A single arm phase II trial of chidamide plus cisplatin in advanced adenoid cystic carcinoma

Summary

Systemic therapy for recurrent or metastatic adenoid cystic carcinoma remains limited, and durable disease control is difficult to achieve. We conducted a prospective, single-arm phase 2 trial of chidamide, a histone deacetylase inhibitor, plus cisplatin in 24 patients with recurrent or metastatic disease. Patients received a short chidamide lead-in followed by combination therapy for up to six cycles. The study did not meet its prespecified objective response target, with a confirmed objective response rate of 13.6% among 22 efficacy-evaluable patients. However, disease control was observed in 86.4% of patients, median progression-free survival was 17.9 months, and median overall survival was 40.3 months. Toxicity was manageable, with no treatment-related deaths. These findings support further evaluation of histone deacetylase inhibitor-platinum strategies as a disease-control approach in this rare cancer, while requiring validation in larger studies.

Graphical abstract

Highlights

• •Prospective phase 2 trial of chidamide plus cisplatin in recurrent or metastatic ACC
• •The prespecified ORR endpoint was not met; confirmed ORR was 13.6% among 22 patients
• •Disease control rate was 86.4%, with median progression-free survival of 17.9 months
• •Toxicity was manageable, with no treatment-related deaths

Health sciences; Medicine; Medical specialty; Dentistry; Internal medicine; Oncology; Therapeutics

Introduction

Adenoid cystic carcinoma (ACC) is a rare salivary gland malignancy characterized by an indolent but persistent clinical course, frequent perineural invasion, local recurrence, and late distant metastasis.¹ Definitive surgery and radiotherapy are the main treatments for localized disease, but recurrent or metastatic ACC remains difficult to manage.^2,3

No established systemic standard of care exists for recurrent or metastatic ACC.^2,3 Conventional cytotoxic chemotherapy, including platinum-based regimens, has produced modest and often non-durable responses.^2,4 Targeted therapies have shown variable activity. Multikinase inhibitors, such as lenvatinib, have shown modest objective response activity but frequent disease stabilization, with median progression-free survival (PFS) of approximately 17–18 months in phase 2 studies, although chronic toxicity can require dose interruption or discontinuation.^5,6,7,8,9 Apatinib has reported higher response estimates in a single-center study, although outcomes across studies remain heterogeneous and toxicity can limit treatment continuation.^10,11,12 Epidermal growth factor receptor and KIT inhibitors have shown limited activity,^10,11 and immune checkpoint blockade has generally underperformed, consistent with the immune-cold biology of ACC.^13,14,15,16 These data underscore the need for mechanism-based strategies that can improve durable disease control rather than relying solely on deep tumor regression.

Epigenetic dysregulation has emerged as a potential therapeutic vulnerability in ACC.^17,18,19 Histone deacetylase (HDAC) inhibitors can modulate chromatin accessibility, promote cell-cycle arrest and differentiation, and enhance sensitivity to DNA-damaging therapy.^18,20,21 Clinically, the pan-HDAC inhibitor vorinostat has shown durable disease control in recurrent or metastatic ACC, supporting further evaluation of this drug class.²² Chidamide, also known as tucidinostat, is an oral benzamide HDAC inhibitor with established clinical use in other malignancies and preliminary activity in ACC.^{19,23,24,25,26} Preclinical ACC models further suggest that HDAC inhibition may sensitize tumor cells to cisplatin-induced DNA damage and promote senescence, providing a rationale for combining chidamide with platinum chemotherapy.^19,27

On this basis, we conducted a prospective, single-arm, phase 2 study of chidamide plus cisplatin in patients with recurrent or metastatic ACC. The study evaluated confirmed objective response rate (ORR) as the primary endpoint and disease control rate (DCR), PFS, overall survival (OS), safety, and patient-reported health-related quality of life as secondary outcomes.

