Phase I Study of Rivoceranib, a Selective VEGFR-2 Angiogenesis Inhibitor, Administered Daily in Patients With Advanced Solid Tumors

Rivoceranib is a highly potent and selective inhibitor of VEGFR-2 and subsequent angiogenesis through this receptor signaling pathway. This phase I study was the rst global study with rivoceranib outside of China in Korean and Caucasian patients and was designed to determine the safety prole (including maximum tolerated dose), pharmacokinetics, and ecacy in patients with advanced solid tumors. Thirty-one adult patients with advanced malignant solid tumors were enrolled to investigate 6 dose levels of rivoceranib. Twenty-ve patients were initially enrolled to 5 dose levels of rivoceranib from 81 to 685 mg and an additional 6 patients were later enrolled in a supplemental study to evaluate the 805 mg dose level. Rivoceranib was very well tolerated. At the 805 mg dose level, 2 dose-limiting toxicities were observed but the 685 mg dose was well tolerated over multiple cycles of therapy. The maximum tolerated dose for rivoceranib was 685 mg (equivalent to 850 mg rivoceranib mesylate) and recommended for further study in patients with advanced solid tumors. The most common adverse events were hypertension (all grades %/ ≥ G3%: 58/29), nausea (42/0), diarrhea (39/0), anorexia (32/3), and fatigue (29/6). Rivoceranib pharmacokinetics were proportional across all dose levels but interpatient variability was high. Of the 31 patients enrolled, 21 were evaluable for ecacy. In this evaluable group, partial response was recorded in 5 patients, stable disease in 10, and disease progression in 6. Results indicate the potential clinical benet of daily rivoceranib in patients with advanced malignant solid tumors with a tolerable safety prole. on the rst experience with rivoceranib of China in and Caucasian patients. This investigated escalating oral daily doses of rivoceranib rivoceranib QD and the QD.


Introduction
In contrast to conventional chemotherapy that targets proliferation of tumor cells, angiogenesis inhibitors primarily target neovascularization and/or survival of tumoral blood vessels [1,2].
Proliferation of endothelial cells is targeted directly and inhibition of the release of proangiogenic growth factors by cancer or stromal cells is targeted indirectly. Vascular endothelial cell growth factor (VEGF) binds to VEGF receptors (VEGFR) inducing a series of vascular angiogenesis reactions such as cell proliferation, migration, blood vessel permeability and migration of stem cells from bone marrow [3][4][5].
VEGFR-2 is regarded as the most sensitive marker for endothelial cell growth that directly controls tumor angiogenesis [9].
VEGFR-2 signaling in tumor vascular endothelial cells is now recognized as a pivotal and rate-limiting step in tumor angiogenesis, and clinical studies have demonstrated that selective inhibition of VEGFR-2 can limit tumor growth and disease progression, resulting in improved overall survival [13].
Rivoceranib (also known as apatinib and YN968D1) is an orally administered, highly selective TKI of VEGFR-2 with demonstrated activity in treating various solid tumors, including gastric cancer [14]. Rivoceranib has been studied in China under the name apatinib in many clinical trials treating a number of solid tumors and was approved by the Chinese FDA for treatment of advanced gastric cancer in December of 2014. Rivoceranib is under further development globally as monotherapy for the treatment of gastric cancer [15].
Here we report the ndings of the phase I dose escalation portion of a phase I/IIa study evaluating for the rst time the safety and e cacy of rivoceranib outside of China in Korean and Caucasian patients with advanced solid tumors.

Patients
The study population consisted of male or female patients of at least 18 years of age with any malignant solid tumors who were refractory or unable to tolerate conventional therapy. Major inclusion criteria included: measurable disease as de ned by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as measured by a suitable radiographic technique; life expectancy of ≥ 3 months; ability to swallow oral tablets; adequate bone marrow, renal, and liver function, and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.

