Abstract
Lessons Learned
SCB01A is a novel microtubule inhibitor with vascular disrupting activity.
This first‐in‐human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity.
SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.
Background
SCB01A, a novel microtubule inhibitor, has vascular disrupting activity.
Methods
In this phase I dose‐escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m2 to the maximum tolerated dose (MTD) based on dose‐limiting toxicity (DLT). SCB01A‐induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints.
Results
Treatment‐related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m2 cohort; grade 3 gastric hemorrhage in the 6.5 mg/m2 cohort; grade 2 thromboembolic event in the 24 mg/m2 cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m2 cohort. The MTD was 24 mg/m2, and average half‐life was ~2.5 hours. The area under the curve‐dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A‐induced neurotoxicity was reversible in vitro.
Conclusion
The MTD of SCB01A was 24 mg/m2 every 21 days; it is safe and tolerable in patients with solid tumors.
Keywords: SCB01A, Microtubule inhibitor, Solid tumor
Discussion
SCB01A is a novel heterocyclic combretastatin A‐4 analog that inhibits tubulin polymerization by attaching to its colchicine‐binding site [1, 2, 3]. This phase I trial aimed to determine the MTD, DLT, safety, preliminary anticancer efficacy, and PK of SCB01A in subjects with advanced solid tumors.
All patients, except one, had measurable lesions. Objective response measurements at the end of the main study revealed that 57.6% (19/33) and 42.4% (14/33) of the subjects had stable disease (SD) and progressive disease (PD), respectively. Tumor response assessment showed no new lesions in 72.7% (24/33) of the subjects (Fig. 1).
Figure 1.
Duration of progression‐free survival stratified by tumor assessments of study subjects at the end of study.Abbreviation: PFS, progression‐free survival.
In the extension study, progression‐free survival was observed in patients with cholangiocarcinoma, laryngeal, buccal, colorectal, and thyroid cancers in the 4 mg/m2 cohort (508 days*), 24 mg/m2 cohort (349 days), 3 mg/m2 cohort (335 days), 4 mg/m2 cohort (330 days), and 16 mg/m2 cohort (224 and 122 days). SD was observed in patients with esophageal cancer (in 10, 24, and 6.5 mg/m2 cohorts at 96, 92, and 86 days, respectively); lung cancer (6.5 mg/m2 cohort; 91 days); cholangiocarcinoma (6.5 mg/m2 cohort; 90 days); and soft tissue sarcoma (10 mg/m2 cohort; 90 days). *Calculated as Main plus Extension study period.
A patient with buccal cancer in the 4 mg/m2 cohort showed a partial response with 46.35% tumor size reduction (Figure 2). Tumor shrinkage was also observed in patients with colorectal cancer (3 and 16 mg/m2 cohorts; 13.65%* and 12.34%) and patients with cholangiocarcinoma (4 mg/m2; 9.75%), laryngeal cancer (24 mg/m2; 6.64%), thyroid cancer (6.5 mg/m2; 5.99%), and pancreatic cancer (4 mg/m2; 5.59%). *Tumor shrinkage rate.
Figure 2.
Best overall response (change in target lesion from baseline) of study subjects.Note: Target lesion for one subject was not measurable.
Six episodes of DLTs were reported in five patients: grade 4 CPK increase (4 mg/m2 cohort; one DLT; cohort size increased to six patients); grade 3 gastric hemorrhage (6.5 mg/m2; one DLT; this patient had continuous gastric bleeding and died, and thus members of the data and safety monitoring board requested enrollment of three additional subjects for safety because of the potential of vascular disrupting agents to induce vascular toxicity); grade 2 thromboembolic event (24 mg/m2; one DLT); grade 3 peripheral sensorimotor neuropathy manifested as lower limb muscle weakness (32 mg/m2); grade 3 aspartate aminotransferase increase; and grade 3 hypertension (32 mg/m2).
