Time course study of long-term biocompatibility and foreign body reaction to intraneural polyimide-based implants.

The foreign body reaction (FBR) against an implanted device is characterized by the formation of a fibrotic tissue around the implant. In the case of interfaces for peripheral nerves, used to stimulate specific group of axons and to record different nerve signals, the FBR induces a matrix deposition around the implant creating a physical separation between nerve fibers and the interface that may reduce its functionality over time. In order to understand how the FBR to intraneural interfaces evolves, polyimide non-functional devices were implanted in rat peripheral nerve. Functional tests (electrophysiological, pain and locomotion) and histological evaluation demonstrated that implanted devices did not cause any alteration in nerve function, in myelinated axons or in nerve architecture. The inflammatory response due to the surgical implantation decreased after 2 weeks. In contrast, inflammation was higher and more prolonged in the device implanted nerves with a peak after 2 weeks. With regard to tissue deposition, a tissue capsule appeared soon around the devices, acquiring maximal thickness at 2 weeks and being remodeled subsequently. Immunohistochemical analysis revealed two different cell types implicated in the FBR in the nerve: macrophages as the first cells in contact with the interface and fibroblasts that appear later at the edge of the capsule. Our results describe how the FBR against a polyimide implant in the peripheral nerve occurs and which are the main cellular players. Increasing knowledge of these responses will help to improve strategies to decrease the FBR against intraneural implants and to extend their usability. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 746-757, 2018.

Pharmacokinetics and tolerability of the new second-generation nonnucleoside reverse- transcriptase inhibitor KM-023 in healthy subjects.

BACKGROUND: KM-023 is a new second-generation nonnucleoside reverse-transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus (HIV) type 1 infection. OBJECTIVE: This study determined KM-023 tolerability and pharmacokinetic characteristics in healthy subjects. MATERIALS AND METHODS: A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 80 healthy South Korean male volunteers. The subjects were allocated to single- or multiple-dose (once daily for 7 days) groups that received 75, 150, 300, or 600 mg drug or placebo in a 4:1 ratio. Safety and pharmacokinetic assessments were performed during the study. Plasma and urine concentrations were quantified using liquid chromatography-tandem mass spectrometry. RESULTS: The average maximum concentration (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC∞) values of KM-023 for the 75-600 mg doses in the single-dose study ranged from 440.2 ng/mL to 1,245.4 ng/mL and 11,142.4 ng · h/mL to 33,705.6 ng · h/mL, respectively. Values of the mean Cmax at a steady state and AUC within the dosing interval ranged from 385.1 ng/mL to 1,096.7 ng/mL and 3,698.9 ng · h/mL to 10,232.6 ng · h/mL, respectively, following 75-600 mg doses in the multiple-dose study. Dose proportionality was not observed for KM-023. KM-023 showed a 0.6-fold accumulation after multiple doses in the 600 mg dose group. The mean half-life values ranged between 20.7 and 31.2 hours. KM-023 was generally well tolerated without serious adverse events. CONCLUSION: KM-023 demonstrated dose- and time-dependent nonlinear pharmacokinetic characteristics after single or multiple doses over a dose range (75-600 mg) in healthy subjects. KM-023 showed favorable tolerability in this study. This Phase I clinical trial information can be used to design further clinical studies appropriately to evaluate KM-023 in patients with HIV-1 infection.

Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer.

