A Phase Ib Study of Sorafenib (BAY 43-9006) in Patients with Kaposi Sarcoma.

LESSONS LEARNED: Oral targeted agents are desirable for treatment of Kaposi sarcoma (KS); however, in patients with HIV, drug-drug interactions must be considered. In this study to treat KS, sorafenib was poorly tolerated at doses less than those approved by the U.S. Food and Drug Administration for hepatocellular carcinoma and other cancers, and showed only modest activity.Sorafenib's metabolism occurs via the CYP3A4 pathway, which is inhibited by ritonavir, a commonly used antiretroviral agent used by most patients in this study. Strong CYP3A4 inhibition by ritonavir may contribute to the observed sorafenib toxicity.Alternate antiretroviral agents without predicted interactions are preferred for co-administration in patients with HIV and cancers for which sorafenib is indicated.
BACKGROUND: We conducted a phase Ib study of sorafenib, a vascular epithelial growth factor receptor (VEGFR), c-kit, and platelet derived growth factor receptor (PDGFR)-targeted treatment in Kaposi sarcoma (KS). We evaluated drug-drug interactions between sorafenib and ritonavir, an HIV medication with strong CYP3A4 inhibitory activity.
METHODS: Two cohorts were enrolled: HIV-related KS on ritonavir (Cohort R) and HIV-related or classical KS not receiving ritonavir (Cohort NR). Sorafenib dose level 1 in cohort R (R1) was 200 mg daily and 200 mg every 12 hours in cohort NR (NR1). Steady-state pharmacokinetics were evaluated at cycle 1, day 8. KS responses and correlative factors were assessed.
RESULTS: Ten patients (nine HIV+) were enrolled: R1 (eight), NR1 (two). Median CD4+ count (HIV+) was 500 cells/µL. Dose-limiting toxicities (DLTs) were grade 3 elevated lipase (R1), grade 4 thrombocytopenia (R1), and grade 3 hand-foot syndrome (NR1). Two of seven evaluable patients had a partial response (PR; 29%; 95% CI 4%-71%). Steady-state area under the curve of the dosing interval (AUCTAU) of sorafenib was not significantly affected by ritonavir; however, a trend for decreased AUCTAU of the CYP3A4 metabolite sorafenib-N-oxide (3.8-fold decrease; p = .08) suggests other metabolites may be increased.
CONCLUSION: Sorafenib was poorly tolerated, and anti-KS activity was modest. Strong CYP3A4 inhibitors may contribute to sorafenib toxicity, and ritonavir has previously been shown to be a CYP3A4 inhibitor. Alternate antiretroviral agents without predicted interactions should be used when possible for concurrent administration with sorafenib. The Oncologist 2017;22:505-e49. © AlphaMed Press; the data published online to support this summary is the property of the authors.

Discussion

Preclinical data supported evaluation of sorafenib in KS. Our primary objective was to evaluate the safety of sorafenib in KS patients and ritonavir–sorafenib pharmacokinetic (PK) interactions [1]. Sorafenib was poorly tolerated, with two patients experiencing DLTs at the first dose level (one in each cohort). The overall response rate (ORR) in seven evaluable patients was 29% (95% CI 4%–71%). Although the maximum tolerated dose (MTD) was not determined, accrual was terminated after review of Cohort R1 safety and efficacy data.

Importantly, patients had well‐controlled HIV and preserved CD4 counts. Such patients generally tolerate standard chemotherapy dosing when co‐administered with appropriate antiretroviral therapy (ART). Poor tolerability was most likely due to drug–drug interactions. Maximum plasma concentration (CMAX) and AUC0‐12h of sorafenib following a 200 mg dose at steady state observed in this trial were within reported ranges [2], [3], [4]. The effects of drug–drug interactions and genetic variants on hepatic metabolism are important [5], [6], [7], and co‐administration with ritonavir, a strong CYP3A4 inhibitor, is a possible contributor to the poor tolerability in Cohort R1 [7], [8]. A phase I study of sunitinib, another CYP3A4‐metabolized drug, in patients with HIV and cancer demonstrated that HIV patients not taking ritonavir tolerated standard dosing, whereas patients receiving ritonavir had higher toxicities at lower doses. Ritonavir was associated with decreases in the sunitinib active metabolite but not the parent drug [7]. In our study, we demonstrated a similar trend toward a 3.8‐fold decrease in the CYP3A4 main active metabolite sorafenib‐N‐oxide [9] in patients receiving ritonavir, while parent sorafenib exposures were only modestly affected. Shunting of metabolism towards other pathways yielding more toxic metabolites may alter tolerability (Fig. 1) and explain the toxicity observed. A limitation of this study is the small sample size, and conclusions on the use of sorafenib with ritonavir cannot be based on PK data alone. Nonetheless, our findings suggest that sorafenib has modest activity and does not have a favorable activity/toxicity profile in patients with KS, and that use of concurrent ritonavir‐based ART and sorafenib should be avoided.