Trial Information
| Disease | Advanced cancer/solid tumor only |
| Stage of Disease/Treatment | Metastatic/advanced |
| Prior Therapy | No designated number of regimens |
| Type of Study | Phase I, 3 + 3 |
| Primary Endpoints | Maximum tolerated dose, recommended phase II dose, dose‐limiting toxicity |
| Secondary Endpoints | Safety, efficacy, pharmacokinetics, progression‐free survival |
| Additional Details of Endpoints or Study Design | |
| Patient eligibility: Patients aged ≥18 years with malignant solid tumors who failed to respond to all conventional and standard therapies were eligible. Patients were excluded if they had been treated with drugs metabolized by CYP1A2 or CYP2D6 in the past 3 weeks, had a history of exposure to SCB01A or its analogs, or had significant cardiopulmonary disease, brain or central nervous system tumors, or other poorly controlled systemic diseases. | |
| Study design: This was an open‐label, single‐arm dose‐escalation study. The main study comprised rapid titration, followed by a 3 + 3 study design of two SCB01A treatment cycles. An extension study was conducted for subjects who completed the main study. Patients received 3‐hour intravenous infusion of SCB01A at doses of 2, 3, 4, 6.5, 10, 16, 24, and 32 mg/m2 starting from day 1 of a 21‐day treatment cycle until disease progression, intolerable drug‐related toxicity, or consent withdrawal by subject. Subjects considered to benefit from the treatment were allowed to continue the treatment in the extension study phase at the discretion of the physician in charge. | |
| Dose escalation or de‐escalation was based on the occurrence of treatment‐related adverse events (AEs) during the treatment cycles. All AEs were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. If one patient experienced DLT, then the cohort was increased to six patients. If no other patient experienced any DLT, the next dose level was evaluated. If two or more patients in a cohort experienced DLTs, the previous dose level was designated as the MTD. Subjects experiencing DLTs were permanently discontinued from the study. The recommended dose for a future phase II study will be at or below the MTD based on safety and PK data. | |
| Pharmacokinetics: Plasma samples collected during cycles 1 and 2; prior to infusion; and at 30 minutes and 1, 2, 2.5, 3, 3.5, 4, 6, 10, 21, and 24 hours after the start of infusion were assayed for SCB01A by validated methods (unpublished data) and PK parameters based on a noncompartmental model. | |
| Statistical analysis: The GraphPad PRISM software program was used for analyses. The waterfall plot was used to analyze the duration of progression‐free survival (PFS). The quantitative results are expressed as median and range. | |
| Investigator's Analysis | Drug tolerable, efficacy indeterminant |
Drug Information
| Generic/Working Name | SCB01A |
| Company Name | SynCore Biotechnology Co. Ltd |
| Drug Type | Small molecule |
| Drug Class | Microtubule‐targeting agent |
| Dose | 2, 3, 4, 6.5, 10, 16, 24, and 32 milligrams (mg) per squared meter (m2) |
| Route | i.v. |
| Schedule of Administration | SCB01A was administered via intravenous infusion once per 3 weeks. |
Dose‐Escalation Table
| Dose level | Dose of drug: SCB01A | Number enrolled | Number evaluable for toxicity |
|---|---|---|---|
| Main study | |||
| 1 | 2 | 1 | 1 |
| 2 | 3 | 1 | 1 |
| 3 | 4 | 6 | 6 |
| 4 | 6.5 | 9 | 9 |
| 5 | 10 | 3 | 3 |
| 6 | 16 | 3 | 3 |
| 7 | 24 | 6 | 6 |
| 8 | 32 | 4 | 4 |
| Total | 33 | 33 | |
| Extension study | |||
| 1 | 2 | 1 | 1 |
| 2 | 3 | 1 | 1 |
| 3 | 4 | 1 | 1 |
| 4 | 6.5 | 4 | 4 |
| 5 | 10 | 2 | 2 |
| 6 | 16 | 1 | 1 |
| 7 | 24 | 2 | 2 |
| 8 | 32 | ||
| Total | 12 | 12 | |
Patient Characteristics
| Number of Patients, Male | 25 (75.8% of study enrollees were male) |
| Number of Patients, Female | 8 |
| Age | Median (range): 56.4 (40.6–74.2) years |
| Performance Status: ECOG |
0 — 17 (51.5) 1 — 16 (48.5) |
| Cancer Types or Histologic Subtypes |
Esophageal cancer, 8 (24.2) Colorectal cancer, 7 (21.2) Cholangiocarcinoma, 6 (18.2) Thyroid cancer, 3 (9.1) Head and neck cancer, 3 (9.1) Lung cancer, 1 (3.0) Nasopharyngeal cancer, 1 (3.0) Pancreatic cancer, 1 (3.0) Soft tissue sarcoma, 1 (3.0) Neuroendocrine carcinoma, 1 (3.0) Pancreatic neuroendocrine tumor, 1 (3.0) |
Primary Assessment Method
| Number of Patients Screened | 54 |
| Number of Patients Enrolled | 33 |
| Number of Patients Evaluable for Toxicity | 33 |
| Number of Patients Evaluated for Efficacy | 33 |
| Evaluation Method | RECIST 1.1 |
| Response Assessment SD | n = 19 (57.6%) |
| Response Assessment PD | n = 14 (42.4%) |
| (Median) Duration Assessments PFS | 43 days; confidence interval, 41–90 |
Adverse Events
Table 2.
