Phase I, First‐in‐Human, Dose‐Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Vorolanib in Patients with Advanced Solid Tumors

Abstract

Lessons Learned.

• Pharmacokinetic results underscore that the vorolanib (X‐82) study design was successful without the need for further dose escalation beyond 400 mg once daily (q.d.).

• Therefore, the recommended dose of X‐82 as a single agent in patients with advanced cancer is 400 mg q.d.

Background.

Vorolanib (X‐82) is a novel, oral, multikinase vascular endothelial growth factor (VEGF) receptor/platelet‐derived growth factor (PDGF) receptor inhibitor that was developed on the same chemical scaffold as sunitinib, but designed to improve upon the safety profile while maintaining the efficacy of sunitinib. By targeting the VEGF and PDGF receptors, X‐82 was expected to disrupt tumor angiogenesis and be active in a broad spectrum of solid tumors. Therefore, we determined the maximum tolerated dose (MTD) and characterized the preliminary pharmacokinetics and clinical tumor response of X‐82 as a single agent in patients with advanced solid tumors.

Methods.

Adult patients with advanced solid tumors received X‐82 as tablets or capsules (once daily [q.d.] or b.i.d.) every 4 weeks. Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity.

Results.

Fifty‐two patients received study treatment in 17 cohorts. X‐82 capsule dosing was as follows: cohorts 1–6 (20–400 mg q.d.) and cohorts 7–8 (140–200 mg b.i.d.). Patients in cohorts 9–17 received 50–800 mg q.d. tablet dosing. The median time on treatment was 58 days. X‐82 blood pharmacokinetics appeared dose‐independent with a t_1/2 of 5.13 hours and 6.48 hours for capsule and tablet formulations, respectively. No apparent accumulation was observed after 21 days of daily dosing.

Conclusion.

X‐82 had a safety profile consistent with its mechanism of action. It has a short half‐life and was well tolerated by most patients. Study enrollment ended prior to the determination of the MTD because of the apparent saturation of absorption at 400–800 mg. The recommended dose of X‐82 as a single agent in patients with advanced cancer is 400 mg q.d.

Discussion

The study planned to determine the MTD and preliminary pharmacokinetic (PK) characteristics of X‐82, administered as a single agent in a continuous daily dosing schedule, in patients with advanced solid tumors. The study began with a capsule formulation of X‐82. To improve the absorption and exposure of X‐82, a tablet formulation was available with protocol Amendment 3, and patients receiving capsules had the option to switch to the tablet formulation based on availability.

Table 1. Treatment‐related adverse events (incidence ≥5%; n = 52).

Data are presented as n (%).

Abbreviation: —, no occurrence.

Patients on cohorts 1–6 received 20–400 mg once‐daily capsule dosing and patients on cohorts 7 and 8 received 140–200 mg twice‐daily capsule dosing. Patients on cohorts 9–17 received 50–800 mg once‐daily tablet dosing. Patients were enrolled sequentially into these cohorts. No dose‐limiting toxicities were observed in the dose levels explored. However, enrollment was stopped prior to determination of the MTD because of the apparent saturation of absorption at 400–800 mg. The recommended dose of X‐82 monotherapy in patients with advanced cancer is 400 mg once daily.

To achieve the PK/pharmacodynamic (PD) model reported by Mendel et al., X‐82 was designed to have a short t_1/2 and no accumulation in humans. The PK results underscore that our X‐82 study design was successful without the need for further dose escalation beyond 400 mg once daily. In summary, X‐82 was well tolerated by most patients, with the most common treatment‐related grade 3 adverse event (AE) being proteinuria (4%). There were no grade ≥ 4 AEs or deaths thought to be related to X‐82. This safety profile is consistent with the mechanism of action. Further improvements in the treatment of advanced cancers with X‐82 will likely await identification of and successful combination with other agents.

Figure 1.

Best response as change from baseline for the sum of target lesions (n = 49). Two patients stopped study treatment during Cycle 1 because of clinical progression and were not reassessed for response. †Hurthle cell carcinoma. ††Pancreatic cancer.

Trial Information

Disease

Advanced cancer/solid tumor only

Stage of Disease/Treatment

Metastatic/advanced

Prior Therapy

More than two prior regimens

Type of Study – 1

Phase I

Type of Study – 2

3 + 3

Primary Endpoint

Maximum tolerated dose

Secondary Endpoint

Pharmacokinetics

Secondary Endpoint

Safety

Secondary Endpoint

Efficacy

Secondary Endpoint

Proportion of patients with an overall tumor response (complete response + partial response)

Secondary Endpoint

Duration of response

Secondary Endpoint

Proportion of patients with stable disease

Additional Details of Endpoints or Study Design

 

Additional Notes on Prior Therapy: Dose escalation phase: There was no limit on the amount of prior chemotherapy; dose expansion phase: ≤3 prior cytotoxic treatment regimens, and at least 1 regimen must have included a platinum‐containing agent.