Results

Twenty-two of 24 treated patients were efficacy evaluable

Between June 2018 and February 2020, 24 patients received at least one dose of chidamide plus cisplatin and were included in the safety population (Figure 1). Two patients had no post-baseline tumor assessment because of withdrawal of consent (n = 1) and decline in performance status (n = 1), leaving 22 patients in the efficacy-evaluable population. Among these patients, 11 (50.0%) completed all six planned cycles, and 11 (50.0%) discontinued treatment early because of withdrawal of consent (n = 5), radiographic progression (n = 4), or unacceptable toxicity (n = 2).

Figure 1.

Patient disposition and analysis populations

Flow diagram showing patient enrollment, treatment exposure, and analysis populations. Of 24 enrolled patients who received at least one dose of chidamide plus cisplatin and were included in the safety population, 22 had at least one post-baseline tumor assessment and comprised the efficacy-evaluable population. Two patients were excluded from efficacy analysis because of withdrawal of consent (n = 1) or decline in performance status (n = 1). Among the efficacy-evaluable patients, 11 completed all six planned cycles, and 11 discontinued treatment early because of withdrawal of consent (n = 5), disease progression (n = 4), or unacceptable toxicity (n = 2). Abbreviations: ACC, adenoid cystic carcinoma; ECOG, Eastern Cooperative Oncology Group; R/M, recurrent or metastatic.

Most patients had metastatic disease and short disease-free intervals

Baseline characteristics are summarized in Table 1. Among the 24 treated patients, the mean age was 48.5 years (standard deviation, 10.9), and 11 patients (45.8%) were male. Fifteen patients (62.5%) had a disease-free interval (DFI) of less than 30 months. At study entry, 23 patients (95.8%) had distant metastases and were classified as stage IVC disease; lung metastases were present in 20 patients (83.3%). Twelve patients (50.0%) had received no prior systemic therapy, and 12 (50.0%) had received at least one prior systemic regimen. Baseline global health status scores were available for 22 patients, with a median score of 42.5 (range, 28 to 83).

Table 1.

Baseline characteristics of the treated population

Characteristic	Value
Sex
Male	11 (45.8)
Female	13 (54.2)
Age, years
Mean (standard deviation)	48.5 (10.9)
Disease-free interval, yearsa
Mean (standard deviation)	3.2 (4.1)
<30 months	15 (62.5)
≥30 months	9 (37.5)
Primary site
Submandibular gland	9 (37.5)
Oropharynx	1 (4.2)
Oral cavity	3 (12.5)
Palate	2 (8.3)
Maxillary sinus	1 (4.2)
Tongue	3 (12.5)
Parotid gland	3 (12.5)
Trachea	1 (4.2)
Thyroid	1 (4.2)
Initial treatment
Surgery alone	2 (8.3)
Surgery plus adjuvant therapy	19 (79.2)
Palliation	2 (8.3)
Particle-beam radiation	1 (4.2)
Prior systemic therapy regimens
0	12 (50.0)
1	6 (25.0)
2	2 (8.3)
3	4 (16.7)
Distant metastases
Yes	23 (95.8)
No	1 (4.2)
Clinical stageb
IVA	1 (4.2)
IVC	23 (95.8)
Sites of metastasisc
Lung	20 (83.3)
Pleura or chest wall	7 (29.2)
Bone	6 (25.0)
Lymph nodes	4 (16.7)
Liver	2 (8.3)
Cancer-related pain	6 (25.0)
Baseline EORTC QLQ-C30 global health status scored
Median (range)	42.5 (28–83)

Data are No. (%) unless otherwise indicated.

EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30.

^aDisease-free interval was calculated from completion of initial treatment to first documented recurrence or metastasis.

^bClinical staging was determined according to the American Joint Committee on Cancer Cancer Staging Manual, 8th edition.

^cSites of metastasis were not mutually exclusive.

^dBaseline European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 global health status scores were available for 22 patients.