Figure 1.

Hepatic metabolism of sorafenib. Elimination of sorafenib occurs mainly in the liver through CYP3A4 oxidative metabolism. M2 is produced by oxidation of sorafenib via CYP3A4 and is the major circulating active metabolite. M7 is produced through the glucoronidation of the parent compound by UGT1A9. Ritonavir is a strong inhibitor of the CYP3A4 pathway, and inhibition of CYP3A4 may lead to the increased production of other metabolites through alternate pathways. Figure modified from PharmGKB pathway with permission from PharmGKB and Stanford University (https://www.pharmgkb.org/pathway/PA165959537).

Abbreviations: M, metabolite; M2, Sorafenib N‐oxide; R, ritonavir.

Although these results do not support its further study or use in KS, our PK and safety findings inform treatment of patients with HIV and cancers for which sorafenib is indicated, particularly those with hepatocellular carcinoma, a tumor with increasing incidence [10]. Caution in using sorafenib in patients with HIV and cancers for which it is approved is advised. Although this study did not conclusively show that ritonavir affected sorafenib metabolism, the results are suggestive, and concurrent ritonavir or other strong CYP3A4 inhibitors should be avoided. ART without predicted strong CYP3A4 interactions should be preferred for concurrent treatment of HIV in patients with cancers best treated by sorafenib.

Trial Information

Kaposi's sarcoma

Any

No designated number of regimens

Phase I

3 + 3 phase I design

Toxicity

Pharmacokinetics

Pharmacodynamic

Safety

Efficacy

Active but too toxic as administered in this study

Drug Information

Sorafenib

Nexavar

Bayer

Small molecule

milligrams (mg) per flat dose

oral (po)

Cohort R ‐ dose level 1 was 200 mg orally once daily. Cohort NR‐ dose level 1 was 200 mg twice daily. In all cohorts, sorafenib was given orally continuously over 21‐day cycles.

Patient Characteristics

10

0

KS prognostic factors1: n (%)—T1: 6 (67%); I1: 1 (11%), S1: 1 (11%)

Revised TS stage2 (AIDS KS prognostic criteria): Good, 8 (89%); Poor, 1 (11%)

1Risk factors based on AIDS Clinic Trials Group (ACTG) staging criteria. T1: edema or ulceration, extensive oral mucosa KS, or visceral KS; I1: CD4+ T‐cells <150 cells/mL; S1: history of opportunistic infections or thrush, and/or “B” symptoms present, and/or Karnofsky Score <70%, and/or other HIV‐related disease.

2Revised AIDS KS prognostic criteria, excludes CD4+ as a risk factor.

Median (range): 49 years (35–72 years)

Median (range): 2 (0–4)

0 — 4 (40%)

1 — 6 (60%)

2 — 0

3 — 0

unknown —

Patients accrued between January 2006 and February 2012. Patient characteristics are as follows:

Race: Black 2 (20%); White 8 (80%)

Detectable circulating KSHV: 7 (70%)

Tumor associated edema: 6 (60%)

Greater than 50 KS lesions: 10 (100%)

Prior therapy for KS: 8 (80%)

HIV seropositive: 9 (90%)

Median time since last KS treatment (months): 22 (range 2–108)

CD4+ (cells/microL) median (range): 500 (35–747)

CD4+ <200 cells/microL: 1 (11%)

HIV VL <50 copies/mL: 7 (78%)

Median time on antiretroviral therapy (ART) (months*): 22 (range 3.5–108)

*Defined as months on specific ART regimen used at the time of screening visit.

