Abstract
Background
Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors.
Patients and methods
Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1.
Results
Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response.
Conclusions
The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.
Key words: phase I trial, paclitaxel, TAK-659
Highlights
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TAK-659 was designed to inhibit SYK which is overexpressed as a mechanism of resistance to paclitaxel.
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The combination of paclitaxel and TAK-659 showed a favorable safety profile.
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The combination of paclitaxel and TAK-659 showed preliminary activity in patients with taxane-refractory advanced cancers.
Introduction
Paclitaxel is a commonly used anticancer drug that acts by inhibiting microtubules in dividing cancer cells, thus inducing cell cycle arrest in the G2/M phase.1 Despite initial responses, tumors can frequently become resistant to paclitaxel, which limits the durability of response. Various mechanisms of resistance have been identified in paclitaxel-resistant tumors, including tubulin mutations, MDR1 overexpression, and chromosomal instability.2 More recently, overexpression of spleen tyrosine kinase (SYK) has also been identified as a possible mechanism of resistance to paclitaxel.3 SYK is a cytoplasmic non-receptor tyrosine kinase that is highly expressed in hematopoietic cells and drives several physiologic pathways involved in immune system regulation.4 In addition to its physiologic role, aberrant SYK has been implicated in cell cycle progression and pro-cancer survival in multiple tumor types.4, 5, 6 When paired samples of recurrent and primary ovarian cancer were tested for SYK expression, post-chemotherapy samples showed higher h-scores and more up-regulation of SYK expression. Additionally, paclitaxel-resistant cell lines had higher levels of SYK expression compared to parental cells and the degree of paclitaxel sensitivity was shown to correlate with p-SYK/SYK ratio.3
Several inhibitors of SYK have been discovered, but clinical development has been hampered by high rates of adverse events, likely due to non-selectivity and off-target inhibition.7, 8, 9 Therefore, TAK-659 has been designed with a focus on improving potency and selectivity. Preclinical data suggested that TAK-659 inhibits cellular proliferation in various cell lines,10 and that SYK inactivation enhances microtubule stability in paclitaxel-resistant tumors and potentiates paclitaxel cytotoxicity in vitro and in vivo.3 To the best of our knowledge, the combination of TAK-659 and paclitaxel has not previously been clinically studied, and the use of TAK-659 in patients with advanced solid tumors has not previously been reported.
We designed the current phase I clinical trial (NCT03756818) primarily to define the maximum tolerated dose (MTD) and safety profile of the combination of TAK-659 and paclitaxel. Secondary objectives included evaluating clinical response signals to the combination of TAK-659 and paclitaxel in patients with taxane-refractory tumors and analyzing pharmacokinetic interactions between TAK-659 and paclitaxel.
Patients and methods
We tested the combination of TAK-659 and paclitaxel in eligible participants using a phase I trial design. Our investigator-initiated study was approved by the institutional review board at The University of Texas MD Anderson Cancer Center before starting study-related procedures. All aspects of the study were conducted in accordance with the Declaration of Helsinki and the International Conference of Harmonisation and Good Clinical Practice guidelines.11,12
Eligibility criteria
We included patients aged ≥18 years who were diagnosed with advanced solid tumors that were refractory to standard therapy or had no effective curative-intent standard therapy available at the time of study initiation. All patients had prior taxane-based therapy. Additional inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and the presence of adequate organ and marrow function, defined as neutrophil count ≥1500/μl, platelet count ≥100000/μl, total bilirubin ≤1.5 the upper limit of normal (ULN; except patients with Gilbert syndrome, who needed to have total bilirubin ≤3.0 mg/dl), alanine aminotransferase ≤2.5 the ULN (or ≤5 the ULN in patients with persistent liver metastases), serum creatinine ≤1.5 the ULN (or calculated creatinine clearance ≥45 ml/min by the Cockcroft-Gault method), albumin ≥3.0 g/dl (≥30 g/l), and international normalized ratio (INR) ≤1.4. Patients with clinically significant concurrent medical illnesses, patients with a history of clinically significant allergic reactions to the study drugs or any analogs, and patients who were still recovering from major procedures or traumatic injuries were excluded.
