Lonafarnib has demonstrated nanomolar potency, competitively inhibiting FTPase in preclinical models and three published phase I monotherapy studies have defined its toxicities, MTD, and anti-tumor activity [2
]. In vitro, lonafarnib is synergistic with cisplatin and additive with gemcitabine [3
]. Clinically, lonafarnib and gemcitabine demonstrates efficacy (two PRs and one minimal response) in pancreatic cancer [9
] and urothelial cancer (9 CR, 1PR in 33 patients) [45
]. This study was designed to establish the dose for further study in gemcitabine and cisplatin active malignancies with potential Ras mutations such as NSCLC.
In this study, gemcitabine and cisplatin with lonafarnib was not well-tolerated: frequent myelosuppression, gastrointestinal toxicity, malaise, anorexia, and fatigue, prompted 9 out of 22 patients to discontinue study participation. Thrombocytopenia limited the ability to give day 15 gemcitabine in >50% of patients. Limited results from the PK studies did not indicate any parameters or interactions that would predict these toxicities. Gemcitabine and cisplatin alone have substantial grade 3/4 toxicities: gemcitabine (1,000–1,250 mg/m2
weekly) and cisplatin (60–100 mg/m2
day 1 q21 or q28 days) in advanced untreated NSCLC, previously treated breast and ovarian cancers: 12–57% neutropenia, 16–52% thrombocytopenia, 20 and 25–32% nausea and emesis [15
]. The hematologic toxicity in our phase I study population was much higher, with 91% of patients previously treated with a median of 3.5 prior chemotherapy regimens. Most of the high hematologic toxicity limiting lonafarnib dose escalation is attributed to cisplatin and gemcitabine; the degree of lonafarnib contribution to these toxicities is not known.
The substantial gastrointestinal toxicity following gemcitabine and cisplatin was due to inadequate anti-emetic therapy in cohort 1, as corticosteroids for delayed emesis and prophylactic anti-nauseants were not allowed. Cisplatin is highly emetogenic (>90% of patients suffer emesis without anti-emetics); patients had difficulty recovering from cisplatin-induced emesis without prophylactic anti-emetics and lonafarnib induced worsening nausea. When the anti-emetic protocol was amended in cohorts 2 and 3, nausea and vomiting severity was reduced (only one grade 3 incidence) in these patients in all cycles.
By intent-to-treat analysis, the patient assigned to Dose Level 3 who actually treated at Dose Level 2 and developed hematologic DLT would have established the MTD at Dose Level 2, since the DLT would have been attributed to the assigned Dose Level 3. However, analysis of the seven patients actually treated at Dose Level 2 revealed two DLTs, and one patient with grade 3 and 4 gastrointestinal toxicities not considered DLT (unrelated to lonafarnib), which were not clinically tolerable. Therefore, based on the actual doses patients received and their first cycle toxicities, Dose Level 1 (lonafarnib 75 mg BID, gemcitabine 750 mg/m2 day 1, 8, 15 with cisplatin 75 mg/m2 day 1 q28 days) was established as the MTD. Unfortunately, the MTD was not tolerable for continuous subsequent dosing: gemcitabine was held for six doses in the seven cycles (21 doses) of therapy and was reduced twice for hematologic toxicity in three patients. Dose reductions of gemcitabine were frequent, and over 50% of patients did not receive day 8 or 15 on the 28-day schedule. Despite the study closing early without establishing the MTD for the 21-day schedule (cohort 3), it appeared better tolerated: there were no DLTs and gemcitabine was only held for three doses of nine cycles (18 doses) in five patients, with only two dose reductions. Therefore, lonafarnib 75 mg BID, gemcitabine 750 mg/m2 day 1, 8 with cisplatin 75 mg/m2 day 1 q 21 days would be the recommended dose for further studies. However it is of concern that these doses are lower than clinically established efficacious doses for gemcitabine and cisplatin [1
Systemic exposure (Cmax
) to gemcitabine and cisplatin did not appear influenced by concomitant administration of lonafarnib 75 mg or 100 mg BID. A phase II study of lonafarnib with gemcitabine in urothelial cancers supports that lonafarnib does not affect gemcitabine PK [45
]. Mean trough plasma concentrations of lonafarnib 75 mg BID, in combination with gemcitabine, (123–347 ng/mL) were similar to previous clinical trials with lonafarnib [5
]. Minimal lonafarnib plasma concentrations (Cmin
) at the MTD of 75 mg BID in this study did not reach preclinical target concentrations (>1 µM) to inhibit Ras and critical protein farnesylation and to inhibit tumor growth; [6
] however, they were achieved with 100 mg BID doses, which is consistent with other reports [2
Moreover, patients who were treated with lonafarnib 75 mg BID did not demonstrate a shift in HDJ-2 activity, indicating a negative PD effect with low biochemical activity of lonafarnib; whereas, the two patients treated with lonafarnib 100 mg BID showed a detectable level of unfarnesylated HDJ-2 at baseline, with one of these two patients demonstrated >10% increase in unfarnesylated HDJ-2 over pre-treatment, indicating biological activity. The HDJ-2 chaperone protein should undergo mobility shifts when FTPase is inhibited and is a validated sensitive marker of FPTase inhibition at lonafarnib levels >6.25 nM [4
]. Yet no anti-tumor responses were observed at lonafarnib 100 mg BID; while they were noted at 75 mg BID, bringing into question the PD predictability of the assay in this study or possibly indicating that the anti-tumor response were due to chemotherapy alone. Data from the SPA FTPase ex vivo assays were insufficient to clarify the HDJ-2 gel findings; enzyme assays generally underestimate the degree of FTPase, [4
] and small sample numbers, inter-and intra-patient variability rendered these studies inconclusive. An immunohistochemical assay of prelaminin A accumulation in buccal mucosa cells has been a sensitive PD marker of FTI in other phase I studies, and may help to clarify biological results [2
Despite phase I clinical studies determining the MTD of lonafarnib to be 300 mg daily or 200 mg BID alone, [5
] these dose levels could not be achieved in this study due to excessive toxicity. When lonafarnib was combined with gemcitabine, hematologic and gastrointestinal DLTs limited the doses of lonafarnib and established the MTD as lonafarnib 150 mg q am, 100 mg q pm with 1,000 mg/m2
gemcitabine days 1, 8, and 15, q28 days [9
]. When the feasibility of these doses was tested in the phase II setting of 33 patients with urothelial cancers, this combination was tolerated and efficacious with a response rate of 32.3% (nine PRs and one CR) [45
]. However, the dose intensity of gemcitabine was 75.5% and in the 33 patients, grade 3 toxicities were observed: neutropenia (18%), thrombocytopenia (18%), anemia (27%), fatigue (30%), diarrhea (12%), and nausea and vomiting (10% of patients) indicating that there is additive hematologic and gastrointestinal toxicity when lonafarnib was combined with gemcitabine [45
]. This effect is even more pronounced when combined with platinum-based combinations with higher inherent hematologic and gastrointestinal toxicity.