Toxicities were mainly hematologic and manageable

Safety was assessed in all 24 treated patients (Table 2). Hematologic adverse events were most common. Neutropenia occurred in 13 patients (54.2%), including grade 3 or 4 neutropenia in 4 (16.7%). Leukopenia occurred in 11 patients (45.8%), thrombocytopenia in 10 (41.7%; grade 3 or 4, n = 1 [4.2%]), and anemia in 4 (16.7%). The most common nonhematologic adverse events were nausea (8 patients, 33.3%) and vomiting (7 patients, 29.2%), each with one grade 3 event. Dose reductions occurred in 3 patients (12.5%), including chidamide dose reduction in 2 (8.3%). Two patients discontinued treatment because of adverse events, and no treatment-related deaths were reported.

Table 2.

Adverse events in the treated population

Adverse event	Any grade, no. (%)	Grade 3 or 4, no. (%)
Neutropenia	13 (54.2)	4 (16.7)
Leukopenia	11 (45.8)	0 (0.0)
Thrombocytopenia	10 (41.7)	1 (4.2)
Nausea	8 (33.3)	1 (4.2)
Vomiting	7 (29.2)	1 (4.2)
Anemia	4 (16.7)	0 (0.0)
Constipation	3 (12.5)	0 (0.0)
Fatigue	3 (12.5)	0 (0.0)
Pain	2 (8.3)	0 (0.0)
Diarrhea	1 (4.2)	0 (0.0)
Decreased red blood cell count	1 (4.2)	0 (0.0)
Upper abdominal pain	1 (4.2)	0 (0.0)
Increased AST	1 (4.2)	1 (4.2)
Stomach pain	1 (4.2)	0 (0.0)
Gastrointestinal symptoms	1 (4.2)	0 (0.0)
Hypoalbuminemia	1 (4.2)	0 (0.0)
Upper respiratory tract infection	1 (4.2)	0 (0.0)
Decreased hemoglobin	1 (4.2)	0 (0.0)
Tremor	1 (4.2)	0 (0.0)
Myelosuppression	1 (4.2)	1 (4.2)
Increased ALT	1 (4.2)	0 (0.0)

Data are No. (%). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Disease control was frequent despite limited objective response

Among the 22 efficacy-evaluable patients, confirmed partial response occurred in 3 patients (13.6%), stable disease in 16 (72.7%), and progressive disease in 3 (13.6%); no complete response was observed (Table 3). The confirmed ORR was 13.6%, and the prespecified objective response target was not met. The DCR was 86.4% (19 of 22; 95% CI, 65.1 to 97.1). The Kaplan-Meier estimated 6-month PFS rate was 71.0% (95% CI, 58.8 to 93.6), and 17 patients (77.3%) remained progression-free for at least 6 months.

Table 3.

Efficacy outcomes in the efficacy-evaluable population

Outcome	Value
Best overall response
Complete response	0 (0.0)
Confirmed partial response	3 (13.6)
Stable disease	16 (72.7)
Progressive diseasea	3 (13.6)
Confirmed objective response rateb	3 (13.6)
95% CI	2.9 to 34.9
Disease control ratec	19 (86.4)
95% CI	65.1 to 97.1
6-month progression-free survival rated	71.0%
95% CI	58.8 to 93.6
Progression-free for ≥6 monthse	17 (77.3)

Data are No. (%) unless otherwise indicated.

CI, confidence interval.

^aOne patient had progressive disease based on progression of non-target lesions.

^bConfirmed objective response rate was defined as complete response or confirmed partial response according to Response Evaluation Criteria in Solid Tumors, version 1.1. Objective responses required confirmation.

^cDisease control rate was defined as the proportion of patients with a best overall response of complete response, partial response, or stable disease.

^dThe 6-month progression-free survival rate was estimated using the Kaplan-Meier method.

^eThis value represents the observed proportion of patients who remained progression-free for at least 6 months.

Individual tumor changes and PFS intervals are shown in Figure 2, and longitudinal target lesion changes are shown in Figure S1. Median PFS was 17.9 months (95% CI, 7.2 to not estimable; 12 events), and median OS was 40.3 months (95% CI, 22.8 to not estimable; 13 deaths) in the efficacy-evaluable population (Figure 3). In exploratory analyses, early tumor shrinkage after cycle 2 was associated with longer progression-free and OS, whereas prior systemic therapy status was not significantly associated with outcomes (Figure S2; Tables S1 and S2). A descriptive comparison by treatment completion status is provided in Table S3.