Study design
This was a six-cohort dose-escalation study of daily TAK-659 plus weekly intravenous paclitaxel (either 60 mg/m2 or 80 mg/m2; Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.103486). We used a modified zone-based 3 + 3 design, followed by dose expansion at dose level 4 for further evaluation of toxicity and efficacy. For safety assessment purposes, an additional three patients were allowed per dose level.
Study procedures
The trial was conducted at the Department of Investigational Cancer Therapeutics in The University of Texas MD Anderson Cancer Center. After providing written informed consent, patients received paclitaxel and TAK-659 in 28-day cycles until disease progression or intolerable toxicity. Paclitaxel (60 mg/m2 or 80 mg/m2) was administered to patients via 1-hour intravenous infusion on days 1, 8, and 15. Blood was collected within 24 hours after the start of infusion on day 1 and day 15 of cycle 1 for paclitaxel pharmacokinetic analysis. Participants were administered dexamethasone, diphenhydramine, and cimetidine or ranitidine before their paclitaxel infusions. TAK-659 was administered orally at a dose of 60, 80, or 100 mg/day. Blood was collected within 24 hours after the dose was administered on days 1 and 15 of cycle 1 to determine TAK-659 pharmacokinetics. Patients were followed regularly through clinical examination, and routine laboratory tests were assessed weekly during cycle 1 and then once every subsequent cycle.
Safety assessments
We used the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 to grade the severity of study-related adverse events.13 Safety endpoints of the study included incidence of adverse events, dose-limiting toxicities (DLTs), withdrawals or changes to the treatment regimen (dose delay and dose reduction) due to adverse events, and mortality. Definitions of DLTs are included in Supplementary Methods, available at https://doi.org/10.1016/j.esmoop.2024.103486. The MTD was defined as the dose level at which >33% of patients experienced a DLT in their first treatment cycle.
Efficacy assessment
All patients who received at least one dose of any of the study agents were considered evaluable for efficacy. Patients had restaging scans carried out every 2 cycles (8 weeks) using the same imaging modality that was used during screening. Tumor markers, if applicable, were tested once with each imaging study or more frequently as indicated. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors guidelines (version 1.1; RECIST 1.1).14
Pharmacokinetic and pharmacodynamic analysis
Blood samples for pharmacokinetic analyses of TAK-659 and paclitaxel were drawn on cycle 1 day 1 before the first dose and at 0.5, 1, 2, 4, 8, and 24 hours after dosing. Sample collection was repeated on cycle 1 day 15. Plasma concentrations of paclitaxel and TAK-659 were determined using liquid chromatography-mass spectroscopy. Pharmacokinetic parameters were derived by noncompartmental analysis using PKSolver.
Pharmacokinetic parameters for paclitaxel were estimated using an intravenous infusion input model and included terminal elimination half-life, maximum plasma concentration (Cmax), area under the plasma concentration–time curve from time 0 to the last measurable time point (AUC0-t), area under the plasma concentration–time curve from time 0 to infinity (AUC0-inf), volume of distribution, and clearance. Similar parameters were estimated for TAK-659 using noncompartmental analysis with an extravascular input model. Time when Cmax occurred was also included in these measurements for TAK-659.
Statistical analysis
Statistical analyses were carried out using IBM SPSS Statistics for Windows, version 28 (IBM Corp, Armonk, NY). Time to treatment take-off was defined as the time from treatment start date until date of treatment take-off or last follow-up. Overall survival was defined as the time from treatment start date to date of death or last follow-up. Differences in pharmacokinetic parameters on day 1 versus day 15 were tested using an unpaired t-test in GraphPad Prism version 7.03 software (La Jolla, CA). Likewise, statistically significant differences in mean plasma concentrations of TAK-659 at each time point for day 1 and day 15 were tested using an unpaired t-test. Statistical inferences were based on two-sided t tests at a significance level of P < 0.05.