PURPOSE: BMS-641988 is an androgen receptor antagonist with increased potency relative to bicalutamide in both in vitro and in vivo prostate cancer models. A first-in-man phase I study was conducted to define the safety and tolerability of oral BMS-641988 in patients with castration-resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN: Doses were escalated from 5 to 150 mg based on discrete pharmacokinetic parameters in cohorts of three to six subjects. After establishing safety with 20 mg of BMS-641988 in the United States, a companion study was opened in Japan to assess differences in drug metabolism between populations. RESULTS: Sixty-one men with CRPC were treated with daily BMS-641988. The pharmacokinetics (PK) of BMS-641988 and its active metabolites were proportional to dose. One patient experienced an epileptic seizure at a dose of 60 mg administered twice. Despite achieving target drug exposures, antitumor activity was limited to one partial response. Seventeen of 23 evaluable patients (74%) exhibited stable disease on imaging (median 15 weeks; range 8-32), and 10 of 61 patients (16%) achieved a ≥ 30% decline in levels of prostate-specific antigen (PSA). Partial agonism was seen within the context of this study upon removal of the drug as evidenced by a decrease in PSA. CONCLUSIONS: Although the clinical outcomes of predominantly stable disease and partial agonism were similar to what was observed in the preclinical evaluation of the compound, the limited antitumor activity of BMS-641988 at therapeutic dose levels coupled with an episode of seizure activity led to study closure.

A phase II trial of amonafide in patients with endometrial cancer: a Gynecologic Oncology Group Study.

Twenty-nine evaluable patients with endometrial cancer were treated with amonafide 300 mg/m2 for 5 consecutive days every 3 weeks. Two partial responses (8%) were seen. Hematologic toxicity was severe or life-threatening in 13 patients occurring as follows: leukopenia in 13 patients (45%); thrombocytopenia in 10 patients (34%); granulocytopenia in 13 patients (45%); and anemia in four patients (14%). In view of the low response rate and high toxicity, this dose schedule of amonafide does not warrant further investigation in endometrial cancer.

A phase II trial of amonafide in patients with mixed mesodermal tumors of the uterus: a Gynecologic Oncology Group study.

Amonafide demonstrated a poor response rate and substantial toxicity in patients who had measurable, advanced mixed mesodermal tumors of the uterus. Amonafide-a drug that acts through intercalation of tumor DNA-was used to treat 16 patients who had measurable, advanced mixed mesodermal tumors of the uterus as part of a Gynecologic Oncology Group (GOG) Phase II study. The starting dose was 300 mg/m2 intravenously over 1 hour for 5 consecutive days every 3 weeks. Severe or life-threatening hematologic toxicity occurred in 50% of the patients. Two patients experienced vomiting requiring hospitalization. Other toxicities were not severe. One patient had a partial response and one had stable disease, each lasting 4 months. This dose schedule was associated with poor response rate and substantial toxicity.

Amonafide in patients with leiomyosarcoma of the uterus: a phase II Gynecologic Oncology Group study.

Twenty-six evaluable patients who had leiomyosarcoma of the uterus were treated with amonafide, 300 mg/m2, for 5 consecutive days every 3 weeks. One partial response (4%) resulted. Hematologic toxicity was substantial, with grade 3 or 4 events occurring as follows: leukopenia, 12 patients (46%); thrombocytopenia, 4 patients (15%); and granulocytopenia, 7 patients (27%). One patient had transient grade 4 renal failure. Considering the poor activity and substantial toxicity that was observed, no further studies are planned by the Gynecologic Oncology Group using amonafide at this dose schedule in leiomyosarcomas.

An ECOG phase II study of amonafide in unresectable or recurrent carcinoma of the head and neck (PB390). Eastern Cooperative Oncology Group.

The purpose of this study was to determine the efficacy and toxicity of amonafide in unresectable or recurrent head and neck cancer and to determine if the degree of toxicity with amonafide correlated with the acetylator phenotype of the patient. Thirty patients were registered on the study and received amonafide, 300 mg/m2, over two hours each day for five consecutive days every 21 days. There was one partial response (3%) which lasted four months. The dose-limiting toxicity was myelosuppression. Acetylator phenotype was determined prior to treatment using HPLC to quantitate caffeine metabolites in urine samples after administration of caffeine. This pharmacokinetic evaluation was performed in 21 patients and revealed that (17/21) 81% of the patients were slow acetylators and 19% of the patients were rapid acetylators. No association was found between acetylator phenotype and toxicity in our patient population. Based on this study, it appears that amonafide given at 300 mg/m2 for 5 consecutive days every 21 days is not active in squamous cell carcinoma of the head and neck, and that acetylator status does not correlate with toxicity.

Individualized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender.