 

Dose Escalation Schema: Once‐daily dosing regimen used an accelerated titration scheme that evaluated at least one patient per 28‐day cycle before escalation to the next dose level. This accelerated titration scheme was to be followed by a 3 + 3 dose escalation (see Protocol Amendment 2). However, based on preliminary PK data from patients in this study, an apparent saturation in absorption of the drug capsule was observed, with a plateau in drug exposure at q.d. doses ≥160 mg. As a result, b.i.d. dosing was employed to further increase exposure and evaluate toxicity (Protocol Amendment 2). A new X‐82 tablet formulation was introduced at a starting dose of 50 mg once or twice daily depending on data evaluation from the prior cohort using a 3 + 3 design.

 

Investigator's Analysis

Active and should be pursued further

Drug Information

Drug 1

 

Generic/Working Name

X‐82

Trade Name

Vorolanib

Company Name

Equinox Sciences, LLC

Drug Type

Small molecule

Drug Class

Angiogenesis ‐ antivascular

Dose

X‐82 Capsule formulation: 20 mg and 100 mg (for patients enrolled prior to amendment 3); Tablet formulation: 50 mg and 100 mg (for patients enrolled after amendment 3)

Route

p.o.

Dose Escalation Table

Each X‐82 dose was a cohort. For the 150 mg q.d., there were two cohorts: Cohort 11, 150 mg q.d., five patients; and Cohort 12, 150 mg q.d., three patients.

Abbreviations: b.i.d., twice daily; q.d., once daily.

Patient Characteristics

Number of Patients, Male

38 (73%)

Number of Patients, Female

14 (27%)

Stage

Advanced

Age

Median (range): 64 (40–80)

Number of Prior Systemic Therapies

Median (range): not collected

Performance Status: ECOG

0 — 34 (65%)

1 — 18 (35%)

2 — 0

3 — 0

Unknown — 0

Other

Race: white, 49 (94%); black, 1 (2%); American Indian/Alaskan Native, 2 (4%)

Cancer Types or Histologic Subtypes

Breast, 1 (2%)

Lung, non‐small cell, 1 (2%)

Lung, small cell, 2 (4%)

Ovarian ‐ platinum sensitive, 3 (6%)

Ovarian ‐ primary platinum resistant, 2 (4%)

Ovarian ‐ secondary platinum resistant, 2 (4%)

Ovarian ‐ platinum refractory, 3 (6%)

Pancreatic, 1 (2%)

Endometrial, 6 (12%)

Colorectal, 8 (15%)

Sarcoma, 2 (4%)

Renal, 3 (6%)

Gastrointestinal stroma, 1 (2%)

Other*, 17 (33%)

*Carcinoid (3, 6%); cervical (2, 4%); clear cell ovary; gastric, Hurthle cell carcinoma of right thyroid; liver; melanoma; neuroendocrine carcinoid tumor; parotid gland; squamous cell carcinoma of the vulva; thyroid; unknown primary; uterine; and vagina (1 patient each, 2%).

 

Primary Assessment Method

Title

Assessment

Number of Patients Enrolled

52

Number of Patients Evaluable for Toxicity

52

Number of Patients Evaluated for Efficacy

49

Evaluation Method

RECIST 1.1

Response Assessment CR

n = 1 (2%)

Response Assessment PR

n = 1 (2%)

Response Assessment SD

n = 25 (51%)

Response Assessment PD

n = 20 (41%)

Response Assessment OTHER

n = 2 (4%)

(Median) Duration Assessments PFS

2 months, CI: 95%

(Median) Duration Assessments TTP

2 months, CI: 95%

(Median) Duration Assessments Response Duration

5 months

(Median) Duration Assessments Duration of Treatment

58 days

Outcome Notes

Other = missing, 2 (4%). Note that 11 patients (22%) had stable disease and were on study for at least six cycles.

Adverse Events

Abbreviation: NC/NA, no change from baseline/no adverse event.

Serious Adverse Events

Note that two patients experienced a serious adverse event of grade 3 anemia that was unrelated to X‐82. In addition, two patients experienced a serious adverse event of grade 3 dyspnea that was unrelated to X‐82.

