A Phase I Dose-Escalation Study to Evaluate the Safety and Tolerability of Evofosfamide in Combination with Ipilimumab in Advanced Solid Malignancies.

PURPOSE: As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically "cold" cancers, which are intrinsically insensitive to immunotherapy, as well as in "hot/warm" metastatic cancers that are, atypical of such cancers, resistant to immunotherapy. PATIENTS AND METHODS: In a phase I, 3+3 dose-escalation trial (NCT03098160), evofosfamide (400-640 mg/m2) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1-2, while the latter was administered on day 8 of cycles 1-4. Response was assessed using immune-related RECIST and retreatment was allowed, if deemed beneficial, after completion of cycle 4 or at progression. RESULTS: Twenty-two patients were enrolled, of whom 21 were evaluable, encompassing castration-resistant prostate cancer (n = 11), pancreatic cancer (n = 7), immunotherapy-resistant melanoma (n = 2), and human papillomavirus-negative head and neck cancer (n = 1). Drug-related hematologic toxicities, rash, fever, nausea, vomiting, and elevation of liver enzymes were observed in > 10% of patients. The most common drug-related grade 3 adverse event was alanine aminotransferase elevation (33.3%). Two patients discontinued ipilimumab and 4 required evofosfamide deescalation due to toxicity. Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease. The best responses were observed at 560 mg/m2 evofosfamide. Preexisting immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved peripheral T-cell proliferation and increased intratumoral T-cell infiltration into hypoxia. CONCLUSIONS: No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted.

Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity.

BACKGROUND AND PURPOSE: Esophageal cancer incidence is increasing and is rarely curable. Hypoxic tumor areas cause resistance to conventional therapies, making them susceptible for treatment with hypoxia-activated prodrugs (HAPs). We investigated in vivo whether the HAP evofosfamide (TH-302) could increase the therapeutic ratio by sensitizing esophageal carcinomas to radiotherapy without increasing normal tissue toxicity. MATERIALS AND METHODS: To assess therapeutic efficacy, growth of xenografted esophageal squamous cell (OE21) or adeno (OE19) carcinomas was monitored after treatment with TH-302 (50 mg/kg, QD5) and irradiation (sham or 10 Gy). Short- and long-term toxicity was assessed in a gut mucosa and lung fibrosis irradiation model, sensitive to acute and late radiation injury respectively. Mice were injected with TH-302 (50 mg/kg, QD5) and the abdominal area (sham, 8 or 10 Gy) or the upper part of the right lung (sham, 20 Gy) was irradiated. Damage to normal tissues was assessed 84 hours later by histology and blood plasma citrulline levels (gut) and for up to 1 year by non-invasive micro CT imaging (lung). RESULTS: The combination treatment of TH-302 with radiotherapy resulted in significant tumor growth delay in OE19 (P = 0.02) and OE21 (P = 0.03) carcinomas, compared to radiotherapy only. Irradiation resulted in a dose-dependent decrease of crypt survival (P < 0.001), mucosal surface area (P < 0.01) and citrulline levels (P < 0.001) in both tumor and non-tumor bearing animals. On the long-term, irradiation increased CT density in the lung, indicating fibrosis, over time. TH-302 did not influence the radiation-induced short-term and long-term toxicity, confirmed by histological evaluation. CONCLUSION: The combination of TH-302 and radiotherapy might be a promising approach to improve the therapeutic index for esophageal cancer patients.

A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma.

PURPOSE: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma. Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard, which is selectively activated under hypoxia. This trial was designed as a phase I/II study investigating evofosfamide in combination with dexamethasone, and in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. PATIENTS AND METHODS: Fifty-nine patients initiated therapy, 31 received the combination of evofosfamide and dexamethasone, and 28 received the combination of evofosfamide, bortezomib, and dexamethasone. Patients were heavily pretreated with a median number of prior therapies of 7 (range: 2-15). All had previously received bortezomib and immunomodulators. The MTD, treatment toxicity, and efficacy were determined. RESULTS: The MTD was established at 340 mg/m2 evofosfamide + dexamethasone with dose-limiting mucositis at higher doses. For the combination of evofosfamide, bortezomib, and dexamethasone, no patient had a dose-limiting toxicity (DLT) and the recommended phase II dose was established at 340 mg/m2. The most common ≥grade 3 adverse events (AE) were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients), and leukopenia (9 patients). Skin toxicity was reported in 42 (71%) patients. Responses included 1 very good partial response (VGPR), 3 partial response (PR), 2 minor response (MR), 20 stable disease (SD), and 4 progressive disease (PD) for evofosfamide + dexamethasone and 1 complete response (CR), 2 PR, 1 MR, 18 SD, and 5 PD for evofosfamide + bortezomib + dexamethasone. Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months. CONCLUSIONS: Evofosfamide can be administered at 340 mg/m2 twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma.