Amonafide is extensively metabolized, including conversion by N-acetylation to an active metabolite. Our previous studies have shown that fast acetylators of amonafide have increased toxicity, and we have recommended doses of 250 and 375 mg m-2 day-1 for 5 days, for fast and slow acetylators, respectively. Despite phenotype-specific dosing, significant variability in leukopenia persisted. The goal of this study was to construct and validate a pharmacodynamic model-based dosing strategy for amonafide, to try to further decrease inter-patient variability in leukopenia. The model was based on a training data set of 41 patients previously treated with amonafide. The first cycle nadir WBC was modelled as a function of dose, acetylator phenotype and baseline patient factors. This model was validated prospectively on patients similar to those in our previous studies. Based on the training data set, the optimal model was defined by three factors: acetylator phenotype, gender, and pretreatment WBC. Using this model and a target WBC nadir of 1700 microliters-1, six dosing strata were prospectively evaluated. A total of 24 fast acetylators received either 238 or 276 mg m-2 day-1 and 20 slow acetylators received between 345 and 485 mg m-2 day-1. The mean (+/- SE) error (deviation from target nadir) was 430 (+/- 240) cells microliters-1. Submaximal treatment (yielding grade 0-1 leukopenia) was limited to 20% of patients, while 55% experienced grade 2-3 toxicity. A complex dosing strategy for amonafide is feasible, employing prospective acetylator phenotyping, model-guided dosing, and adaptive control.

Clinical pharmacokinetics of amonafide (NSC 308847) in 62 patients.

Amonafide (A) demonstrates dose-related increases in area under the curve (AUC) and Cmax values. Total body clearance for A (ranging from 44.2 to 53.8 L/hr/m2) is relatively constant within the dosing range of this study. The dose-related increase of AUC was also observed for the two identified metabolites, acetylamonafide (AA) and noramonafide (NA). A and NA plasma data could be described by a four-compartmental model (two compartments for A, one compartment each for NA and AA). The fitting for NA was poor owing to its low plasma concentration. The terminal half-lives for A, NA, and AA were in the range of 3-6 hr. No cumulative accumulation of parent compound or metabolites was detected after daily administration, The concentrations of A, NA, and AA 24 hr after dosing were either below or very close to the quantitative limits of the assay. Polymorphic disposition of A was confirmed by a frequency distribution of AUC value versus dose plot.

Phase II study of Mitonafide in advanced and relapsed colorectal cancer.

BACKGROUND: This study investigated the antitumoral activity in colorectal cancer and toxicity of a 5-day continuous infusion of a new cytostatic agent, Mitonafide, that had previously shown to be neurotoxic when administered as a short daily x 5 days infusion. PATIENTS AND METHODS: Seventeen chemotherapy-naive patients with advanced or relapsed colorectal cancer and measurable disease entered the study. All but one received a 120-hour (5-day) continuous infusion of Mitonafide at a starting dose of 200 mg/m2/day every 3 weeks. Toxicity evaluation was performed after each course and response assessment every 2 courses using the standard World Health Organization (WHO) criteria completed by the "Mini-mental state" test for cognitive status examination. RESULTS: Sixteen patients received a total of 41 courses of Mitonafide which resulted to be severely myelotoxic. In total, 13/16 patients had WHO grade 3-4 neutropenia, 7 of them with infection, and the treatment had to be stopped in 3 patients after only 1 course due to excessive toxicity. No central nervous system toxicity was observed. No objective responses were evidenced. CONCLUSIONS: At the dose and schedule of administration used, Mitonafide is not active in colorectal cancer and induces severe myelotoxicity thus not deserving further studies in this indication.

Phase II study of mitonafide in non-small cell lung cancer (NSCLC).