Summary of major incidence (>10%) or severity (grade ≥ 3) of treatment‐related adverse events and dose‐limiting toxicities in the main study (by subject)
| Adverse event | Dose level | Total (n = 33) | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2 mg/m2 (n = 1) | 3 mg/m2 (n = 1) | 4 mg/m2 (n = 6) | 6.5 mg/m2 (n = 9) | 16 mg/m2 (n = 3) | 24 mg/m2 (n = 6) | 32 mg/m2 (n = 4) | ||||||||||
| Grade | Grade | Grade | Grade | Grade | Grade | Grade | Grade | |||||||||
| 1–2 | 3–4 | 1–2 | 3–4 | 1–2 | 3–4 | 1–2 | 3–4 | 1–2 | 3–4 | 1–2 | 3–4 | 1–2 | 3–4 | 1–2 | 3–4 | |
| Anemia | 1 | 2 | 1 | 1 | 4 | 1 | ||||||||||
| Gastric hemorrhage | 1 a | 1 | 2 | |||||||||||||
| Nausea | 1 | 1 | 1 | 1 | 3 | 7 | ||||||||||
| Mucositis oral | 1 | 1 | 1 | 1 | ||||||||||||
| Vomiting | 1 | 1 | 2 | 2 | 3 | 3 | ||||||||||
| Fatigue | 1 | 2 | 3 | 6 | ||||||||||||
| Fever | 3 | 1 | 3 | 7 | ||||||||||||
| Cranial nerve infection | 1 | 1 | ||||||||||||||
| Peritoneal infection | 1 | 1 | ||||||||||||||
| Sepsis | 1 | 1 | ||||||||||||||
| ALT increase | 2 | 2 | 4 | |||||||||||||
| AST increase | 1 | 1 a | 1 | 1 | ||||||||||||
| CPK increase | 1 a | 1 | 1 | 2 | 1 | |||||||||||
| Platelet count decrease | 1 | 1 | ||||||||||||||
| Back pain | 1 | 1 | ||||||||||||||
| Peripheral sensorimotor neuropathy | 1 | 2 | 1 | 1 a | 4 | 1 | ||||||||||
| Hypophosphatemia | 1 | 1 | ||||||||||||||
| Thromboembolic event | 1 a | 1 | ||||||||||||||
| Hypertension | 1 a | 1 | ||||||||||||||
Note: Subjects in the 10 mg/m2 dose group (n = 3) did not experience treatment‐related adverse events.
Adverse event is indicated as dose‐limiting toxicity.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase.
Table 3.