Results
Patient characteristics
We included 49 patients who were enrolled and received at least one dose of TAK-659 and paclitaxel between 25 March 2019 and 31 December 2021. All patients had prior taxane-based therapy (Table 1). A total of 40 patients were treated during dose escalation and 9 ovarian cancer patients were treated in the dose-expansion phase. The most common cancer types were ovarian cancer (n = 12; 25%), prostate cancer (n = 8; 16%), head and neck cancers (n = 5; 10%), breast cancer (n = 4; 8%), and pancreatic cancers (n = 4; 8%; Table 1). At the time of data cut-off, all 49 patients were taken off the study because of disease progression (n = 37; 76%), withdrawal of consent (n = 4; 8%), physician’s decision (n = 3; 6%), treatment-unrelated death during the study (n = 3; 6%), and intolerance to the study drugs (n = 2; 4%).
Table 1.
Patient demographic and clinical characteristics (n = 49)
| Variable | Result |
|---|---|
| Sex, n (%) | |
| Female | 32 (65) |
| Male | 17 (35) |
| Age, years | |
| Median | 61 |
| Range | 30-78 |
| Race, n (%) | |
| White | 34 (69) |
| Black or African American | 8 (16) |
| Asian | 6 (12) |
| Other | 1 (2) |
| Tumor type, n (%) | |
| Breast | 4 (8) |
| Endometrial | 3 (6) |
| Pancreatic | 4 (8) |
| Sarcoma | 3 (6) |
| Thymic | 2 (4) |
| Cholangiocarcinoma | 2 (4) |
| Head and neck | 5 (10) |
| Prostate | 8 (16) |
| Cervical | 3 (6) |
| Othersa | 3 (6) |
| Ovarian | 12 (25) |
| Prior taxane, n (%) | |
| Paclitaxel | 28 (57) |
| Nab-paclitaxel | 23 (47)b |
| Cabazitaxel | 6 (12)c |
| Docetaxel | 33 (67)d |
Other disease types: uterine carcinosarcoma of unknown origin, esophageal (one case each).
Including 17 patients who also received docetaxel.
Including five patients who also received docetaxel.
Including 3 patients who received paclitaxel, 5 patients who received cabazitaxel, and 17 patients who received nab-paclitaxel.
Safety
All 49 patients who received at least one dose of the study drugs were evaluated for adverse events. There were no treatment-related death events. Six patients (12%) had the dose of TAK-659 reduced including two patients (4%) who needed a second dose reduction of TAK-659. Nine patients (18%) had their paclitaxel dose reduced. Two patients were removed off study because of toxicity. The MTD was not reached in dose escalation.
The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), decreased white blood cell count (n = 26; 53%), increased lipase (n = 23; 47%), increased amylase (n = 22; 45), and anemia (n = 14; 29%). Table 2 shows the most frequent treatment-emergent adverse events. Grade 3 or more events happened in 23 patients (47%). The most common grade 3 or higher adverse events were decreased neutrophil count (n = 7; 14%), elevated lipase (n = 6; 12%), anemia (n = 5; 10%), increased amylase (n = 4; 8%), and decreased white blood cell counts (n = 4; 8%). Higher rates of adverse events were observed at higher dose levels. Only two patients had drug-related serious adverse events.
Table 2.
Treatment-emergent adverse events occurring in at ≥10% of included patients (n = 49)
| Adverse event |
n (%) |
|||
|---|---|---|---|---|
| Grade 1 | Grade 2 | Grade 3 | All grades | |
| Increased aspartate aminotransferase | 31 (63) | 12 (24) | 3 (6) | 43 (88) |
| Increased alanine aminotransferase | 26 (53) | 5 (10) | 1 (2) | 31 (65) |
| Decreased neutrophil count | 20 (41) | 20 (41) | 7 (14) | 26 (54) |
| Decreased white blood cell count | 23 (47) | 18 (37) | 4 (8) | 26 (54) |
| Increased lipase | 21 (43) | 7 (14) | 6 (12) | 26 (54) |
| Increased serum amylase | 19 (39) | 14 (29) | 4 (8) | 23 (48) |
| Anemia | 3 (6) | 9 (18) | 5 (10) | 22 (46) |
| Oral mucositis | 7 (14) | 2 (4) | 0 (0) | 14 (29) |
| Increased alkaline phosphatase | 7 (14) | 0 (0) | 0 (0) | 9 (19) |
| Decreased platelet count | 6 (12) | 3 (6) | 0 (0) | 7 (15) |
| Maculopapular rash | 5 (10) | 2 (4) | 1 (2) | 6 (13) |
Antitumor activity
Five patients were not evaluable by RECIST 1.1 due to lack of restaging imaging; these patients were excluded from the efficacy analysis. Of the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response and 4 (9%) achieved a partial response, thus the disease control rate was 36% (Table 3; Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.103486). Table 3 shows response rates in each dose level and disease type. Objective responses were observed in patients with ovarian cancer (n = 2; both had prior paclitaxel therapy), breast cancer (n = 1; had prior nab-paclitaxel therapy), and head and neck cancer (n = 1; had prior paclitaxel and docetaxel therapy). Of the 12 patients with stable disease, 3 patients (1 with breast cancer and prior docetaxel treatment, 1 with cervical cancer and prior paclitaxel treatment, and 1 with head and neck cancer and prior paclitaxel treatment) had prolonged stable disease that lasted for at least 6 months (Table 3; Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.103486). The median time to treatment take-off was 2 months (95% confidence interval 1.6-2.4 months) and the median overall survival was 6 months (95% confidence interval 3.5-8.5 months).