Study design
This was a multi-site, open-label, safety, pharmacokinetics (PK), and preliminary e cacy study of rivoceranib. Patients were enrolled into the study at 2 sites: Asan Medical Center in Seoul, Korea, and Huntsman Cancer Institute in Salt Lake City, USA. The study used a standard 3 + 3 dose-escalation scheme to establish the maximum tolerated dose (MTD) over a 28-day Dose-Limiting Toxicity (DLT) assessment period. The initial doses investigated in the study were 81 mg, 201 mg, 403 mg, 604 mg, and 685 mg PO QD (corresponding to 100 mg, 250 mg, 500 mg, 750 mg, and 850 mg rivoceranib mesylate) (NCT01497704). An additional dose level was added in a separate supplemental study at Asan Medical Center to investigate the 805 mg PO QD dose level (1,000 mg rivoceranib mesylate) because the MTD was not reached in the initial 81-685 mg PO QD dose range (NCT02711969). Patients received rivoceranib daily in continuous 28-day cycles until disease progression, intolerable side effects, or withdrawal of consent.
Rivoceranib was supplied in blister packs containing 10-tablets of either 81 mg or 201 mg of rivoceranib (as 100 mg or 250 mg rivoceranib mesylate respectively) and was administered once a day.
The primary objective was to investigate the safety and tolerability of a 28-day cycle of daily rivoceranib oral therapy while the secondary objectives were: to evaluate the PK pro le of rivoceranib after a single dose and at steady-state; to obtain information regarding the pharmacodynamics of rivoceranib in humans; and to obtain additional information regarding the e cacy of rivoceranib in humans.

Study evaluations
All patients who received at least one dose of rivoceranib were considered evaluable for safety. Adverse events (AEs) were graded according to NCI-CTCAE v4.03 and were recorded at each visit along with concomitant medications.
An AE was considered a DLT if it occurred during the rst 28-days of therapy and met one of the following criteria: at least possibly related to rivoceranib; grade 4 event; grade 3 febrile neutropenia; grade 3 hematologic toxicity with duration > 7 days; grade 3 nonhematologic toxicity including grade 3 nausea, vomiting, and diarrhea that continued despite optimal medical management. If a DLT occurred in any dose, the cohort was expanded to 6 patients. If 2 DLTs were experienced the dose level was deemed intolerable. Prior to escalation to the next dose level, the medical monitor prepared a safety report that was reviewed and approved by all investigators and study personnel.
Patients were evaluated using RECIST v1.1 using an appropriate imaging technique such as CT scan or MRI at baseline (Day − 22 to − 1) and approximately every 8 weeks thereafter (every two 28-day cycles of treatment). The same imaging modality used at baseline was used consistently throughout all evaluations throughout the study to monitor a given patient. The ECOG performance assessment was performed at baseline (Day − 14 to − 1), at the end of the rst 28-day cycle, and every two 28-day cycles after.

Pharmacokinetics and pharmacodynamics
Blood samples for determination of plasma PK pro les of rivoceranib that followed single (Day 1) and multiple dosing (after 28-days continuous dosing) were collected during the study. Blood was collected prior to dosing; at 30 and 60 minutes, and at 2, 4, 6, 8, 10, 24, and 48 hours (single dose only) after dosing. Rivoceranib was isolated from plasma using liquid-liquid extraction and concentrations were determined using a validated HPLC-MS/MS method. The following pharmacokinetic parameters were calculated by non-compartmental modeling methods: the maximum observed concentration (C max ), time corresponding to occurrence of C max (t max ), total clearance (CL/F), volume of distribution (V z /F), elimination rate constant (λ z ), half-life (t ½ ), and area under the concentration time curve (AUC (0−t) and AUC (0−∞) ) and the percentage of the AUC (0−∞) extrapolated to in nity (AUC%).

Results
Patients and drug exposure A total of 31 patients were enrolled (25 patients in the initial phase I study and 6 patients in the supplemental 805 mg dose level expansion study). Of these, 13 were discontinued, with 8 patients discontinuing due to adverse events (AEs). The mean dose taken was 500 mg with an average duration of therapy of 5 months.
Patient baseline characteristics are presented in Table 1. Patient median age was 63 and most patients were male (68%) and Caucasian (58%). The majority of patients had gastric cancer (GC) (42%) with other tumor types including colorectal (13%), sarcoma (10%), and a broad range of other tumor types. This patient population was heavily pretreated with 52% of all patients having received at least 3 prior lines of therapy and 29% of patients having received at least 4 prior lines. Most patients had received prior platinum and uoropyrimidines (68% and 61% respectively) and 36% had received some form of a prior anti-angiogenic agent. Pancreatic carcinoma 2 (7) Renal cell carcinoma 2 (7) Neuroendocrine tumor 2 (7) Other 5 (16)