Kaposi sarcoma, HIV‐associated: 9

Classic Kaposi sarcoma, HIV‐negative: 1

Primary Assessment Method

29

10

10

7

Modified AIDS Clinical Trial Group Criteria

n = 0

n = 2

n = 4

n = 1

3 months

Seven patients (five in Cohort R1, two in Cohort NR1) were evaluable for response. Best responses were PR in two patients (R1), stable disease (SD) in four (three in R1, one in NR1), and progressive disease (PD) in one (NR1). The ORR was 2/10 (20%; 95% CI 3%–56%) in all patients and 2/7 (29%; 95% CI 4%–71%) in patients evaluable for response. Duration of PR was 3 months in the two responding patients. Median duration of SD was 4 cycles (range 1–5). Of six patients with tumor‐associated edema, five showed objective improvement with ≥2 cm decrease (range 2–5 cm) in circumference of affected limbs at the end of treatment, and one of these obtained a PR. One with severe tumor‐associated edema had improved range of motion in affected limbs, decreased weight, and decreased serous ooze after 1 cycle.

Adverse Events

Dose‐Limiting Toxicity

Pharmacokinetics/Pharmacodynamics

Assessment, Analysis, and Discussion

Study terminated before completion

Active but too toxic as administered in this study

KS is an angioproliferative tumor caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus‐8 [11], [12], [13]. HIV infection substantially increases KS risk [14] and accounts for more than 80% of KS in the U.S. High prevalence of HIV and KSHV coinfection has led to a high incidence of KS in areas of sub‐Saharan Africa [16]. In AIDS‐associated KS, combination ART is indicated but often insufficient. Current therapies for KS are limited by cumulative toxicities. Effective and less toxic approaches are needed. Oral agents are particularly desirable for resource‐limited settings.

Paracrine stimulation by pro‐angiogenic factors produced in part by KSHV‐infected cells contributes to KS pathogenesis. KS spindle cells express vascular epithelial growth factor (VEGF) receptors (R) types 2 and 3 (VEGFR‐2, VEGF‐R3), platelet‐derived growth factor (PDGF)‐R [17], [18], [19], [20], and c‐kit [21]. In vitro, spindle cells derived from KS patients proliferate in response to VEGF, VEGF‐C (a ligand for VEGF‐R3), and PDGF [17], [19], [20]. Sorafenib is a tyrosine kinase inhibitor (TKI) of VEGFR2, VEGFR3, PDGFR, and c‐kit [17], [18], [19], [20], [22], making it a rational agent to treat KS. However, prospective evaluation of novel cancer therapies in people with HIV for safety and PK interactions with antiretroviral agents is important [23].

Our primary objective in this phase Ib study was to evaluate the safety and tolerability of sorafenib in KS patients and the effect of ritonavir on levels of sorafenib [1]. Overall, sorafenib was poorly tolerated, with two patients experiencing DLTs at the first dose level (one in R1 and one in NR1). Additionally, five patients had grade 3 toxicities that did not meet DLT criteria and found the drug difficult to tolerate. The ORR in seven evaluable patients was 29% (95% CI 4%–71%). Although the MTD was not determined, accrual was terminated after review of Cohort R1 safety and efficacy data. Our safety and PK data suggest ritonavir, a strong CYP3A4 inhibitor, affects sorafenib metabolism by decreasing production of sorafenib‐N‐oxide and shunting the metabolism towards more toxic metabolites.

Although small, this phase Ib study provides valuable information to help inform treatment decisions for medical oncologists treating HIV‐associated tumors. Sorafenib [24] is indicated for the treatment of hepatocellular carcinoma (HCC) and other tumors in people with HIV [25], [26]. Increased toxicity has been described in a limited number of patients co‐administered ritonavir [27], [28], while other studies report that sorafenib was relatively well tolerated [29], [30], [31]. The largest retrospective series included 27 patients with HIV and HCC treated with 400 mg sorafenib twice daily. In that study, 93% were co‐administered ART. No information on number of patients on ritonavir was available, although protease inhibitor‐based therapy was common during that study time period (2007–2010). AEs were graded retrospectively, a source of bias and underreporting. Nonetheless, diarrhea, palmar‐plantar erythrodysesthesia syndrome, and hypertension were the most common grade 3–4 AEs, observed in 15%, 15%, and 11% of patients, respectively, higher than reported in the phase III trial that helped establish approval of sorafenib in HCC (8%, 8% and 2%) [24] and consistent with potential drug–drug interactions.