Does cyclophosphamide still play a role in glomerular diseases?

Cyclophosphamide is a prodrug that is converted to inactive carboxy-cyclophosphamide, acrolein and phosphoramide mustard, an agent that adds alkyl groups to oxygen and nitrogen atoms of guanine, one of the four nitrogen bases that form the DNA nucleotides, causing DNA cross-links and introducing DNA breaks. These cytotoxic and mutagenic effects mainly occur in proliferating cells. Repair mechanisms may prevent DNA damage in quiescent cells, but they may be insufficient to contrast the side effects of cyclophosphamide if high doses of the drug are used. Most adverse events are dose- and age-dependent. Phosphoramide mustard can cause bone marrow toxicity, gonadal toxicity, and may favor the development of leukemia, bladder cancer and other types of malignancy. Acrolein can produce hemorrhagic cystitis and even bladder fibrosis when given for prolonged periods. A number of precautional measures should be taken to prevent these untoward events. In particular, long-term administration and high doses of cyclophosphamide should be avoided whenever possible. Today the indications to cyclophosphamide in glomerular diseases are more restricted than in the past, but the drug is still used as a steroid-sparing agent in steroid-sensitive minimal change disease and focal segmental glomerulosclerosis. In membranous nephropathy, cyclophosphamide, alternated or associated with corticosteroids, proved to be beneficial in obtaining remission of nephrotic syndrome and preserving renal function. Cyclophosphamide is considered as a first-line treatment for rapidly progressive glomerulonephritis and the hectic phases of lupus nephritis. In conclusion, cyclophosphamide is a cheap drug that may be useful in a number of glomerular diseases but it may lead to severe side effects. A close monitoring of blood count and clinical conditions, as well as low cumulative doses of cyclophosphamide are strongly recommended when using the drug in patients with renal diseases.

The fate of new fosfamides in phase III studies in advanced soft tissue sarcoma.

For decades, doxorubicin alone or in combination with ifosfamide has been used in advanced soft tissue sarcoma (STS). In 2014, a comparison of doxorubicin alone versus the combination with ifosfamide (in the randomised phase III EORTC 62012) showed no difference in overall survival (OS), but a difference in response and progression-free survival (PFS) were observed in favour of the combination but at the expense of increased toxicity. Newer fosfamides, with slightly different modes of action, and potentially less toxicity, namely evofosfamide and palifosfamide have recently been tested in randomised phase III clinical trials in STS. The TH CR-406/SARC021 (June 2017) and the PICASSO III (September 2016) studies compared doxorubicin, as the standard arm, to doxorubicin in combination with evofosfamide and palifosfamide, respectively. In both studies, the combination arm produced increased response rates but at the expense of higher toxicity. However, there was no difference in OS or PFS in favour of the combination. Importantly, the median OS of patients receiving standard of care, doxorubicin, in both studies appeared improved from 12.8 months (95.5% CI 10.5-14·III) in the EORTC 62012 to 16.9 months (95% CI 14.8 to 22.9) in PICASSO III and 19.0 months (95% CI 16.2-22.4) in TH CR-406/SARC021. The results of these three randomised phase III studies highlight several critical issues related to the design and conduct of such trials in STS. We discuss these issues aiming to contribute to the ongoing debate about the optimal approach to perform clinical research in STS.

Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. METHODS: We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m2 via bolus injection administered over 5-20 min or continuous intravenous infusion for 6-96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m2 intravenously for 30-60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. FINDINGS: Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1·06, 95% CI 0·88-1·29; p=0·527), with a median overall survival of 18·4 months (95% CI 15·6-22·1) with doxorubicin plus evofosfamide versus 19·0 months (16·2-22·4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3-4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3-4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one (<1%) patient in the doxorubicin alone group (lactic acidosis [n=1]). INTERPRETATION: The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting. FUNDING: Threshold Pharmaceuticals.

PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma.