Figure 2.

Individual tumor changes and progression-free survival intervals

(A) Waterfall plot showing the best percentage change from baseline in the sum of target lesion diameters for individual patients, ordered by depth of response. Dashed lines indicate the Response Evaluation Criteria in Solid Tumors, version 1.1 thresholds for partial response (−30%) and progressive disease (+20%). Asterisks indicate confirmed partial responses.

(B) Swimmer plot showing PFS intervals, time to first documented partial response, and clinically relevant events. Each horizontal bar represents an individual patient, and bar length corresponds to the PFS interval from treatment initiation. Bar colors indicate best overall response according to Response Evaluation Criteria in Solid Tumors, version 1.1. Symbols indicate time to first documented partial response, completion of six cycles of treatment, discontinuation due to progressive disease or adverse events, withdrawal of consent, and death. See also Figure S1. Abbreviations: AE, adverse event; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 3.

Kaplan-Meier estimates of progression-free and overall survival

Kaplan-Meier curves showing PFS and OS in the efficacy-evaluable population. Time zero was the date of first study treatment, including the chidamide lead-in.

(A) PFS (n = 22; 12 events), with events defined as radiographic progression or death. Median PFS was 17.9 months (95% CI, 7.2 to not estimable).

(B) OS (n = 22; 13 deaths). Median OS was 40.3 months (95% CI, 22.8 to not estimable). Shaded bands denote 95% CIs; tick marks indicate censoring. Abbreviations: CI, confidence interval; NE, not estimable.

Global health status scores were summarized descriptively

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status scores were available for 22 patients at baseline and for fewer patients during treatment. In observed cases, median scores were higher at cycles 2 and 6 than at baseline by the Wilcoxon matched-pairs signed-rank test among patients with paired assessments (Figure 4). Questionnaire completion declined over time, with assessments available for 14 patients at cycle 2, 9 at cycle 4, and 9 at cycle 6. These patient-reported outcome data were summarized descriptively.

Figure 4.

Global health status scores during treatment

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status scores during treatment. Scores were scaled from 0 to 100, with higher scores indicating better global health status. Assessments were performed at baseline and at cycles 2, 4, and 6. Data are shown as median with interquartile range for observed cases without imputation. Available assessments were n = 22 at baseline, n = 14 at cycle 2, n = 9 at cycle 4, and n = 9 at cycle 6. Pairwise comparisons were performed using two-sided exact Wilcoxon matched-pairs signed-rank tests. Baseline versus cycle 2: n = 14; baseline versus cycle 4: n = 9; baseline versus cycle 6: n = 9; cycle 2 versus cycle 4: n = 7; and cycle 2 versus cycle 6: n = 7. Abbreviations: C, cycle; IQR, interquartile range; ns, not significant.

Discussion

In this prospective, single-arm phase II study of chidamide plus cisplatin in recurrent or metastatic ACC, the prespecified ORR endpoint was not met. The confirmed ORR was 13.6%, with no complete responses. However, most efficacy-evaluable patients achieved stable disease, the DCR was 86.4%, and median PFS was 17.9 months. The regimen also had a manageable safety profile, with hematologic toxicity as the main adverse event category and no treatment-related deaths. Together, these findings suggest limited objective tumor regression but a disease-control signal in a subset of patients. Given the small sample size, single-arm design, and absence of a randomized comparator, this signal should be considered exploratory rather than definitive evidence of clinical or survival benefit.

The apparent discordance between modest ORR and prolonged PFS should be interpreted in the context of the clinical behavior of recurrent or metastatic ACC. Tumor growth in ACC is often indolent but relentless, and durable disease stabilization may represent a clinically meaningful therapeutic goal.^10,11 At the same time, stable disease can reflect underlying tumor biology, particularly in a nonrandomized study without a contemporaneous control group. In this cohort, most patients had stage IVC disease, and 62.5% had a DFI of less than 30 months. A short DFI is a recognized adverse prognostic feature in recurrent or metastatic ACC, and DFI shorter than 30 months has been associated with poorer recurrent/metastatic survival.^28,29 These features support the presence of clinically active disease in many patients, but they do not exclude natural-history bias. The observed PFS should therefore be viewed as supportive evidence of disease control that requires prospective validation.

