Robert Fram

XMT-1001, a novel polymeric camptothecin pro-drug in clinical development for patients with advanced cancer.

An overview of XMT-1001 is provided in the context of other topoisomerase I inhibitors conjugated to polymers or encapsulated in liposomes. XMT-1001 is a novel polymeric pro-drug derivative of camptothecin (CPT) with a molecular weight of 70 kDa, in which CPT is chemically tethered to a hydrophilic, biodegradable polyacetal polymer, poly(1-hydroxymethylethylene hydroxymethylformal), also called PHF or Fleximer(R). XMT-1001 releases CPT via intermediates camptothecin-20-O-(N-succinimidoglycinate) (CPT-SI), and camptothecin-20-O-(N-succinamidoyl-glycinate) (CPT-SA) over an extended time period. XMT-1001 has an improved therapeutic window compared to CPT and irinotecan in human tumor xenograft models, providing a compelling rationale for clinical development. A unique feature of XMT-1001 is its dual phase release mechanism for CPT which may result in lower levels of CPT in the urine and less bladder toxicity, a serious dose limiting toxicity associated with CPT and CPT conjugated to other polymers. XMT-1001 is being evaluated in patients with advanced cancer in an ongoing Phase 1 trial.

Pharmacokinetics and Antitumor Efficacy of XMT-1001, a Novel, Polymeric Topoisomerase I Inhibitor, in Mice Bearing HT-29 Human Colon Carcinoma Xenografts

Purpose: To evaluate the pharmacokinetics and tissue disposition of macromolecular camptothecin (CPT) drug conjugate, XMT-1001, and irinotecan (CPT-11) in mice bearing HT-29 xenograft tumors. Experimental Design: The antitumor efficacy of XMT-1001 was evaluated in the mouse HT-29 human colon carcinoma xenograft model. XMT-1001 was administered intravenously to female athymic nude (nu/nu) mice bearing established HT-29 xenograft tumors (n = 10) at 15, 30, and 60 mg CPT equivalents/kg on weekly or biweekly schedules. The tumor growth inhibition and tumor growth delay endpoints were used for efficacy evaluation. In the pharmacokinetic study, XMT-1001 was administered intravenously at a pharmacologically relevant dose of 60 mg CPT equivalents/kg × 1 via tail vein or an equimolar dose of CPT-11 at 100 mg/kg i.p. × 1. Mice (n = 3 per time point) were euthanized from 0.083 to 336 hours after XMT-1001 administration and from 0.083 to 24 hours after CPT-11. Plasma, tumor, and tissues were collected from all animals. A liquid chromatography–tandem mass spectrometry assay was used to measure XMT-1001, conjugate release products, CPT-20-O-(N-succinimido-glycinate; CPT-SI) and CPT-20-O-(N-succinamidoyl-glycinate; CPT-SA), and CPT. Results: After XMT-1001 administration, the majority of the plasma exposure is accounted for by conjugated CPT. XMT-1001 exhibited a prolonged exposure of conjugated drug, active conjugate primary release products, CPT-SI and CPT-SA, and active CPT, which was associated with greater antitumor response compared with CPT-11. Conclusions: XMT-1001 provides an extended systemic and tumor exposure of conjugated drug and shows improved antitumor effect compared with CPT-11. Clin Cancer Res; 18(9); 2591–602. ©2012 AACR.

A phase I clinical and pharmacokinetic study of the dolastatin analogue cemadotin administered as a 5-day continuous intravenous infusion