DLTs and dose escalation
DLTs for rivoceranib were identi ed in 3 patients and included malignant hypertension, febrile neutropenia, and anorexia (see Table 2). The MTD was determined to be 685 mg rivoceranib (850 mg rivoceranib mesylate). The original study escalated from 81 mg through to 685 mg without identifying an intolerable dose. A second expansion cohort was later enrolled to investigate the 805 mg dose level (1,000 mg rivoceranib mesylate) and this dose was determined to be intolerable, thereby determining the 685 mg dose level as the MTD.

Adverse Events
A summary of the toxicity pro le of rivoceranib across all investigated dose levels is displayed in Table 3. All patients who received at least one dose of rivoceranib were included in the safety analysis. All patients experienced at least one AE over the duration of the study with 61% of patients experiencing a serious AE (SAE). There were no deaths associated with rivoceranib administration and AEs leading to discontinuation of rivoceranib were seen in only 29% of patients.
Most AEs were of low severity (grade 1 and 2). The most common AEs were hypertension (58%), nausea (42%), diarrhea (39%), and anorexia/decreased appetite (32%). Some AEs were more prevalent at higher doses with hand-foot skin reaction only observed at dose levels ≥ 685 mg/day and anemia occurring in 4 of 6 patients at the 805 mg/day dose level. While hypertension was only observed in 36% of patients receiving 201 mg/day of rivoceranib or less, 76% of patients receiving 403 mg/day or higher experienced hypertension of any grade.

Pharmacokinetics
Derived pharmacokinetic parameters from the blood plasma concentrations of rivoceranib on study day 1 (single dose) and after 28 days of continuous oral dosing (steady-state) are presented in Table 4. After a single oral administration of rivoceranib, absorption was relatively fast, with median T max increasing from 1.98 hours (81 mg dose) to 5.90 hours (805 mg dose). After steady-state was achieved, median T max was more consistent (1.25-4.00 h) and did not display a clear dose-related trend (  Data are presented as mean (standard deviation) or geometric mean (%CV). Abbreviations: C max : maximum observed plasma concentration; T max : time at which maximum plasma concentration is observed; t 1/2 : terminal phase plasma half-life; AUC 0 − 24 : area under the plasma concentration-time curve from 0 to 24 hours; AUC : area under the plasma concentration-time curve to the end of the dosing period; N/C: not calculated. a n-1 subjects available for analysis.
After multiple oral doses, the geometric mean C max increased from 72 ng/ml (81 mg dose) to 943 ng/ml (403 mg dose) then decreased to 503 ng/ml at the 805 mg dose. Geometric %CV for C max at steady-state ranged from 50-130%. AUC increased with dose from 599 h•ng/ml (81 mg dose) to 8,002 h•ng/ml (805 mg dose) with a %CV range of 28-122%. With single dose as well as steady-state, average half-life (t 1/2 ) was consistent 8.7-13.4 hours for all the doses except for steady-state dose of 685 mg dose where t 1/2 was 27.2 hours.
Dose proportionality analysis revealed that the pharmacokinetics of rivoceranib were proportional between 81 mg and 805 mg following single and multiple dose administration for C max and AUC 0 − 24 , AUC 0−∞ , and AUC (Table 5). E cacy E cacy across all dose levels is presented in Table 6. Overall, 21 out of the 31 enrolled patients had tumor assessments beyond baseline and were included in the e cacy analysis. Partial responses were observed in 5 patients (3 GC, 1 mesothelioma, and 1 renal cell carcinoma [RCC]), yielding an objective response rate (ORR) of 24% (95% con dence interval [CI]: 6-42%). Stable disease was observed as a best response in an additional 10 patients, yielding a disease control rate of 71% (95% CI: 52-91%). Progressive disease as a best response was observed in 6 patients (29%) and no patients achieved a complete response. Of the partial responses achieved during the study, 3 were highly durable with one response continuing 34.0 months (GC), a second continuing 12.0 months (RCC), and the last continuing 9.2 months (GC). The median progression-free survival (mPFS) for all patients was 5.1 months (95% CI: 2.0-13.1). In the gastric cancer subset of patients, the mPFS was 4.5 months (95% CI: 1.2-16.8) (Fig. 1).