Table 3.
Best overall response in 49 treated patients
| Variable | Not evaluable | PD | PR | SD | Total |
|---|---|---|---|---|---|
| Tumor type, n | |||||
| Breast | 1 | 1 | 1 | 1a | 4 |
| Cervical | 1 | 0 | 0 | 2a | 3 |
| Cholangiocarcinoma | 0 | 2 | 0 | 0 | 2 |
| Endometrial | 0 | 3 | 0 | 0 | 3 |
| Head and neck | 0 | 2 | 1 | 2a | 5 |
| Others | 1 | 2 | 0 | 0 | 3 |
| Ovarian | 1 | 6 | 2 | 3 | 12 |
| Pancreatic | 1 | 3 | 0 | 0 | 4 |
| Prostate | 0 | 4 | 0 | 4 | 8 |
| Sarcoma | 0 | 3 | 0 | 0 | 3 |
| Thymic | 0 | 2 | 0 | 0 | 2 |
| Dose level, n | |||||
Dose level 1
|
1 | 4 | 0 | 1a | 6 |
Dose level 2A
|
0 | 3 | 2 | 0 | 5 |
Dose level 2B
|
0 | 4 | 0 | 2 | 6 |
Dose level 3A
|
1 | 5 | 0 | 2a | 8 |
Dose level 3B
|
2 | 4 | 1 | 1 | 8 |
Dose level 4
|
1 | 8 | 1 | 6a | 16 |
| Total, n | 5 | 28 | 4 | 12 | 49 |
PD, progressive disease; PR, partial response; SD, stable disease.
SD ≥6 months in one patient.
Pharmacokinetic analyses of TAK-659 and paclitaxel interaction
For patients given paclitaxel at a dose of 60 mg/m2, there was a statistically significant increase in AUC0-t and AUC0-inf from day 1 to day 15. There was also a trend for decrease in the volume of distribution and clearance from day 1 to day 15. Compared with cycle 1 day 1, patients who were administered paclitaxel at 60 mg/m2 on cycle 1 day 15 exhibited an ∼28% increase in exposure (AUC) and an ∼20% reduction in clearance. However, for patients receiving the higher dose (80 mg/m2), no statistical differences in any pharmacokinetic parameters between day 1 and day 15 were observed (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2024.103486).
Patients receiving TAK-659 at a dose of 60 mg, 80 mg, or 100 mg exhibited a statistically significant increase in AUC0-t and AUC0-inf from day 1 to day 15. There was a significant elevation of Cmax at day 15 for the 80-mg and 100-mg dosing cohorts. Among all TAK-659 dosing cohorts, the volume of distribution and clearance both decreased between day 1 and day 15, but these results were statistically significant only in the 60-mg dosing cohort. Furthermore, in the 60-mg dosing cohort, there was a 41% increase in terminal elimination half-life, but this was determined not to be statistically significant (P = 0.1650; Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2024.103486).