Purpose Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites. The PICASSO III trial compared doxorubicin plus palifosfamide with doxorubicin plus placebo in patients who had received no prior systemic therapy for metastatic soft tissue sarcoma. Patients and Methods Patients were randomly assigned 1:1 to receive doxorubicin 75 mg/m2 intravenously day 1 plus palifosfamide 150 mg/m2/d intravenously days 1 to 3 or doxorubicin plus placebo once every 21 days for up to six cycles. The primary end point was progression-free survival (PFS) by independent radiologic review. Results In all, 447 patients were randomly assigned to receive doxorubicin plus palifosfamide (n = 226) or doxorubicin plus placebo (n = 221). Median PFS was 6.0 months for doxorubicin plus palifosfamide and 5.2 months for doxorubicin plus placebo (hazard ratio, 0.86; 95% CI, 0.68 to 1.08; P = .19). Median overall survival was 15.9 months for doxorubicin plus palifosfamide and 16.9 months for doxorubicin plus placebo (hazard ratio, 1.05; 95% CI, 0.79 to 1.39; P = .74). There was a higher incidence of grade 3 to 4 adverse events in the doxorubicin plus palifosfamide arm (63.6% v 50.9%) including a higher rate of febrile neutropenia (21.4% v 12.6%). Conclusion No significant difference in PFS was observed in patients receiving doxorubicin plus palifosfamide compared with those receiving doxorubicin plus placebo. The observed median PFS and overall survival in this large, international study can serve as a benchmark for future studies of doxorubicin in metastatic soft tissue sarcoma.

Phase I study of evofosfamide, an investigational hypoxia-activated prodrug, in patients with advanced leukemia.

Tumor hypoxia causes resistance to radiation and chemotherapy. Evofosfamide (TH-302) has exhibited specific hypoxia-dependent cytotoxicity against primary acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples in vitro. Based on these findings, a Phase I study of evofosfamide was designed for patients with relapsed/refractory leukemia (NCT01149915). In this open-label study, patients were treated with evofosfamide as a 30-60 min/day infusion on Days 1-5 of a 21-day cycle (Arm A, n = 38) or as a continuous infusion over 120 hr over Days 1-5 of a 21-day cycle (Arm B, n = 11). Forty-nine patients were treated including 39 (80%) with AML and 9 (18%) with ALL. Patients had received a median of five prior therapies. In Arm A, the dose-limiting toxicities (DLTs) were grade 3 esophagitis, observed at a dose of 550 mg/m(2) . The maximum tolerated dose (MTD) was a daily dose of 460 mg/m(2) . In Arm B, the DLTs were grade 3 stomatitis and hyperbilirubinemia, observed at a daily dose of 460 mg/m(2) . The continuous infusion MTD was a daily dose of 330 mg/m(2) . Hypoxia markers HIF-1α and CAIX were highly expressed in leukemic bone marrow and were significantly reduced after evofosfamide therapy. The combined overall response rate in Arms A and B was 6% (2 CR/CRi and 1 PR), with all responses seen in Arm A. Evofosfamide has shown limited activity in heavily pretreated leukemia patients. Further evaluation investigating evofosfamide in combination with cytotoxic or demethylating agents is warranted. Am. J. Hematol. 91:800-805, 2016. © 2016 Wiley Periodicals, Inc.

Tumor hypoxia is a therapeutic target in soft-tissue sarcoma.

TH-302 shows antitumor activity in combination with doxorubicin in advanced soft-tissue sarcoma.

An improved synthesis of lysosomal activated mustard prodrug for tumor-specific activation and its cytotoxic evaluation.

Cyclophosphamide, an alkylating agent widely used as anticancer agent, biotransformed in vivo to unstable phosphoramidic mustard and acrolein, where the latter metabolite has been found responsible for hemorrhagic cystitis and renal toxicity. Being one of the most popular strategies to avoid these deleterious effects, prodrug design has been attempted, which can, in addition, enable selective drug targeting. Our efforts to design, synthesize and evaluate the enzymatically activated prodrug phosphorodiamidic mustard as potential candidate for selective chemotherapy in antibody-directed enzyme prodrug therapy or prodrug monotherapy strategies are described. We propose an improved synthesis of prodrug 14, consisting of a galactose moiety, a spacer and a cytotoxic drug and its cytotoxicity has been investigated. The prodrug 14 has been found to be nontoxic (in vitro) which could be a valuable candidate for further development.