Another FTI, tipifarnib, combined with gemcitabine and cisplatin could be delivered with adequate tipifarnib levels for activity [2
]. Tipifarnib has higher FTI activity than lonafarnib in vitro (0.45–0.57 vs. 4.9–7.8 nM IC50s in human and bovine assays, respectively), with approximately 5–10 fold higher potency in Ras processing assays over lonafarnib in human cancer cell lines [17
]. Tipifarnib’s higher FTI potency and perhaps improved therapeutic index may allow better dose-escalation to active FTI doses in combination with chemotherapy than lonafarnib. Dose-limiting thrombocytopenia and/or neutropenia established the MTD of tipifarnib at 300 mg po BID, gemcitabine 1,000 mg/m2
day 1, 8 and cisplatin 75 mg/m2
day 1, every 21 days [2
]. High efficacy [eight PRs (four NSCLC, two ovarian, one bile duct and one hepatocellular cancer), and one CR (NSCLC)] was observed, and correlated with farnesylation inhibition in vivo in patient buccal mucosal cells at these tipifarnib doses [2
]. However, frequent severe nausea, vomiting, and myelosuppression occurred in the ten patients at the MTD despite excluding heavily pre-treated patients: two patients had dose limiting neutropenia and thrombocytopenia in cycle 1 and in subsequent cycles required a dose reduction of 25–30% of all drugs, and nine patients required gemcitabine and cisplatin dose reductions due to severe nausea and vomiting and fatigue. Therefore for chronic administration, tipifarnib at 300 mg BID with × 14 days, gemcitabine 750 mg/m2 day 1, 8 and cisplatin 60 mg/m2 day 1 on a 21-day schedule was recommended instead of the MTD. Of note, these doses were also significantly lower than the standard efficacious gemcitabine and cisplatin doses in clinical use [11
]. As the 21-day schedule of gemcitabine and cisplatin appears to have much less hematologic toxicity and is more tolerable; from the beginning, our study should have assessed a 21-day schedule rather than the 28-day schedule, excluded heavily pre-treated patients, and explored a discontinuous dosing schedule to decrease cumulative toxicity to make this therapy more “deliver-able.”
Gemcitabine and cisplatin have demonstrated response rates of 29–62% in previously treated advanced breast cancer patients in the phase II setting; however, a high incidence of thrombocytopenia (up to 32%) was observed necessitating gemcitabine dose reduction [14
]. The two responding breast cancer patients in this study were heavily pre-treated with prior chemotherapy but neither had any prior cisplatin, and the patient with a CR did not receive prior gemcitabine. As both gemcitabine and cisplatin are active in previously treated breast cancer, it is possible that lonafarnib did not contribute to the anti-tumor effects, as target concentrations were not reached. However, there may be other unmeasured chemotherapy or anti-tumor modulating effects. Lonafarnib is synergistic with cisplatin and additive with gemcitabine in vitro, and active against breast carcinoma xenografts [31
]. FTIs alone are clinically very active in breast cancer [21
]: a phase II study of tipifarnib dosed continuously in 76 advanced breast cancer patients demonstrated 4 PR and 6 SD lasting >24 weeks, and when dosed for 21 out of 28 days, 5 PRs and 3 prolonged SD were noted in 35 patients [21
]. Therefore, further exploration of lonafarnib and other FTIs with chemotherapy in breast cancer may be warranted.
This combination was originally planned to be taken forward in NSCLC, but this study was terminated early due lack of efficacy and survival benefit and high toxicity in a Phase III study of lonafarnib, paclitaxel, and carboplatin in advanced NSCLC [39
]. Lonafarnib may increase nausea, vomiting, neutropenia and thrombocytopenia in combination with chemotherapy [9
] and these toxicities prohibit achieving efficacious lonafarnib target FTPase inhibitory levels. Therefore, pursuing lonafarnib combination therapy with chemotherapy doublets, particularly platinums with high gastrointestinal and hematologic toxicities profiles, is of questionable value.