Summary of treatment‐related adverse events and severity (grade ≥ 3) in the extension study (by subject)
| Adverse Events | Dose level | Total (n = 12) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 3 mg/m2 (n = 1) | 4 mg/m2 (n = 3) | 6.5 mg/m2 (n = 3) | 10 mg/m2 (n = 2) | 24 mg/m2 (n = 2) | ||||||||
| Grade | Grade | Grade | Grade | Grade | Grade | |||||||
| 1–2 | 3–4 | 1–2 | 3–4 | 1–2 | 3–4 | 1–2 | 3–4 | 1–2 | 3–4 | 1–2 | 3–4 | |
| Nausea | 1 | 1 | ||||||||||
| Esophageal pain | 1 | 1 | ||||||||||
| Vomiting | 1 | 1 | 1 | 1 | ||||||||
| Fatigue | 1 | 1 | ||||||||||
| Edema trunk | 1 | 1 | ||||||||||
| Fever | 1 | 1 | ||||||||||
| Chills | 1 | 1 | ||||||||||
| Rash maculo‐papular | 1 | 1 | 2 | |||||||||
| Radiation recall reaction | 1 | 1 | ||||||||||
| ALP increase | 1 | 1 | ||||||||||
| ECG QT corrected interval prolonged | 1 | 1 | ||||||||||
| GGT increase | 1 | 1 | ||||||||||
| Pain in extremities | 1 | 1 | ||||||||||
| Hyperglycemia | 1 | 1 | ||||||||||
| Hypertriglyceridemia | 1 | 1 | ||||||||||
| Hyperuricemia | 1 | 1 | ||||||||||
| Glycosuria | 1 | 1 | ||||||||||
| Cough | 1 | 1 | ||||||||||
| Pharyngolaryngeal pain | 1 | 1 | ||||||||||
Note: Subjects in the 16 mg/m2 dose group (n = 1) did not experience treatment‐related adverse events.
Abbreviations: ALP, alkaline phosphatase; ECG, electrocardiogram; GGT, γ‐glutamyltransferase.
Dose‐Limiting Toxicities
| Dose level | Number enrolled | Number evaluable for toxicity | Number with a dose‐limiting toxicity | Dose‐limiting toxicity information |
|---|---|---|---|---|
| 2 | 1 | 1 | ||
| 3 | 1 | 1 | ||
| 4 | 6 | 6 | 1 | G4 CPK increase |
| 6.5 | 9 | 9 | 1 | G3 gastric hemorrhage |
| 10 | 3 | 3 | ||
| 16 | 3 | 3 | ||
| 24 | 6 | 6 | 1 | G2 thromboembolic event |
| 32 | 4 | 4 | 3 |
G3 AST increase G3 peripheral sensorimotor neuropathy G3 hypertension |
Abbreviations: AST, aspartate aminotransferase; CPK, creatine phosphokinase; G, grade.
Pharmacokinetics/Pharmacodynamics
| Dose (mg/m2) | Patient number | C max (ng/mL) | AUC (ng*h/mL) | CL (L/h/m2) | t 1/2 (h) | V d (L) |
|---|---|---|---|---|---|---|
| 2 | 1 | 27.2 | 92.2 | 20.8 | 0.8 | 24.5 |
| 3 | 1 | 57.4 | 327.0 | 9.1 | 3.3 | 41.6 |
| 4 | 6 | 56.7 ± 9.9 | 219.4 ± 55.5 | 17.9 ± 3.9 | 1.9 ± 0.4 | 49.1 ± 13.1 |
| 6.5 | 9 | 94.3 ± 18.5 | 481.3 ± 214.2 | 15.0 ± 5.1 | 2.8 ± 1.3 | 51.5 ± 9.5 |
| 10 | 3 | 90.1 ± 25.5 | 436.6 ± 263.2 | 28.4 ± 15.1 | 1.6 ± 0.7 | 56.1 ± 14.2 |
| 16 | 3 | 217.7 ± 100.0 | 1,350.5 ± 1,296.2 | 19.2 ± 12.2 | 2.8 ± 2.3 | 50.1 ± 10.9 |
| 24 | 6 | 355.0 ± 140.3 | 2,003.5 ± 1,154.8 | 14.7 ± 6.2 | 2.5 ± 1.1 | 44.3 ± 6.6 |
| 32 | 4 | 362.3 ± 69.3 | 2,362.2 ± 709.7 | 14.3 ± 3.4 | 3.0 ± 0.8 | 59.2 ± 2.9 |
Data are presented as mean ± SD. See also Table 1: Pharmacokinetic parameters after a 3‐hour SCB01A infusion in two cycles.