Purpose: The dolastatins are a class of naturally occurring cytotoxic peptides which function by inhibiting microtubule assembly and tubulin polymerization. Cemadotin is a synthetic analogue of dolastatin 15 with potent antiproliferative and preclinical antitumor activity. This report describes a phase I study to evaluate the administration of cemadotin to adult cancer patients by a 5-day continuous intravenous (CIV) infusion. Methods: All patients had histologically confirmed refractory solid tumors. The dose was escalated from an initial level of 2.5 mg/m2 (0.5 mg/m2 daily) according to a modified Fibonacci algorithm. A minimum of three patients was evaluated at each dose level until the maximum tolerated dose (MTD) was established. Treatment was repeated every 21 days until patients were removed from the study due to toxicity or disease progression. Drug-related toxicities were evaluated and graded by the U.S. National Cancer Institutes Common Toxicity Criteria. A radioimmunoassay (RIA) that detected both the parent drug and its metabolites with an intact N-terminal region of the molecule was used for pharmacokinetic studies. Results: Twenty heavily pretreated patients received a total of 40 courses of cemadotin over five dose levels ranging from 2.5 to 17.5 mg/m2. Reversible dose-related neutropenia was the principal dose-limiting toxicity and 12.5 mg/m2 was established as the MTD. Nonhematologic toxicities attributed to the drug were moderate, and there was no evidence of the cardiovascular toxicity noted in the prior phase I studies of cemadotin given IV as a 5-min injection or 24-h infusion. There were no objective antitumor responses. Time courses of the cemadotin RIA equivalent concentration in whole blood were defined in 14 patients during the first cycle of therapy. The RIA-detectable species exhibited apparent first-order pharmacokinetics across the entire range of doses. The mean ± SD of the observed steady-state blood concentration at the 12.5 mg/m2 MTD was 282 ± 7 nM (n=3). Blood levels decayed monoexponentially following the end of the infusion, with a mean half-life of 13.2 ± 4.3 h (n=14) in all patients. Mean values (n=14) of the total blood clearance and apparent volume of distribution at steady state were 0.52 ± 0.09 l/h/m2 and 9.9 ± 3.3 l/m2, respectively. Conclusions: The cardiotoxic effects of cemadotin were completely avoided by administering it as a 120-h CIV infusion. Thus, cardiovascular toxicity appears to be associated with the magnitude of the peak blood levels of the parent drug or its metabolites, whereas myelotoxicity is related to the duration of time that blood levels exceed a threshold concentration. Nevertheless, the data acquired during the extensive clinical experience with cemadotin requires careful examination to assess whether advancing this compound into disease-oriented efficacy studies is merited.

Phase I and Pharmacokinetic Study of LU79553, a DNA Intercalating Bisnaphthalimide, in Patients With Solid Malignancies

PURPOSE To determine the maximum-tolerated dose and characterize the pharmacokinetic behavior of LU79553, a novel bisnaphthalimide antineoplastic agent, when administered as a daily intravenous infusion for 5 days every 3 weeks. PATIENTS AND METHODS Patients with advanced solid malignancies received escalating doses of LU79553. Plasma sampling and urine collections were performed on both days 1 and 5 of the first course. RESULTS Thirty patients received 105 courses of LU79553 at doses ranging from 2 to 24 mg/m(2)/d. Proximal myopathy, erectile dysfunction, and myelosuppression precluded the administration of multiple courses at doses above 18 mg/m(2)/d. These toxicities were intolerable in two of six patients after receiving three courses at the 24-mg/m(2)/d dose level. At the 18-mg/m(2)/d dose, one of six patients developed febrile neutropenia and grade 2 proximal myopathy after three courses of LU79553. The results of electrophysiologic, histopathologic, and ultrastructural studies supported a drug-induced primary myopathic process. A patient with a platinum- and taxane-resistant papillary serous carcinoma of the peritoneum experienced a partial response lasting 22 months. Pharmacokinetics were dose-independent, optimally described by a three-compartment model, and there was modest drug accumulation over the 5 days of treatment. CONCLUSION Although no dose-limiting events were noted in the first two courses of LU79553, cumulative muscular toxicity precluded repetitive treatment with LU79553 at doses above 18 mg/m(2)/d, which is the recommended dose for subsequent disease-directed evaluations. The preliminary antitumor activity noted is encouraging, but the qualitative and cumulative nature of the principal toxicities, as well as the relatively small number of patients treated repetitively, mandate that rigorous and long-term toxicologic monitoring be performed in subsequent evaluations of this unique agent.

The spectrum of genitourinary abnormalities in patients with cryptorchidism, with emphasis on testicular carcinoma

A spectrum of genitourinary abnormalities occur in patients with cryptorchidism; the most important is the enhanced susceptibility to developing testis cancer. While the etiologic basis for developing testis cancer in cryptorchid patients remains controversial, failure of normal testicular development—testicular dysgenesis—may underlie carcinogenesis in the cryptorchid testis. This report reviews these associations as well as the characteristics of testis cancer in the cryptorchid testis and the evidence supporting early orchiopexy.

Abstract B52: Phase 1 study of XMT‐1001, a novel water soluble camptothecin conjugate, given as an intravenous infusion once every three weeks to patients with advanced solid tumors