BACKGROUND: The new intercalative agent Mitonafide was shown in early clinical trials to be toxic to the central nervous system when administered as a short intravenous infusion, but not when given as a 120-hour continuous infusion. Thus, clinical development in different tumor types was pursued using only this administration schedule. PATIENTS AND METHODS: Forty-nine patients with previously untreated non-small cell lung cancer (NSCLC) and at least one measurable site received Mitonafide as a 120-hour continuous (5 days) infusion every 3 weeks. The starting dose was 170 mg/m2/day x 5 in the first 26 patients and 200 mg/m2/day x 5 in the remainder. Patients were evaluated for toxicity after each course and for response every two courses and remained on treatment until excessive toxicity or disease progression were observed. A special test, the "Mini-mental state", was used to assess patients' cognitive functions. RESULTS: Of the 49 patients entered, 42 were evaluable for response and toxicity. Toxicity consisted mainly of myelosuppression and no neurologic side effects were observed. Only one patient presented a partial response. CONCLUSIONS: Although definitively safe with this schedule of administration, Mitonafide is not active in NSCLC.

Amonafide: An active agent in the treatment of previously untreated advanced breast cancer--a cancer and leukemia group B study (CALGB 8642).

Amonafide is a new imide derivative of naphthalic acid. The drug had demonstrated significant activity in preclinical studies and some activity in Phase I trials. The drug is extensively metabolized and detected in plasma and urine. Its toxicity has previously been correlated to the formation of an active metabolite, N-acetyl-amonafide. Amonafide was chosen for inclusion in the Cancer and Leukemia Group B (CALGB) master metastatic breast cancer protocol. CALGB 8642 randomizes previously untreated metastatic breast cancer patients either to one of several Phase II agents given for up to four cycles and then followed by standard cyclophosphamide-doxorubicin-5-fluorouracil, or to immediate treatment with standard cyclophosphamide-doxorubicin-5-fluorouracil. The end point of CALGB 8642 is to assess the difference in survival, toxicity, and overall response when limited exposure to Phase II agents precedes standard chemotherapy. This report deals only with amonafide as a Phase II agent. Comparisons with the cyclophosphamide-doxorubicin-5-fluorouracil arm will not be addressed. Patients had to have histologically documented measurable breast cancer and a performance status of 0-1. Patients could not have had prior chemotherapy for metastatic disease. Prior adjuvant chemotherapy was permitted. Patients could not have visceral crisis. Amonafide was given at 300 mg/m2/day i.v. for 5 days, and repeated at 21-day intervals for a maximum of four cycles. Escalation and reduction in dose was mandated dependent on hematotoxicity or lack thereof. Toxicity was primarily hematological and bimodal: 32% had grade 3 or 4 leukopenia and 24% had grade 3 or 4 thrombocytopenia; 22% had no leukopenia and 44% had no thrombocytopenia. The response rate was 18%, including one complete response. When response was analyzed by hematological toxicity, there was a 35.7% response if patients had leukopenia grade 3/4 (versus 8.3%, P = 0.08). There was a 50% response if patients had thrombocytopenia grade 3/4 (versus 7.1%, P = <0.01). We conclude that amonafide is somewhat active in previously untreated breast cancer patients. There may be a steep dose-response curve, based on the significant correlation between myelosuppression and response. Rates of responses in patients adequately dosed (i.e., with significant hematotoxicity) with amonafide ranged from 35 to 50%. Further studies will incorporate individualized dosing based on pretreatment acetylator phenotyping.

Population pharmacodynamic study of amonafide: a Cancer and Leukemia Group B study.

PURPOSE: To determine if variability in toxicity of amonafide during phase II trials could be correlated with pharmacokinetic variability. PATIENTS AND METHODS: Seventy-three patients enrolled onto three Cancer and Leukemia Group B (CALGB) phase II trials of amonafide (300 mg/m2 daily for 5 days) were studied, using a limited sampling strategy (45 minutes and 24 hours) to estimate the amonafide area under the plasma concentration-time curve (AUC). Concentrations of N-acetyl-amonafide, an active metabolite, were also determined. RESULTS: The primary determinant of toxicity at a fixed dose of amonafide was the extent of N-acetylation. Fast acetylators (36% of patients) had significantly greater toxicity than slow acetylators (64% of patients), with median WBC nadirs of 500/microL and 3,400/microL, respectively (P < or = .001). In a multivariate analysis, lower pretreatment WBC count, lower albumin level, and nonwhite race were also independently associated with toxicity. Further analysis of interracial differences demonstrated that minority women had slower clearance of amonafide (P = .026) and a higher incidence of grade 4 leukopenia (P = .042). CONCLUSION: The highly variable toxicity of amonafide is primarily due to genetic differences in N-acetylation. Other genetic (race) and acquired factors (baseline WBC count and albumin level) also appear to influence the extent of toxicity observed following administration of this agent.