Abbreviations: AUC, area under the curve up to a measurable time point; CL, clearance; C max, maximum concentration; t 1/2, half‐life; V d, distribution volume at terminal phase.
Assessment, Analysis, and Discussion
| Completion | Study completed |
| Investigator's Assessment | Drug tolerable, efficacy indeterminant |
Vascular disrupting agents (VDAs) target established tumor vasculature and induce acute and marked blood supply shutdown leading to tumor ischemia and necrosis [4, 5, 6]. Current VDA monotherapy causes significant solid tumor necrosis but has limited effects on tumor growth. Tumor growth retardation or prevention or angiogenesis inhibition in surviving tumor cells may improve clinical outcomes. VDAs bind to tubulin and cause microtubule depolymerization, cytoskeletal rearrangements, and actin stress fiber activation in endothelial cells, thereby changing cell morphology and leading to vascular shutdown [7, 8, 9, 10, 11].
In vitro and in vivo antitumor activity, pharmacological, and pharmacokinetic (PK) studies were conducted to characterize the effects of SCB01A [12, 13, 14, 15, 16, 17]. Table 1 shows PK parameters after a 3‐hour SCB01A infusion in two treatment cycles. The PK profile of SCB01A revealed a linear maximum plasma concentration (C max) and area under the curve (AUC)–dose response. The elimination half‐life (t 1/2) of SCB01A was approximately 2.5 (0.8–3.3) hours, and the t 1/2 of metabolites BPR0L082 and BPR0L119 was 7–9 hours (data not shown). Two‐way analysis of variance showed no statistical differences in PK of each dose group between cycles 1 and 2 (n = 1–9; p > .05) [18]. There was dose dependence over 2–32 mg/m2 and no evidence of drug saturation. Clearance and volume of distribution were relatively constant across this dose range (Fig. 3). Safety data showed that 72.7% of the subjects (24/33) experienced treatment‐related adverse events (AEs) and treatment‐independent AEs at 10 mg/m2. Twenty‐nine episodes of serious AEs (SAEs) (treatment‐related or not) occurred in the 4, 6.5, 10, 24, and 32 mg/m2 cohorts (39.4% [13/33] of all subjects). The most common SAEs were coded under the primary System Organ Class of Infections and Infestations, followed by Gastrointestinal Disorders. The remaining categories were observed in <10% of the subjects.
Table 1.
Pharmacokinetic parameters after a 3‐hour SCB01A infusion in two cycles
| Dose (mg/m2) | Patient number | C max (ng/mL) | AUC (ng*h/mL) | CL (L/h/m2) | t 1/2 (h) | V d (L) |
|---|---|---|---|---|---|---|
| 2 | 1 | 27.2 | 92.2 | 20.8 | 0.8 | 24.5 |
| 3 | 1 | 57.4 | 327.0 | 9.1 | 3.3 | 41.6 |
| 4 | 6 | 56.7 ± 9.9 | 219.4 ± 55.5 | 17.9 ± 3.9 | 1.9 ± 0.4 | 49.1 ± 13.1 |
| 6.5 | 9 | 94.3 ± 18.5 | 481.3 ± 214.2 | 15.0 ± 5.1 | 2.8 ± 1.3 | 51.5 ± 9.5 |
| 10 | 3 | 90.1 ± 25.5 | 436.6 ± 263.2 | 28.4 ± 15.1 | 1.6 ± 0.7 | 56.1 ± 14.2 |
| 16 | 3 | 217.7 ± 100.0 | 1,350.5 ± 1,296.2 | 19.2 ± 12.2 | 2.8 ± 2.3 | 50.1 ± 10.9 |
| 24 | 6 | 355.0 ± 140.3 | 2,003.5 ± 1,154.8 | 14.7 ± 6.2 | 2.5 ± 1.1 | 44.3 ± 6.6 |
| 32 | 4 | 362.3 ± 69.3 | 2,362.2 ± 709.7 | 14.3 ± 3.4 | 3.0 ± 0.8 | 59.2 ± 2.9 |
Data are presented as mean ± SD.