Discussion
This study reported on the rst experience with rivoceranib (also known as apatinib) outside of China in Korean and Caucasian patients. This study investigated 6 escalating oral daily doses of rivoceranib from 81 mg to 805 mg rivoceranib PO QD and determined that the maximum tolerated dose, and the dose recommended for further investigation is 685 mg PO QD.
Rivoceranib was generally well tolerated in the study with 82.3% of all reported adverse events grade 1 and grade 2. All patients experienced at least one treatment-emergent AE with 74% of patients experiencing an AE that was deemed related to administration of rivoceranib. Seventy-seven percent of patients experienced an AE ≥ grade 3 in severity, and 61% had serious adverse events. The reported adverse events were consistent with toxicities related to advanced cancer with the notable exception of hypertension and hand-foot syndrome which are related to the anti-angiogenic mechanism of action and common in other compounds in the same class [16].
The adverse event pro le was highly similar to that seen in the dose escalation study performed in China; however, while rates of proteinuria were reported at approximately 30% in the Chinese study, this AE was largely unreported in this study. The tolerability of the drug is supported by the long durations of treatment in many of the subjects with 2 patients receiving the drug daily for approximately 3 years and 3 additional patients receiving rivoceranib for over 1 year.
Statistically, the determination of dose proportionality could not be excluded for both single dose and steady-state as the 95% con dence interval of the slope for all dose proportional parameters (C max , AUC) contained 1. Visually, however, it appeared that at steady-state C max plateaued at 403 mg while AUC leveled off at 403 mg and higher. At single 201 mg dose, C max and AUC were > 3fold lower than in previously published report (conducted after this study) evaluating ethnic difference on pharmacokinetics of rivoceranib [17]. The difference in the study could be explained by low subject size in current population, variation in exposure in healthy vs patient population or due to presence of large variblity in exposure due to low bioavailability.
While the search for circulating biomarkers which are predictive of response to anti-angiogenic therapy has been unsuccessful, the decrease in VEGFR-2 levels over time is indicative of on-target inhibition and is similar to the decrease observed in other studies in gastric cancer with inhibitors of VEGFR-2 [18].
This study presented signi cant evidence of the antitumor activity of rivoceranib with 24% of evaluable patients exhibiting partial responses (30% decrease or greater from baseline). An additional 10 patients had a best response of stable disease, yielding an overall disease control rate of 71%. Of note, most of the partial responses were very durable with 3 patients maintaining the partial response for 9 months or longer and one patient maintaining for 34 months. Three of the partial responses occurred in patients receiving the 685 mg daily dose; however, responses were also observed at both the 403 mg and 201 mg doses. This data compared well with the reported phase I study of rivoceranib in China where they reported a similar ORR and DCR (19% and 84% respectively) [19].
Progression-free survival was also very promising in this highly pre-treated patient population with a mPFS of 5.1 months for all patients and 4.5 months for the advanced/metastatic gastric cancer patient population. As overall survival was not included as an objective in the study, collection of survival data was limited only to deaths that occurred while patients participated in the trial.
Overall, death was only reported in 3 patients during the conduct of the study and no deaths were deemed related to rivoceranib.
Overall, this study reports the rst experience with rivoceranib outside of China and demonstrated that the results observed in China were highly replicable with similar e cacy and safety pro les in Caucasian and Korean patients. Further investigation of rivoceranib in solid tumors is already underway outside of China with ongoing programs in gastrointestinal cancers including gastric and colorectal cancer and other solid tumors. [20][21][22]. A prospective, randomized, double-blinded, placebo-controlled, phase III study (the ANGEL study) to evaluate the e cacy and safety of rivoceranib plus best supportive care in patients with advanced or metastatic gastric cancer [15] (NCT03042611) has been completed and a phase III study in rst-line hepatocellular carcinoma of rivoceranib in combination with the anti-PD-1 inhibitor camrelizumab (NCT03764293) is currently in progress.