Phase II study of amonafide in patients with recurrent glioma.

Amonafide, a novel imide derivative with broad preclinical antitumor activity, achieves significant cerebrospinal fluid levels in animal models. In order to test its antitumor activity in patients with recurrent diffuse infiltrative glioma of the astrocytic and oligodendroglial type, we performed a phase II clinical trial. Of the 22 eligible and evaluable patients treated, 2 (9%) experienced tumor regression lasting more than one year. No other patients experienced tumor regression; one remained stable more than six months. Toxicities consisted primarily of myelosuppression, vomiting, and venous irritation at the infusion site. We conclude that amonafide has minimal activity in recurrent glioma patients. Further investigations are not warranted in this study population.

Phase II study of amonafide in the treatment of patients with advanced squamous cell carcinoma of the head and the neck. An Illinois Cancer Center study.

Amonafide (nafidimide), a synthetic organic compound with an inhibitory effect on cellular replication, was used in a phase II study conducted by the Illinois Cancer Center in order to assess its efficacy and toxicity in advanced or recurrent squamous cell cancer of the head and neck. Eligible patients had received no more than one prior adjuvant or neoadjuvant chemotherapy, had normal bone marrow, renal and hepatic function, ECOG performance status of 0-2, and bidimensionally measurable disease. Eligible patients were administered amonafide at a starting dose of 300 mg/m2 for five consecutive days every 3 weeks with dose escalation or de-escalation according to established hematologic criteria in the absence of disease progression. Nineteen of 22 entered patients were evaluable for response and all patients were evaluable for toxicity. Eleven of 19 patients achieved stable disease. Median time to progression after start of treatment was 57 days, for the 18 patients for whom the date of progression is known. There were no partial or complete responses. Hematologic toxicity was dose limiting with grade 3-4 neutropenia in 50 percent of patients and 4 deaths associated with neutropenic sepsis. Non-hematologic toxicity was mild to moderate with nausea and vomiting predominating. In this study, amonafide was a myelotoxic, inactive treatment in advanced/recurrent head and neck cancer. Further use in head and neck cancer appears unwarranted.

Phase II trial of gallium nitrate, amonafide and teniposide in metastatic non-small cell lung cancer. An Eastern Cooperative Oncology Group study (E2588).

Fifty-five patients with metastatic non-small cell lung cancer (NSCLC) were entered into this phase II randomized study for evaluating three new agents: gallium nitrate, amonafide and teniposide. The patients had to have ECOG performance status 0 or 1, no prior chemotherapy, and adequate hematological, hepatic and renal functions. Forty-seven patients were eligible and evaluable. Fourteen were randomized to receive gallium nitrate, 18 to amonafide and 15 to teniposide. Seventy-four percent of eligible patients were male. The majority of patients (89%) had an ECOG performance status 1. ECOG grade 4 toxicity occurred twice in patients on gallium nitrate, seven times on amonafide and 18 times on teniposide. The cause of death was attributed to amonafide in one patients (from sepsis) and to teniposide in two patients (due to infection and leukopenia). There was no objective response in all the patients entered. The overall survival times ranged from 2 weeks to 156 weeks with a medium of 23 weeks. There were no survival differences among the three treatment arms. We conclude that gallium nitrate, amonafide and teniposide are inactive in metastatic NSCLC and do not warrant any further testing in this disease.

Phase II trial of amonafide for the treatment of advanced, hormonally refractory carcinoma of the prostate. A Southwest Oncology Group study.