Assessment, Analysis, and Discussion

Completion

Study terminated before completion

Terminated Reason

Did not fully accrue

Investigator's Assessment

Active and should be pursued further

Vascular endothelial growth factor receptor (VEGFR) and platelet‐derived growth factor receptor (PDGFR) are cell surface tyrosine kinase receptors that represent targets for anticancer therapy in solid tumors. The combined effect on VEGFR and PDGFR with similar potency is thought to contribute to the increased efficacy of sunitinib (SU11248) over other tyrosine kinase inhibitors (TKIs) such as sorafenib, in patients with renal cell carcinoma, that primarily target VEGFR [1]. Vorolanib (X‐82) was developed on the same chemical scaffold as sunitinib, targets all isoforms of VEGFR and PDGFR, and was designed to improve the safety profile while maintaining the efficacy of sunitinib.

Clinical studies showed that sunitinib has a long t_1/2 (>40 hours) as well as large distribution and accumulation in various tissues [2]. This observation required sunitinib dosing holidays as reflected in the U.S. Food and Drug Administration‐approved dose of 50 mg once daily with 4 weeks on and 2 weeks off (4/2) treatment in metastatic renal cell carcinoma [3]. However, murine pharmacokinetic (PK)/pharmacodynamic (PD) studies of sunitinib suggested that constant inhibition of VEGFR2 and PDGFRβ phosphorylation was not required for efficacy; at highly efficacious doses, inhibition was sustained for 12 hours of a 24‐hour dosing interval [4]. With a t_1/2 of about 2 hours in mice, sunitinib displayed intermittent inhibition with daily dosing; however, as the t_1/2 in humans is much longer, daily dosing results in constant inhibition. X‐82 was designed to have a short t_1/2 in humans to meet the PK/PD requirement of intermittent inhibition with daily dosing. X‐82 was also designed to have a smaller volume of distribution in tissues because its therapeutic targets, VEGFR and PDGFR, are in blood vessels. It was hypothesized that if X‐82 had a short t_1/2 and did not accumulate in tissues, it would meet the requirement of intermittent inhibition and minimize the potential for toxicity, while maintaining antitumor activity similar to sunitinib.

The objective of this study was to determine the maximum tolerated dose (MTD) and preliminary PK of single‐agent X‐82 in patients with advanced solid tumors. The expectation was that an improved safety profile would allow daily dosing of X‐82 and permit combination modalities currently precluded by safety concerns with sunitinib. Enrollment was stopped prior to determination of the MTD because of the apparent saturation of absorption at 400–800 mg. We believe that X‐82 proved to be less toxic, as proteinuria (two patients, 4%) was the most common treatment‐related adverse event reported. Additionally, we considered the intermittent suppression to be clinically effective. In a small phase I/II trial in patients with renal cell carcinoma (about half TKI naïve, half received prior TKI), its efficacy was comparable to other TKIs, but much better tolerated, consistent with the PK/PD model. Finally, the drug sponsor, Xcovery, LLC, has three clinical trials ongoing to investigate the X‐82 combination with anti‐programmed cell death protein 1 therapies (NCT03511222, NCT03583086, NCT03602547).

Figures and Tables

Figure 2.

Cycle 1 Day 22 arithmetic mean plasma concentration time curves with tablet formulation of X‐82.

Table 2. Cycle 1 Day 22 mean PK parameters in patients administered X‐82 tablets.

Abbreviations: AUC, area under the plasma‐concentration time curve from time zero to 22 days; C_max, peak drug concentration; fast, fasting; fed, with meal; PK, pharmacokinetic; T_max, time to maximum observed concentration; t_1/2, terminal half‐life.

Table 3. Cancer antigen 125 response (n = 14).

^aOne patient achieved stable disease and remained on treatment for at least six cycles.

Figure 3.

Time to progression (TTP). Sample size, 49 patients; median progression‐free survival (95% confidence interval [CI]): 2.00 (1.8–3.7); median TTP (95% CI): 2.00 (1.8–3.7).

Figure 4.

Progression‐free survival. Sample size, 49 patients; median progression‐free survival (95% confidence interval): 2.00 (1.8–3.7).

Disclosures

Johanna C. Bendell: Tyrogenix (RF); Manish R. Patel: Pfizer, Exelixis, Celgene, Bayer, Janssen (H); Kathleen N. Moore: AstraZeneca, Genentech/Roche, Immunogen, Tesaro, Clovis, OncoMed, Janssen, Merck, Aravive (C/A), PTC Therapeutics, Lilly (RF); Hendrik‐Tobias Arkenau: Sarah Cannon/HCA (E), Guardant, Roche, Servier (C/A, H); Gary Dukart: Xcovery Holdings, Inc. (C/A, OI); Kim Harrow: Xcovery Holdings, Inc. (E, OI [company owns stock in Equinox Sciences, LLC]); Chris Liang: Xcovery Holdings, Inc. (E). The other author 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