Statistical analysis of the grouped concentration–time plots revealed several significant differences in averaged concentrations of TAK-659 between day 1 and day 15. For patients administered TAK-659 60 mg, there was a statistically significant increase in TAK-659 concentrations at 0.5 h from day 1 to day 15. For patients administered TAK-659 80 mg, there was a statistically significant increase at 8 h from day 1 to day 15, and for the 100-mg dosing group, there were statistically significant increases at 4 h and 8 h from day 1 to day 15 (Figure 1).
Figure 1.
Mean (±standard deviation) plasma concentration–time profiles of TAK-659 following administration of 60 mg (top), 80 mg (middle), or 100 mg (bottom) to patients on cycle 1 day 1 (black line) and cycle 1 day 15 (blue line). ∗P < 0.05; ∗∗P < 0.01.
Patients had, on average, higher plasma concentrations of TAK-659 at day 15 compared with day 1 (Figure 1). These increased concentrations generally manifested as elevated exposure (AUC) and Cmax. Of note, TAK-659 AUC0-t significantly increased from day 1 to day 15 by 40%, 66%, and 91% in the 60-mg, 80-mg, and 100-mg dosing groups, respectively. TAK-659 clearance decreased by 36%, 31%, and 46% from day 1 to day 15 in the 60-mg, 80-mg, and 100-mg dosing groups, respectively.
Discussion
In the current study, we have explored the possible use of combined paclitaxel and TAK-659, a SYK inhibitor, in patients with advanced solid cancers. TAK-659 was hypothesized to sensitize SYK-dependent paclitaxel-resistant malignant clones to treatment with paclitaxel, possibly leading to clinical benefit in patients with advanced solid tumors. The primary objective of the current study was to evaluate the safety and MTD of combined TAK-659 and paclitaxel. Secondary objectives included the assessment of efficacy and pharmacokinetic properties of both drugs.
Our data showed that the combination of TAK-659 and paclitaxel generally had a tolerable safety profile, with few patients requiring dose modifications or treatment cessation. Throughout the course of the study, increasing doses of TAK-659 resulted in increased rates of adverse events, and most adverse events occurred at dose level 4 (100 mg oral TAK-659 + 80 mg/m2 intravenous paclitaxel). Overall, we were not able to determine MTD due to the small number of patients experiencing DLTs. This was similarly the case in a phase I trial of TAK-659 monotherapy in patients with acute myeloid leukemia (AML), where MTD was not reached at doses of up to 160 mg daily.15 However, another phase I trial of TAK-659 in patients with B-cell lymphoma suggested an MTD of 100 mg once daily.16 This aligns with our findings that a dose above 80 mg of oral TAK-659 is more likely to cause adverse events, and doses higher than this should plausibly be avoided in future studies. The recommended phase II dose of TAK-659 is 80 mg daily.
In the current study, the most common treatment-related adverse events were increased aspartate aminotransferase, increased alanine aminotransferase, decreased neutrophil count, and decreased white blood cell count. Most treatment-related toxicities were either grade 1 or 2, and were quite manageable. This is consistent with data from trials in the hematology field, in which most treatment-related adverse events were asymptomatic with reversible laboratory abnormalities.16,17 However, in a trial done in AML, there was an increased risk of bleeding in patients receiving TAK-659, likely due to thrombocytopenia in the context of platelet dysfunction in patients with AML.15 In preclinical studies, the use of TAK-659 along with other SYK inhibitors led to central dysregulation of platelet functional responses, which could explain the possible increase in bleeding events in AML.18 In the current study, treatment-emergent thrombocytopenia of any grade was reported in 15% of patients, with no grade 3 events or toxicity-related bleeding. Therefore, the likelihood of complicated thrombocytopenia in solid tumors appears relatively low based on our preliminary data, although this will need to be validated in larger phase II trials.
Clinical benefit was observed in patients with ovarian, prostate, breast, cervical, and head and neck cancers. In patients with evaluable disease, the disease control rate was 36% and the objective response rate was 9%. In addition, three patients had prolonged stable disease that lasted for over 6 months, which remains clinically meaningful in the context of prior resistance to taxane-based therapy. Various tumor types were included in the study, and hence definitive conclusions on differential activity according to cancer site of origin cannot be reached. To the best of our knowledge, this is the first clinical trial to report the clinical activity of TAK-659 in solid tumors. Prior trials in patients with diffuse large B-cell lymphoma and AML showed promising results.15, 16, 17,19 Although preliminary data from our study suggest signals of activity, larger phase II trials are needed for validation of these findings.