Abbreviations: AUC, area under the curve up to a measurable time point; CL, clearance; C max, maximum concentration; t 1/2, half‐life; V d, distribution volume at terminal phase.
Figure 3.
PK profile of SCB01A. (A): Plasma concentration‐time profiles of SCB01A. (B): Maximum plasma concentration of SCB01A. (C): Area under the curve of SCB01A.Abbreviations: AUC, area under the curve; Cmax, maximum plasma concentration.
Regarding AE severity, creatine phosphokinase increased in one subject in the 4 mg/m2 cohort, which was considered probably treatment related and life‐threatening or disabling (grade 4 event). The first death occurred in the 6.5 mg/m2 cohort owing to sepsis, which was unlikely to have been a treatment‐related AE. The second death occurred in the 32 mg/m2 cohort owing to sepsis, which was possibly a treatment‐related AE, during the first cycle. Three other subjects required dosage modification. One subject in the 24 mg/m2 cohort experienced a possibly treatment‐related thromboembolic event, leading to SCB01A discontinuation. Two subjects from the 32 mg/m2 cohort experienced SAEs, leading to SCB01A discontinuation. The SAE observed in one patient (peripheral sensorimotor neuropathy) was probably treatment related, and that observed in the other patient (hypertension) was definitely treatment related (Table 2).
Twelve of the 13 subjects who provided consent and entered the extension study were enrolled. No deaths or life‐threatening AEs were reported. Eleven SAEs were reported in 58.3% (7/12) of the subjects. Three events of grade ≥ 3 severity were considered treatment related (Table 3).
Peripheral sensorimotor neuropathy events (including one dose‐limiting toxicity [DLT] in the 32 mg/m2 cohort) were observed in five subjects receiving SCB01A. Nerve conduction velocity tests were performed in subjects in the 32 mg/m2 cohort who presented with peripheral neuropathy (data not shown); the results suggested sensorimotor polyneuropathy and sensory‐predominant, mixed‐type, length‐dependent polyneuropathy.
A cultured dorsal root ganglion (DRG) cell study was conducted to assess SCB01A neurotoxicity [19]. DRG cells were incubated for 6, 18, 24, and 48 hours with serial dilutions of SCB01A (0.625–5 nM). DRG fiber length was compared; toxicity reactions were determined using (3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay [20].
DRG cells treated with 1.25 nM SCB01A (Fig. 4) showed reduced fiber length. SCB01A showed dose‐dependent neurotoxicity; it reduced cell viability and fiber length at ≥2.5 nM. Fiber length reduction recovered spontaneously after continuous SCB01A exposure at <2.5 nM but not at ≥2.5 nM for 48 hours. Fiber length was restored after 24‐hour exposure to 2.5 nM SCB01A, provided SCB01A was washed out after 6 hours of cumulative treatment. SCB01A neurotoxicity was reversible during cumulative exposure. A post hoc analysis of the PK profile of subjects with neuropathy (data not shown) indicated significantly higher C max and AUC and lower terminal elimination rate constant. Clearance rate was associated with neuropathological AEs.
Figure 4.
Response of dorsal root ganglion cells at different treatment concentrations and exposure durations of SCB01A.
AEs and efficacies observed in this study were similar to those reported for VDAs (Table 4). The partial response in one patient with buccal cancer was consistent with the activity of combretastatin A‐4 phosphate (CA4P) in Chinese patients with refractory nasopharyngeal carcinoma [21]. Neurological toxicity has been a commonly reported DLT during the clinical development of tubulin‐binding agents and could not be effectively prevented or treated [22, 23, 24, 25]. Similar recoverable peripheral sensorimotor neuropathy in this trial was observed when 65 mg/m2 CA4P was administered to Chinese patients with grade 2 lower extremity weakness [21]. These were not seen in western patients. Notably, we did not observe the dose effect of SCB01A on Corrected QT, a kind of wave of ECG interpreting interval prolongation and hypertension.