The historical treatment landscape provides useful but limited context. Conventional cytotoxic regimens, including cyclophosphamide, doxorubicin, and cisplatin (CAP) and other platinum-based combinations, have generally produced modest and often non-durable responses in recurrent or metastatic ACC, with median PFS commonly reported at approximately 6–10 months^{30,31,32,33,34,35,36} Multikinase inhibitors, such as lenvatinib, have produced higher rates of disease stabilization and median PFS estimates of approximately 17–18 months in prospective studies.^11,32,35,37 The median PFS observed in the present study appears within the range reported for some active systemic approaches in ACC. However, cross-study comparisons are limited by differences in eligibility criteria, prior therapy, baseline disease kinetics, tumor burden, imaging schedules, and endpoint definitions. These data should not be interpreted as evidence that chidamide plus cisplatin is superior to existing systemic options, but they provide a rationale for further evaluating HDAC inhibitor-platinum strategies in clinically selected or biomarker-informed ACC populations.

Individual-level efficacy displays further support a pattern of limited tumor regression with disease stabilization. Waterfall, swimmer, and spider plots showed confirmed shrinkage in only a minority of patients, whereas several patients maintained stable target lesion burden over prolonged intervals. Although early tumor shrinkage was associated with longer PFS and OS in exploratory analyses, this post-baseline association was limited by the small sample size and number of events and should be interpreted descriptively. These findings help characterize treatment kinetics but do not alter the primary conclusion that the prespecified ORR endpoint was not met.

The biological rationale for combining chidamide with cisplatin remains plausible but unproven. HDAC inhibition can alter chromatin regulation, promote cell-cycle arrest or differentiation, and increase sensitivity to DNA-damaging therapy.^18,20,21 The chidamide lead-in was intended to test this epigenetic-priming concept clinically.^18,38 Because this study did not include paired tumor biopsies, pharmacodynamic assays, or molecular stratification, it cannot establish target engagement, sequence dependence, or a mechanistic link between HDAC inhibition and disease control.^39,40 Future studies should integrate pharmacodynamic and molecular endpoints to identify tumors most likely to benefit from HDAC inhibitor-platinum therapy.^41,42

Patient-reported outcomes provide additional context but should be interpreted cautiously. Among patients with available EORTC QLQ-C30 assessments, global health status scores increased during treatment. However, the analysis was based on observed cases without imputation, and questionnaire completion declined over time. Later assessments may therefore overrepresent patients who remained on treatment and were clinically well enough to complete questionnaires, introducing potential informative missingness. These data support tolerability among assessed patients but should not be considered definitive evidence of population-level HRQoL improvement.

Limitations of the study

This study has several limitations inherent to rare-tumor research. It was conducted at a single center, included a small number of patients, and did not include a randomized control group or central radiologic review. The confidence intervals around key survival estimates were wide, including an upper confidence bound for PFS that was not estimable, reflecting limited precision. The absence of formal pre-enrollment tumor growth-rate assessment limits the ability to separate treatment-associated disease control from the natural history of ACC. Subgroup and multivariable analyses were exploratory and underpowered, with potential model instability and residual confounding. Treatment-completion analyses were vulnerable to guarantee-time bias because patients had to remain clinically stable long enough to complete all planned cycles. The absence of molecular stratification also leaves open whether specific genomic or epigenetic states, including MYB/MYBL1 programs, NOTCH1 status, or chromatin features, modulate sensitivity to HDAC inhibitor-platinum therapy. These limitations should inform subsequent multicenter, biomarker-enriched trials with independent response verification, prespecified success thresholds, and endpoints that better capture durable disease control in ACC.

Resource availability

Lead contact

Requests for further information and resources should be directed to and will be fulfilled by the lead contact, Junning Cao (cao_junning@126.com).