Introduction: XMT‐1001 is a water soluble macromolecular conjugate of camptothecin (CPT). In this novel CPT pro‐drug, CPT is conjugated with a 70 kDa biodegradable hydrophilic polyacetal, poly (1‐hydroxymethylethylene hydroxymethylformal). XMT‐1001 has an improved therapeutic window compared with CPT and irinotecan in human tumor xenograft models, providing a compelling rationale for its clinical development. Methods: This is an open label, dose escalation study of XMT‐1001 given as an IV infusion once every 3 weeks. The objectives of the Phase 1 study are to determine the maximum tolerated dose (MTD) and to assess safety and pharmacokinetics (PK) of XMT‐1001. Initially 3 patients (pts) are entered at each dose level, with expansion to 6 pts if there is a dose limiting toxicity. Analyses of plasma and urine were performed for XMT‐1001 (conjugated CPT), 2 major drug release products, and for unconjugated (free) CPT. Results: Forty six patients with refractory solid tumors have received 141 cycles of XMT‐1001 at 13 dose levels ranging from 1.0–64.2 mg CPT equivalents (equiv.)/m2. Two pts had Grade (Gr) 3 infusion reactions consistent with hypersensitivity to study drug. Symptoms reversed upon discontinuation of study drug. Upon introduction of new clinical trial material with an improved formulation, no infusion reactions suggestive of hypersensitivity have occurred (25 pts, 79 cycles). No hemorraghic cystitis or ≥ Gr 3 diarrhea was noted. Gr 2 neutropenia occurred in 1 pt treated at 15.4 mg CPT equiv./m2. Stable disease was observed in 12 of 43 evaluable pts with the following tumor types and dose levels expressed in mg CPT equiv./m2: NSCLC (1.0 mg/m2, 6 wks; 20.5 mg/m2, 30 wks to date; 36.3 mg/m2, 18 wks to date), nasopharyngeal (36.3 mg/m2, 12 wks to date), ovarian (4.9 mg/m2, 12 wks), pancreas (4.9 mg/m2, 36 wks), appendiceal (7.3 mg/m2, 12 wks), bile duct (9.1 mg/m2, 18 wks), basal cell (11.6mg/m2, 6 wks), colon (15.4 mg/m2, 18 wks), gastric (20.5 mg/m2, 12 wks), and rectal (27.3mg/m2, 6 wks). The PK of XMT‐1001 (conjugated CPT) demonstrates dose proportional increases in exposure XMT‐1001 and confirms the formation of its expected release products. Levels of free CPT in urine have been low. Conclusions: 1. XMT‐1001 can be given safely to patients; 2. XMT‐1001 has a favorable PK profile; 3. Prolonged stable disease lasting ≥ 12 weeks was seen in 9 patients with advanced, refractory tumors at doses below MTD. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B52.

Abstract 2664: Pharmacokinetics of a novel fumagillol conjugate XMT-1107 in the rat and the dog

XMT-1107 is a novel polymer fumagillol derivative, comprised of the small molecule XMT-1191 conjugated to a 70 kDa biodegradable, hydrophilic polyacetal, poly(1-hydroxymethylethylene hydroxymethylformal) (PHF). The conjugated drug XMT-1107 is a prodrug that improves the pharmacokinetics (PK) of the active compound XMT-1191 and demonstrates significant antitumor activity in multiple rodent xenograft models providing a compelling rationale for clinical development. We evaluated the metabolism and PK of XMT-1107 in the rat and the dog and expect that the preclinical dog toxicokinetic (TK) data provide better guidance than the rat data for the assessment of XMT-1107 safety/PK in humans. XMT-1107 metabolism was studied in rodent, dog and human plasma as well as in liver microsomes. The PK of XMT-1107 was studied in rat and dog at a variety of doses and schedules. The extent and duration of the exposure was monitored over 120 hours post dosing. The analytical determinations of XMT-1107 and small molecule metabolites were carried out by LC/MS/MS. XMT-1107 was metabolized in rodent, dog and human plasma producing XMT-1191 and XMT-1201 (via conjugated XMT-1201) as major and minor metabolites, respectively. Considering that XMT-1201 does not bind to or inhibit MetAP2, the molecular target of XMT-1107, conjugated and free XMT-1191 are of most interest since conjugated XMT-1191 is a prodrug and XMT-1191 is its active release product. In both species the PK of conjugated and free XMT-1191 was approximately dose proportional with no marked gender differences. Consistent 2,000-4,000 fold differences between conjugated XMT-1191 and free XMT-1191 plasma exposure (AUC0–120) and Cmax suggest that observed pharmacological effects may result from extravascular distribution of conjugated XMT-1191 and local release of XMT-1191 rather than from systemic exposure to free XMT-1191. Conjugated XMT-1191 has a low volume of distribution, slow systemic clearance and is characterized by a t1/2 ranging from 27-35 hours in rat and 47-68 hours in dog. The 1.8-2.0-fold increase in conjugated XMT-1191 plasma t1/2 observed in dog relative to rat was accompanied by an approximately proportional increase in dose normalized exposure (AUC0–120) to conjugated XMT-1191 and conjugated XMT-1201. The rates for in vitro release of XMT-1191 and XMT-1201 from XMT-1107 in dog and human plasma were similar and at least 2 times lower than the release rates for corresponding compounds in rat plasma, suggesting that dog TK may be more predictive of human XMT-1107 PK compared to rat TK. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2664.