Despite our inability to escalate to standard doses, the ORR of 29% with sorafenib was comparable to observed response rates with other anti‐angiogenic agents and TKIs for KS. For example, ORRs in studies evaluating imatinib and bevacizumab in KS were 33% and 31%, respectively [21], [32]. Interestingly, there was evidence of a clinical effect related to decreased tumor‐associated edema in most patients with edema at baseline [32]. However, it is unclear why only modest tumor regression is observed, given the strong rationale. One possibility is redundancy of angiogenic pathways in KS. Better results may require combination with agents that target KS through other mechanisms.

KSHV‐infected dendritic cells overproduce IL‐12p40, a common subunit for IL‐12 and IL‐23. Despite modest antitumor effect, evaluating 14 serum factors associated with KS pathogenesis, we found a statistically significant decrease in the amount of IL‐12p40 between baseline and the end of cycle 1 (p = .002), suggesting that sorafenib has some effect on KSHV‐induced signaling [33]. Signal transducer and activator of transcription 3 (STAT3) activation by KSHV in endothelial and dendritic cells [34], [35] has been implicated in increased immunosuppressive cytokines, including IL‐23 [35], and indirect downregulation of phospho‐STAT3 by sorafenib [36] is a potential mechanism for our observed IL‐12p40 findings. Further evaluation of STAT3 inhibition in KSHV‐associated diseases is warranted [37]. We also noted a potential trend towards decreased bFGF (p = .018), a growth factor implicated in KS pathogenesis [18]. Our results are similar to findings in non‐small‐cell lung cancer [38] and consistent with a potential role for bFGF downregulation by sorafenib in the treatment of HCC [39], [40].

In summary, sorafenib is relatively poorly tolerated in patients with KS when co‐administered with ritonavir and has modest activity. Although these results do not support its further study or use in KS, findings from this study inform treatment of patients with HIV and cancers for which sorafenib is indicated, particularly those with HCC, a tumor with increasing incidence [10]. Prospective data on co‐administration of ART and cancer therapeutics are important, as concerns regarding toxicity contribute to treatment disparities in patients with HIV and cancer [10]. Caution in using sorafenib in patients with HIV and cancers for which it is approved is advised. Although this study did not conclusively show that ritonavir affected sorafenib metabolism, the results are suggestive, and concurrent ritonavir or other strong CYP3A4 inhibitors should be avoided. Antiretroviral agents without predicted strong CYP3A4 interactions are available and preferred for concurrent treatment of HIV in patients with cancers best treated by sorafenib. Sorafenib dose modification may be required even if an alternate ART regimen is used.

Adverse events represent the worst grade for each patient that was possibly, probably, or definitely related to sorafenib during the entire course of treatment.

Abbreviations: NA, no adverse event; NC, no change from baseline.

Table 1.

Select pharmacokinetic parameters for sorafenib and sorafenib N‐oxide

Numbers displayed as mean ± standard error of the mean. Comparisons used Mann–Whitney test.

Abbreviations: AUCTAU, area under the curve of the dosing interval; CMAX, maximum plasma concentration; Rit, ritonavir.

Table 2.

Baseline characteristics

Risk factors based on ACTG staging criteria. T1: Edema or ulceration, extensive oral mucosa KS, or visceral KS, I1: CD4 < 150 cells/mL, S1: History of opportunistic infections or thrush, and/or “B” symptoms present, and/or Karnofsky Score <70%, and/or other HIV‐related disease.

Revised AIDS KS Prognostic Criteria, excludes CD4 as risk factor.

Months on the specific ART regimen used at time of the screening visit.

Abbreviations: ART, antiretroviral therapy; ECOG, Eastern Cooperative Oncology Group; KS, Kaposi sarcoma; KSHV, Kaposi sarcoma‐associated herpes virus.