Materials availability

This study did not generate new unique reagents.

Data and code availability

• •The patient-level clinical data generated and analyzed in this study are not publicly available because of participant confidentiality. Deidentified data may be available from the lead contact upon reasonable request, subject to institutional and ethical approvals.
• •This study did not generate original code.
• •Any additional information required to reanalyze the data reported in this study is available from the lead contact upon request.

Acknowledgments

We thank the patients and their families for participating in this study. This work was supported by the National Natural Science Foundation of China (no. 82573874). The funder had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript.

Author contributions

Conceptualization, K.X. and J.C.; methodology, K.X., G.-L.C., and J.C.; investigation, G.-L.C., Y.L., K.X., Q.Z., Z.X., D.J., J.J., F.L., X.L., Y.W., X.H., and J.C.; data curation, G.-L.C., Y.L., and K.X.; formal analysis, G.-L.C., K.X., and Y.L.; writing – original draft, Y.L., G.-L.C., and K.X.; writing – review and editing, all authors; supervision, X.H. and J.C.; funding acquisition, G.-L.C.

Declaration of interests

The authors declare no competing interests.

Declaration of generative AI and AI-assisted technologies in the manuscript preparation process

During the preparation of this manuscript, the authors used ChatGPT to improve language clarity and readability. The authors reviewed and edited the manuscript and take full responsibility for the content.

STAR★Methods

Key resources table

REAGENT or RESOURCE	SOURCE	IDENTIFIER
Chemicals, peptides, and recombinant proteins
Chidamide	Chipscreen Biosciences, China	Trade name: Epidaza®
Cisplatin	Qilu Pharmaceutical Co., Ltd., China	Cisplatin for Injection, 20 mg
Software and algorithms
PASW Statistics	SPSS Inc.	Version 18
Others
EORTC QLQ-C30	European Organisation for Research and Treatment of Cancer	Version 3.0
Deposited data
Clinical study data	This study	Not deposited; available upon reasonable request, subject to institutional and ethical approvals

Experimental model and study participant details

Human participants

This was a single-center, open-label, single-arm phase 2 study of chidamide plus cisplatin in patients with recurrent or metastatic adenoid cystic carcinoma. The study was conducted at Fudan University Shanghai Cancer Center. All 24 participants were of Han Chinese ethnicity. The protocol was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center (IRB 1802181-5-1803), and all patients provided written informed consent. The first participant was enrolled on June 6, 2018. Trial registration materials were submitted to ClinicalTrials.gov on August 4, 2018, and the registration record was posted on August 21, 2018 (NCT03639168).

Eligible patients were adults aged 18 to 75 years with histologically confirmed recurrent or metastatic adenoid cystic carcinoma that was not amenable to curative surgery or radiotherapy. Additional eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0 to 2, life expectancy greater than 3 months, at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors, version 1.1, and adequate organ function. Prior platinum-containing therapy was permitted if the interval from the last platinum dose was greater than 6 months or if complete response or partial response had been achieved with the prior platinum regimen. Patients with platinum-refractory disease, defined as progression within 6 months after the last platinum dose without prior complete response or partial response, were excluded. Other key exclusion criteria included prior histone deacetylase inhibitor exposure, inability to take oral medication, uncontrolled infection, clinically significant cardiovascular disease, and pregnancy or lactation.

Twenty-four patients received at least one dose of study treatment and were included in the safety population. Age and sex were recorded and summarized descriptively. The study was not powered to evaluate associations between sex and treatment outcomes, and no sex-based subgroup analysis was performed.

Method details

Study design and endpoints

The primary endpoint was confirmed objective response rate, assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Key secondary endpoints included disease control rate, progression-free survival, overall survival, health-related quality of life, and safety. The efficacy-evaluable population included patients who received at least one dose of study treatment and had at least one post-baseline tumor assessment.