Since TAK-659 and paclitaxel have overlapping elimination mechanisms (e.g. both are substrates for CYP3A41, 2, a major drug metabolizing enzyme), there could be a potential for a pharmacokinetic-based drug interaction. Based on our pharmacokinetic analysis, patients administered paclitaxel 60 mg/m2 on day 15 exhibited an ∼28% increase in exposure (AUC) and a trend for reduced clearance compared to cycle 1 day 1; however, these findings were not observed in the higher dose group (80 mg/m2). Based on this pharmacokinetics evaluation, it is possible that a drug interaction occurs, albeit modest, resulting in a decreased clearance of paclitaxel from the body and greater accumulation of paclitaxel, which needs to be validated in further studies. Patients administered TAK-659, on average, had higher plasma concentrations at day 15 compared to day 1, as evidenced by the concentration–time plots. This generally manifested as an increase in exposure (AUC) and in some cases Cmax. Notably, TAK-659 AUC0-t significantly increased from day 1 to day 15 by 40%, 66%, and 91% in the 60-mg, 80-mg, and 100-mg dosing groups, respectively. It is unclear if the observed rise in exposure is due to a predictable accumulation before steady-state TAK-659 concentrations are achieved, drug–drug interaction, or a combination of both. TAK-659 clearance decreased by 36%, 31%, and 46% from day 1 to day 15 in the 60-mg, 80-mg, and 100-mg dosing groups, respectively. Statistical significance was only achieved in the 60-mg group, which may be due in part to missing pharmacokinetic data from several patients in the 80-mg and 100-mg dosing cohorts because a 24-hour blood draw level was not available for analysis. Nonetheless, the combined increase in TAK-659 AUC and decrease in TAK-659 clearance are suggestive that a drug interaction occurs when paclitaxel and TAK-659 are co-administered. Due to the inherent limitations of a phase I study, further research is needed to corroborate this finding.
In summary, combined paclitaxel and TAK-659 showed preliminary efficacy in patients with taxane-refractory tumors. Due to the small sample size, results should be interpreted with caution despite data suggesting a tolerable safety profile. The study population was not enriched for SYK overexpression, and it would be interesting in future studies to explore SYK overexpression as a biomarker for efficacy in similar settings. However, signals of efficacy, including stable disease, prolonged stable disease, and partial responses, were observed in several patients which is promising.
Acknowledgements
The authors thank the patients for their participation in this clinical trial, and Erica Goodoff, Senior Scientific Editor in the Research Medical Library at The University of Texas MD Anderson Cancer Center, for editing this manuscript.
Funding
This work was supported by Takeda Pharmaceuticals, Cancer Center Support Grant (CCSG) (grant number: P30CA016672), and Clinical and Translational Sciences Award (CTSA) (grant number: UL1TR003167).
Disclosure
AN reports research funding from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, Immune-Onc Therapeutics, Surface Oncology, Monopteros Therapeutics, BioNTech SE, Seven & Eight Biopharma, and SOTIO Biotech AG; being on advisory board/receiving consulting fees from CTI, Deka Biosciences, Janssen Biotech, NGM Bio, PsiOxus Therapeutics, Immune-Onc Therapeutics, STCube Pharmaceuticals, OncoSec KEYNOTE-695, Genome & Company, CytomX Therapeutics, Nouscom, Merck Sharp & Dohme Corp, Servier, Lynx Health, AbbVie, PsiOxus; travel and accommodation expense from ARMO BioSciences, NeoImmuneTech, NGM Biopharmaceuticals; honoraria for speaking engagements from AKH Inc., The Lynx Group, Society for Immunotherapy of Cancer (SITC), Korean Society of Medical Oncology (KSMO), Scripps Cancer Care Symposium, ASCO Direct Oncology Highlights, European Society for Medical Oncology (ESMO), CME Outfitters. JR reports non-financial support and reasonable reimbursement for travel from European Society for Medical Oncology and Loxo Oncology; receiving consulting and travel fees from Ellipses Pharma, Molecular