Amonafide (benzisoquinolinedione; NSC 308847) was subjected to a Phase II trial for the treatment of advanced hormone-refractory carcinoma of the prostate. In addition to adequate baseline organ functions, patients were required to have a favorable performance status, bidimensionally measurable disease and no prior chemotherapy. Amonafide was given at a dose of 225 mg/m2 intravenously daily for 5 days. Treatment cycles were repeated every 21 days. Dose escalation and reduction schema were used based upon toxicities from preceding cycles. Of 47 patients enrolled, 43 were evaluable. The most common toxicities were hematologic to include leukopenia (72%), granulocytopenia (32.6%), and thrombocytopenia (44.2%). There were no complete responses and only 5 partial responses for an overall response rate of 12% (95% confidence interval: 4-25%). The results indicate that Amonafide, in the dose and schedule tested, lacks sufficient activity against hormone-refractory prostate cancer to warrant further trials.

Bootstrap validation of pharmacodynamic models defined via stepwise linear regression.

When a pharmacodynamic model is to be considered as the basis for individualized drug dosing, validation of the model is clearly warranted. Rigorous validation is problematic when the training data set to be modeled has too few data points and no independent test data set exists. A simulation method known as the bootstrap lends itself particularly well to this dilemma. Bootstrap sampling allows simulation of needed test data sets that mimic the initial data set. Model validation is then undertaken by repeating the model formulation procedure on the bootstrap samples. For illustration, a pharmacodynamic model for leukopenia was constructed by stepwise linear regression from data of 41 patients with cancer treated with the drug amonafide. Stepwise regression analyses were then repeated for 100 bootstrap samples, which verified the initial selection of covariates for the model. Next the regression parameters and residual error standard deviation of the model were repeatedly estimated for 200 additional bootstrap samples. The bootstrap results confirmed the initial formulation of the pharmacodynamic model from the training data set.

A Gynecologic Oncology Group phase II study of amonafide (NSC #308847) in squamous cell carcinoma of the cervix.

Twenty evaluable patients with squamous cell carcinoma of the cervix, who had previously received a cisplatin-containing regimen, were treated with amonafide 300 mg/m2 over 1 hour for 5 consecutive days every 3 weeks. One partial response (5%) was seen. Hematologic toxicity was substantial with severe or life-threatening events occurring as follows: leukopenia, 5 patients (25%); thrombocytopenia, 4 patients (20%); granulocytopenia, 2 patients (10%). One patient experienced acute bilateral open-angle glaucoma immediately after treatment, and another developed gastric ulceration with life-threatening gastrointestinal bleeding. In view of the low response rate and high toxicity, amonafide does not warrant further investigation as second-line chemotherapy in squamous cell carcinoma of the cervix.

Phase II trial of amonafide in patients with advanced metastatic or recurrent endometrial adenocarcinoma. A Southwest Oncology Group study.

Amonafide, a benzisoquinoline-1,3-dione was administered to 38 patients with recurrent or metastatic, bidimensionally measurable endometrial cancer. There were 34 patients with no prior cytotoxic chemotherapy, performance status of 0-2, and normal bone marrow, renal, and hepatic function were eligible for response and toxicity evaluation. Amonafide, 300 mg/m2, was administered intravenously over 1 hour daily for 5 consecutive days. Courses were repeated every 21 days. The major grade 3 or 4 toxicities were hematologic with granulocytopenia in 18 patients (53%), thrombocytopenia in 6 patients (18%), and anemia in 8 patients (24%). Infectious complications occurred in 3 patients (9%). Other side effects included cardiac dysrhythmias, hypotension, pain and phlebitis at the site of injection, nausea, vomiting, and flu-like symptoms. The overall objective response rate was 6% (95% confidence interval of 1-20%); 2 patients had a complete response (6%), 9 patients had stable disease (26%) and 21 patients had progressive disease (62%). Two patients had insufficient follow-up for response determination and are assumed to be nonresponders. The median survival of the eligible patients was 8 months. With the toxicity observed and the low response rate, amonafide at this dose and schedule has no efficacy in the treatment of endometrial cancer.