Treatment and dose modifications

Patients received a chidamide lead-in of 30 mg orally twice weekly for 1 week, followed by combination therapy with chidamide 20 mg twice weekly on a 21-day cycle, given for 2 weeks on and 1 week off, plus cisplatin 25 mg/m² intravenously on days 1 to 3. Treatment was planned for up to six cycles, as tolerated.

For grade 4 hematologic toxicity or grade 3 or 4 nonhematologic toxicity, the next cycle was administered with a 20% reduction in cisplatin dose and a 5-mg reduction in chidamide dose. A second dose reduction by the same increments was allowed for recurrent toxicity. Treatment resumed when the absolute neutrophil count was greater than 1.5 × 10⁹/L, platelet count was greater than 75 × 10⁹/L, creatinine clearance was at least 60 mL/min, and nonhematologic toxicities had recovered to grade 1 or lower, with protocol-specified exceptions. Treatment was discontinued for toxicity-related delays longer than 14 days or persistent intolerance after two dose reductions.

Safety assessments

Adverse events were assessed at each treatment cycle and at the end of treatment and were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The safety population included all patients who received at least one dose of any study drug.

Efficacy assessments

Baseline imaging included whole-body positron emission tomography–computed tomography and contrast-enhanced computed tomography and/or magnetic resonance imaging, as clinically appropriate. Tumor assessments were performed every two cycles, approximately every 6 to 8 weeks, and at the end of treatment. Tumor response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors, version 1.1. Complete response or partial response required confirmation at least 4 weeks after the initial documentation of response. After treatment discontinuation, patients were followed every 3 months during years 0 to 2, every 6 months during years 3 to 5, and annually thereafter.

Health-related quality of life

Health-related quality of life was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, version 3.0, at baseline, every two cycles during treatment, and at the end of treatment when available. Scores were calculated according to the European Organisation for Research and Treatment of Cancer scoring manual and linearly transformed to a 0-100 scale. The global health status/quality-of-life scale was analyzed, with higher scores indicating better health-related quality of life. Missing questionnaires, including assessments not completed after treatment discontinuation, were not imputed. The number of available questionnaires was reported at each assessment time point.

Quantification and statistical analysis

Analyses were conducted using PASW Statistics 18 (SPSS Inc., Chicago, IL). Unless otherwise specified, n represents the number of patients. No randomization, stratification, or blinding was performed because this was a single-arm, open-label study.

The study used a single-stage exact binomial design. With an unacceptable objective response rate of 10% and a target objective response rate of 30%, using a one-sided α of 0.05 and 80% power, 20 efficacy-evaluable patients were required. Allowing for approximately 10% attrition, the planned minimum sample size was 22 patients. The null objective response rate threshold was selected on the basis of the historically limited response activity of systemic chemotherapy in adenoid cystic carcinoma, while recognizing heterogeneity across chemotherapy regimens and study populations.

Objective response rate was defined as the proportion of patients achieving complete response or partial response. Disease control rate was defined as the proportion achieving complete response, partial response, or stable disease. Objective response rate and disease control rate were reported with two-sided 95% confidence intervals calculated using the Clopper-Pearson method.

Progression-free survival was defined as the time from first study treatment to radiographic progression or death, whichever occurred first. Overall survival was defined as the time from first study treatment to death from any cause. Patients without a progression-free survival event were censored at the date of last adequate tumor assessment, and patients without an overall survival event were censored at the date they were last known to be alive. Progression-free survival and overall survival were estimated using the Kaplan-Meier method, with medians and 95% confidence intervals reported where estimable. Comparisons in exploratory survival analyses were performed using the log-rank test.

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 global health status scores were summarized as median with interquartile range for observed cases. Changes from baseline at each on-treatment assessment were evaluated using the Wilcoxon matched-pairs signed-rank test among patients with paired baseline and post-baseline assessments. These analyses were descriptive, and no adjustment for multiplicity was performed.

Exploratory Cox proportional hazards analyses were performed to evaluate associations between selected clinical factors and progression-free survival or overall survival, where applicable. These analyses were considered exploratory because of the limited sample size and number of events.

Additional resources

Clinical trial registration: https://clinicaltrials.gov/study/NCT03639168.