants, personal fees, and nonfinancial support from Celgene during the conduct of the study; grants and personal fees from Halozyme Therapeutics, and Agios Pharmaceuticals; grants from Eli Lilly; and personal fees from Seattle Genetics, Exelixis, Merck & Co, and Codiak Biosciences outside the submitted work. Dr Javle reported being a consultant for QED Therapeutics, Merck & Co, EDO Pharma, Merck Serono, Taiho Pharmaceutical, and Incyte Corp. Dr Varadhachary reported receiving personal fees and being a member of the advisory council of Celgene outside the submitted work. Dr Ahn reported receiving consultant fees from Eisai, Exelixis, Astellas Pharma, Paradigm Biopharma, and Heron Therapeutics outside the submitted work. Dr Ramanathan reported receiving grants from Celgene during the conduct of the study and being employed by Merck & Co after conduct of the study. Dr Bekaii-Saab reported receiving personal fees from Celgene outside the submitted work. Dr Borad reported receiving grants from Celgene during the conduct of the study; grants from Fujifilm, Agios Pharmaceuticals, Halozyme Therpaeutics, Incyte Corp, Basilea Pharmaceutica, Senhwa Biosciences, Toray Pharmaceuticals, EMD Serono, Pieris Pharmaceuticals, Sun Biopharma, Mirna Therapeutics, BiolineRx, ARIAD Pharmaceuticals, Puma Biotechnology, Novartis, and QED Therapeutics; and personal fees from G1 Therapeutics, Inspyr Pharmaceuticals, Exelixis, Immunovative Therapies, OncBioMune Pharmaceuticals Inc, ADC Therapeutics, Systems Oncology, Western Oncolytics, and Lynx Group, outside the submitted work. No other disclosures are reported.

Funding/Support: This study was supported by Celgene.

Role of the Funder/Sponsor: Celgene Corporation had no role in the design and conduct of the trial; collection, management, analysis, and interpretation of the data; approval of the manuscript; or the decision to submit the manuscript for publication. The manuscript was prepared by the authors with the assistance of professional medical writers funded by Celgene.

Additional Contributions: The authors thank the research staff at the University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix, Arizona, as well as the patients and their caregivers for their participation in this trial. Medical writing assistance in the development of this manuscript was provided by Steve Hill, PhD, and Sandralee Lewis, PhD, on behalf of the Investigator Initiated Research Writing Group (an initiative from Ashfield Healthcare Communications, part of UDG Healthcare plc) and was funded by Celgene Corporation.