Partners, IONCTURA, Sardona, Mekanistic, Amgen, Merus, MonteRosa, Aadi and Bridgebio (including serving on the scientific advisory board); consulting fees from Vall d’Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC and Guidepoint; receiving research funding from Blueprint Medicines, Merck Sharp & Dohme, Hummingbird, AstraZeneca, Yingli, Vall d’Hebron Institute of Oncology/Cancer Core Europe; and serving as investigator in clinical trials with Cancer Core Europe, Symphogen, BioAlta, Pfizer, Kelun-Biotech, GlaxoSmithKline, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bicycle Therapeutics, Merus, AadiBioscience, ForeBio, Loxo Oncology, Hutchinson MediPharma, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, MonteRosa, Kinnate, Yingli, Debio, BioTheryX, Storm Therapeutics, Beigene, MapKure, Relay, Novartis, FusionPharma, C4 Therapeutics, Scorpion Therapeutics, Incyte, Fog Pharmaceuticals, Tyra, Nuvectis Pharma. SAP reports clinical trial research support/grant funding through the institution from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc, Alkermes, Aminex Therapeutics, BioMarin Pharmaceutical, Inc, Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd, Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Epigenetix Inc., Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Gene Quantum, Genmab A/S, Gilead Sciences, Inc., GlaxoSmithKline, Helix BioPharma Corp., Hengrui Pharmaceuticals, Co., Ltd., HiberCell, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Jiangsu Simcere Pharmaceutical Co., Ltd., Loxo Oncology, Inc., Lytix Biopharma AS, Medimmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Nectin Therapeutics, Ltd., Novartis Pharmaceuticals, Nurix, Pieris Pharmaceuticals, Inc., Pfizer, Phanes Therapeutics, Principia Biopharma, Inc., Puma Biotechnology, Inc., Purinomia Biotech, Inc., Rapt Therapeutics, Inc., Replimune; Roche/Blueprint, Seattle Genetics, Silverback Therapeutics, Shasqi, Inc., Synlogic Therapeutics, Taiho Oncology, Tesaro, Inc., Theradex Oncology, Toragen Therapeutics, Inc., TransThera Bio, Xencor, Inc, ZielBio, Inc., NCI/NIH, P30CA016672—Core Grant (CCSG Shared Resources); and working as a consultant for CRC Oncology. FMB reports consulting for AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., Calibr (a division of Scripps Research), DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., GT Apeiron, Genentech Inc., Harbinger Health, IBM Watson, Incyte, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, LegoChem Bio, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks; advisory Committee membership for Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Theratechnologies, Zentalis; Sponsored Research (to the institution) from Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.; Honoraria from Dava Oncology; and other (travel related) from European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO), Cholangiocarcinoma Foundation, Dava Oncology. SF receives clinical trial research support/grant funding through the institution from NIH/NCI P30CA016672—Core Grant (CCSG Shared Resources); Abbisko, Antengene, BeiGene, BeyongSpring Pharmaceuticals, Inc., BioAtla, LLC., Boehringer Ingelheim, CUE Biopharma, Inc., DEKA Biosciences, Eli Lilly & Co., Exelixis, Greenfire Bio, Inc., Hookipa Biotech, IMV, Inc., Innovent Biologics, Co., Ltd., Jazz Pharmaceuticlals, K-Group Beta, Lantern Pharma Inc., Lyvgen Biopharm, Co., Ltd., MacroGenics, MediLink Therapeutics, Co. Ltd., Millennium Pharmaceuticals, Inc., Nerviano Medical Sciences, NeuPharma, Inc., NextCure, Inc., Ningbo NewBay Technology Development Co., Ltd., Novartis, NovoCure, Nykode Therapeutics AS., Parexel International, LLC, PharmaMar USA, Inc., Pionyr Immunotherapeutics, Inc., PureTech Health, LLC, Qurgen, Inc., Shanghai Huaota Biopharmaceutical Co., Ltd., Sellas Life Sciences Group, Soricimed Biopharma, Inc., SQZ Biotechnologies, Sumitomo Dainippon, Taiho Oncology and NCCN, Treadwell Therapeutics, Turnstone Biologics, Tyligand Bioscience, Ltd., Virogin Biotech, Ltd. All other authors have declared no conflicts of interest.
Supplementary data
References
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