Dosing Recommendation Based on the Effects of Different Meal Types on Pexidartinib Pharmacokinetics in Healthy Subjects: Implementation of Model-informed Drug Development Strategy.

Pexidartinib, an oral small molecule inhibitor of the colony-stimulating factor 1 receptor, is approved for treatment of adults with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. The original dosing regimen is 400 mg of pexidartinib (2 × 200-mg capsules) twice daily, administered on an empty stomach at least 1 hour before or 2 hours after a meal or snack. Because pexidartinib is likely to be taken over an extended period of time, the ability to take pexidartinib with a meal would simplify timing of administration and potentially improve compliance. Since administering 400 mg of pexidartinib with a low-fat meal increases exposure by ≈60% relative to the fasted state, administering 250 mg of pexidartinib with a low-fat meal (low-fat meal dosing regimen) was predicted to achieve an exposure similar to 400 mg administered during a fasted state (original dosing regimen). Based on clinical trial simulations with two one-sided t-tests and bootstrapping (ie, resampling) analyses, a bioequivalence study (n = 24) would have >90% power to conclude that the original dosing regimen (400 mg fasted twice daily) and the low-fat meal dosing regimen (250 mg with a low-fat meal twice daily) are bioequivalent. This report provides the outcome of the implementation of the model-informed drug development strategy to recommend and justify a low-fat meal dosing regimen for pexidartinib that has the potential to improve patient compliance while maintaining drug exposure.

Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors.

BACKGROUND: Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib. MATERIALS, AND METHODS: Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288. RESULTS: In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases. CONCLUSION: This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury. IMPLICATIONS FOR PRACTICE: This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.

Long-term outcomes of pexidartinib in tenosynovial giant cell tumors.

BACKGROUND: The objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT). METHODS: This was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019. RESULTS: One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months). CONCLUSIONS: This study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT.

Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial.

BACKGROUND: Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection. METHODS: This phase 3 randomised trial had two parts. Part one was a double-blind study in which patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomly assigned via an integrated web response system (1:1) to the pexidartinib or placebo group. Individuals in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study of pexidartinib for all patients. The primary endpoint, assessed in all intention-to-treat patients, was overall response at week 25, and was centrally reviewed by RECIST, version 1.1. Safety was analysed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02371369. FINDINGS: Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for eligibility, 120 patients were randomly assigned to, and received, pexidartinib (n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity caused the data monitoring committee to stop enrolment six patients short of target. The proportion of patients who achieved overall response was higher for pexidartinib than placebo at week 25 by RECIST (24 [39%] of 61 vs none of 59; absolute difference 39% [95% CI 27-53]; p<0·0001). Serious adverse events occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 59 patients in the placebo group. Hair colour changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%) were the most frequent pexidartinib-associated adverse events. Three patients given pexidartinib had aminotransferase elevations three or more times the upper limit of normal with total bilirubin and alkaline phosphatase two or more times the upper limit of normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy. INTERPRETATION: Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery. FUNDING: Daiichi Sankyo.

Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine.

PURPOSE: The activity and safety of eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, were evaluated in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, taxane, and capecitabine. PATIENTS AND METHODS: Eligible patients in this single-arm, open-label phase II study received eribulin mesylate (1.4 mg/m(2)) administered as a 2- to 5-minute intravenous infusion on days 1 and 8 of a 21-day cycle. The primary end point was objective response rate (ORR) assessed by independent review. RESULTS: Of 299 enrolled patients who had received a median of four prior chemotherapy regimens, 291 received eribulin (for a median of four cycles). Of these, 269 patients met key inclusion criteria for the primary efficacy analysis. The primary end point of ORR by independent review was 9.3% (95% CI, 6.1% to 13.4%; all partial responses [PRs]), the stable disease (SD) rate was 46.5%, and clinical benefit rate (complete response + PR + SD > or = 6 months) was 17.1%. The investigator-reported ORR was 14.1% (95% CI, 10.2% to 18.9%). Median duration of response was 4.1 months, and progression-free survival was 2.6 months. Median overall survival was 10.4 months. The most common treatment-related grade 3 or 4 toxicities were neutropenia (54%; febrile neutropenia, 5.5%), leukopenia (14%), and asthenia/fatigue (10%; no grade 4); grade 3 neuropathy occurred in 6.9% of patients (no grade 4). CONCLUSION: Eribulin demonstrated antitumor activity in extensively pretreated patients who had previously received an anthracycline, taxane, and capecitabine, with a manageable tolerability profile.

The odyssey of marine pharmaceuticals: a current pipeline perspective.

The global marine pharmaceutical pipeline consists of three Food and Drug Administration (FDA) approved drugs, one EU registered drug, 13 natural products (or derivatives thereof) in different phases of the clinical pipeline and a large number of marine chemicals in the preclinical pipeline. In the United States there are three FDA approved marine-derived drugs, namely cytarabine (Cytosar-U((R)), Depocyt((R))), vidarabine (Vira-A((R))) and ziconotide (Prialt((R))). The current clinical pipeline includes 13 marine-derived compounds that are either in Phase I, Phase II or Phase III clinical trials. Several key Phase III studies are ongoing and there are seven marine-derived compounds now in Phase II trials. The preclinical pipeline continues to supply several hundred novel marine compounds every year and those continue to feed the clinical pipeline with potentially valuable compounds. From a global perspective the marine pharmaceutical pipeline remains very active, and now has sufficient momentum to deliver several additional compounds to the marketplace in the near future; this review provides a current view of the pipeline.