Table 4.
Comparison of phase I clinical trial outcomes among the antitubulin agents CA4P, BNC‐105P, and SB01 [32, 33]
| Comparison of items |
|
|
|
|---|---|---|---|
|
Mechanism of action |
The mechanism of action of the listed compounds is thought to be to target tubulin of dysmorphic endothelial cells of tumor vasculature and cause tumor death by rapidly and selectively cutting off blood supply to the tumor while leaving normal tissues relatively intact | ||
| Molecular weight | 341.36 |
440.29 (CA4: 316.34) |
496.31 (BNC105: 372.37) |
| Dose‐limiting toxicity | 32 mg/m2 | 90 mg/m2 | 18.9 mg/m2 |
| Maximum tolerated dose | 24 mg/m2 | 60 mg/m2 | 16 mg/m2 |
|
Treatment regimen |
i.v. infusion within 180 minutes, every 21 days | i.v. infusion within 10 minutes, every 21 days (CA4P was administered as a 60 mg/m2 i.v. bolus over 10 minutes on days 1, 8, and 15 every 3 weeks for six cycles in phase II/III trial, 2012) | i.v. infusion within 10 minutes at day 1 and day 8, every 21 days |
| Suggested indication | Head and neck cancer | Thyroid cancer | Renal cell carcinoma, mesothelioma |
|
Antitumor effect |
Stable disease, one partial response | Stable disease, one complete response | Stable disease |
| Adverse effect | Nausea, vomiting (neuropathy, hypertension at DLT dose level) | Cardiovascular disease | Nausea, vomiting, fatigue |
Abbreviations: CA4, combretastatin A‐4; CA4P, combretastatin A‐4 phosphate; DLT, dose‐limiting toxicity.
Five‐day repeated toxicology studies of SCB01A in rats indicated a no observable adverse effect level (NOAEL) of ~1 mg/kg per day (6 mg/m2 per day in humans) for males and 1–5 mg/kg per day (6–30 mg/m2 per day in humans) for females [26]. Both the maximum tolerated dose (MTD) and 5‐day NOAEL in dogs were 1 mg/kg per day (20 mg/m2 per day in humans). These data suggest that the observed human MTD for SCB01A approached the estimated MTD over a 3‐week treatment cycle (unpublished data). Taken together, SCB01A is a promising anticancer agent with antimitotic activity and effective against various malignancies, especially drug‐resistant tumors. Owing to the low t 1/2 and no blood drug retention in the groups between cycles 1 and 2, SCB01A can be given more frequently than once per 3 weeks.
Several VDAs demonstrated promising results as cancer therapeutics in early‐phase clinical development trials. VDA monotherapy shrinks tumors; however, conclusive benefits based on phase III studies are limited [27]. Therefore, the development of combination therapy of VDAs with radiation [28] or other conventional treatments is suggested [29, 30, 31]. Our results will help select the target population that could benefit from SCB01A treatment. This is the first phase I study in humans demonstrating SCB01A toxicity, PK, and preliminary tumor efficacy. SCB01A was found to be safe and well tolerated in patients bearing solid tumors with manageable neurotoxicity.
Disclosures
Shang‐Yin Wu: Novartis; Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim (H), Merck KGaA (Other). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Figures and Tables
Acknowledgments
The authors thank the site staff who supported the clinical procedures. The authors also thank Protech Pharmaservices Corporation for monitoring this study. This work was supported by the SynCore Biotechnology Co. Ltd. and the Technology Development Program of the Ministry of Economic Affairs, Taiwan (grant number 100‐EC‐17‐A‐20‐I1‐0032). The funder provided funding and investigational products.
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Footnotes
- Sponsor: SynCore Biotechnology Co. Ltd.
- Principal Investigators: Chia‐Chi Lin, Her‐Shyong Shiah, Li‐Tzong Chen, Nai‐Jung Chiang
- IRB Approved: Yes
Contributor Information
Chia‐Chi Lin, Email: cclin1@ntu.edu.tw.
Li‐Tzong Chen, Email: leochen@nhri.org.tw.
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