Phase I study of eribulin mesylate administered once every 21 days in patients with advanced solid tumors.

PURPOSE: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of eribulin mesylate (E7389), a halichondrin B analogue, administered every 21 days in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Eribulin mesylate was given as a 1-hour infusion every 21 days at doses of 0.25, 0.5, 1, 2, 2.8, and 4 mg/m(2). The MTD was identified using an accelerated titration design. The pharmacokinetics of eribulin were evaluated in the plasma and urine with the first dose. RESULTS: Twenty-one patients were enrolled. At 4 mg/m(2), three patients experienced a DLT of febrile neutropenia on day 7. The dose level was reduced to 2.8 mg/m(2) where two of three patients experienced dose-limiting febrile neutropenia. Six additional patients were enrolled at 2 mg/m(2) (seven patients in total received this dose) and one of these patients experienced a neutropenic DLT. The MTD of eribulin mesylate was therefore 2 mg/m(2). Nonhematologic toxicities included alopecia, fatigue, anorexia, and nausea. Pharmacokinetic analysis showed linear kinetics for eribulin over the dose range studied and a terminal half-life of 2 days. The plasma-concentration-time profile exhibited a rapid distribution phase followed by a slow elimination phase. Drug clearance was nonrenal. One patient with non-small cell lung cancer achieved an unconfirmed partial response and 12 patients had stable disease. CONCLUSIONS: Eribulin mesylate administered as a 1-hour infusion every 21 days has a manageable toxicity profile at 2 mg/m(2), with further dose escalation limited by neutropenia.

A phase I study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced solid malignancies.

PURPOSE: Eribulin mesylate (E7389), a non-taxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analogue of halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This phase I study determined the maximum tolerated dose (MTD) and pharmacokinetics of eribulin administered on a 3 of 4 week schedule in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Patients received eribulin mesylate (1-hour i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. Dosing began at 0.25 mg/m(2) with escalation guided by dose-limiting toxicities (DLT). MTD, DLTs, safety, pharmacokinetics, and antitumor activity were characterized. RESULTS: Thirty-two patients received eribulin mesylate (0.25, 0.5, 0.7, 1.0, or 1.4 mg/m(2)). Neutropenia was the principal DLT: At 1.4 mg/m(2), two patients experienced grade 4 neutropenia, one of whom also developed grade 3 fatigue; three additional patients experienced grade 3 neutropenia and were not treated during cycle 1 on day 15. Therefore, the MTD was 1.0 mg/m(2). Fatigue (53% overall, 13% grade 3, no grade 4), nausea (41%, all grade 1/2), and anorexia (38% overall, 3% grade 3, no grade 4) were the most common eribulin-related adverse events. Eight patients reported grade 1/2 neuropathy (no grade 3/4). Eribulin pharmacokinetics were dose-proportional over the dose range studied. One patient (cervical cancer) achieved an unconfirmed partial response lasting 79 days. Ten patients reported stable disease. CONCLUSIONS: Eribulin mesylate, given on days 1, 8, and 15 of a 28-day cycle, exhibits manageable tolerability at 1.0 mg/m(2) with further dose escalation limited by neutropenia and fatigue.

Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.

PURPOSE: Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of the marine natural product halichondrin B. This open-label, single-arm, phase II study evaluated efficacy and tolerability of eribulin in heavily pretreated patients with metastatic breast cancer (MBC). METHODS: MBC patients who were previously treated with an anthracycline and a taxane received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia (at day 15), an alternative regimen of eribulin on days 1 and 8 of a 21-day cycle was administered. The primary end point was overall response rate. RESULTS: Of the 103 patients treated, the median number of prior chemotherapy regimens was four (range, one to 11 regimens). In the per-protocol population (n = 87), eribulin achieved an independently reviewed objective response rate (all partial responses [PRs]) of 11.5% (95% CI, 5.7 to 20.1) and a clinical benefit rate (PR plus stable disease > or = 6 months) of 17.2% (95% CI, 10.0 to 26.8). The median duration of response was 171 days (5.6 months; range, 44 to 363 days), the median progression-free survival was 79 days (2.6 months; range, 1 to 453 days), and the median overall survival was 275 days (9.0 months; range, 15 to 826 days). The most common drug-related grades 3 to 4 toxicities were as follows: neutropenia, 64%; leukopenia, 18%; fatigue, 5%; peripheral neuropathy, 5%; and febrile neutropenia, 4%. CONCLUSION: Eribulin demonstrated activity with manageable tolerability (including infrequent grade 3 and no grade 4 neuropathy) in heavily pretreated patients with MBC when dosed as a short IV infusion on days 1 and 8 of a 21-day cycle.