A phase I study of the safety and pharmacokinetics of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma.

PURPOSE: The purpose of this study was to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics and preliminary activity of TH-302, a hypoxia-activated prodrug, in combination with doxorubicin in patients with advanced soft tissue sarcoma. PATIENTS AND METHODS: TH-302 was administered intravenously on days 1 and 8 and doxorubicin 75 mg/m² on day 1 (2 h after TH-302) of every 3-week cycle. TH-302 starting dose was 240 mg/m² with a classic 3 + 3 dose escalation. Pharmacokinetics were assessed on days 1 and 8 of cycle 1. Tumor assessments were performed after every second cycle. RESULTS: Sixteen patients enrolled. Prophylactic growth factor support was added due to grade 4 neutropenia. The MTD was 300 mg/m². DLTs at 340 mg/m² were neutropenia-associated infection and grade 4 thrombocytopenia. Common adverse events included fatigue, nausea and skin rash. There was no evidence of pharmacokinetic interaction between TH-302 and doxorubicin. Five of 15 (33%) evaluable patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. CONCLUSIONS: The hematologic toxicity of doxorubicin is increased when combined with TH-302. This can be mitigated by prophylactic growth factor support. Toxicities were manageable and there was evidence of antitumor activity.

Glufosfamide as a new oxazaphosphorine anticancer agent.

Glufosfamide (ß-D-glucose-isophosphoramide mustard, D-19575) belongs to the oxazaphosphorine class. Glufosfamide is a novel glucose conjugate of ifosfamide in which isophosphoramide mustard, the alkylating metabolite of ifosfamide, is glycosidically linked to the ß-D-glucose molecule. Glufosfamide represents an attractive new agent for cancer therapy. Its mode of action on normal and pathological cells is still under experimental and clinical investigations. An assessment of the anticancer potential of glufosfamide is of key importance in therapy. The researchers reviewed the current knowledge available on glufosfamide tested in the preclinical studies/clinical trials, based on a collection of the original papers and conference abstracts published and relevant articles searched in the SCOPUS and MEDLINE database and websites.

Phase 1 study of the safety, tolerability, and pharmacokinetics of TH-302, a hypoxia-activated prodrug, in patients with advanced solid malignancies.

PURPOSE: The objectives of this phase 1, first-in-human study were to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary activity of the hypoxia-activated prodrug TH-302 in patients with advanced solid tumors. EXPERIMENTAL DESIGN: TH-302 was administered intravenously over 30 to 60 minutes in two regimens: three times weekly dosing followed by 1 week off (arm A) and every 3-week dosing (arm B). RESULTS: Fifty-seven patients enrolled (arm A: N = 37 and arm B: N = 20). The TH-302 dose was escalated from 7.5 to 670 mg/m(2) in arm A and from 670 to 940 mg/m(2) in arm B. The most common adverse events were nausea, skin rash, fatigue, and vomiting. Hematologic toxicity was mild and limited. Grade 3 skin and mucosal toxicities were dose limiting at 670 mg/m(2) in arm A; the MTD was 575 mg/m(2). In arm B, grade 3 fatigue and grade 3 vaginitis/proctitis were dose limiting at 940 mg/m(2); the MTD was 670 mg/m(2). Plasma concentrations of TH-302 and the active metabolite Br-IPM (brominated version of isophosphoramide mustard) increased proportionally with dose. Two partial responses were noted in patients with metastatic small cell lung cancer (SCLC) and melanoma in arm A at 480 and 670 mg/m(2). Stable disease was observed in arms A and B in 18 and 9 patients, respectively. CONCLUSIONS: The MTD of TH-302 was 575 mg/m(2) weekly and 670 mg/m(2) every 3 weeks. Skin and mucosal toxicities were DLTs. On the basis of responses in metastatic melanoma and SCLC, further investigations in these indications were initiated.

Phase I clinical and pharmacokinetic study of the glucose-conjugated cytotoxic agent D-19575 (glufosfamide) in patients with solid tumors.

PURPOSE: D-19575 (glufosfamide: ß-D-glucosylisophosphoramide mustard) is an alkylating agent in which isophosphoramide mustard, the cytotoxic metabolite of ifosfamide, is covalently linked to ß-D-glucose. We have performed a phase I study to determine the safety profile, pharmacokinetics, and antitumor activity of D-19575 in Japanese patients with advanced solid tumors METHODS: Patients were treated with escalating doses of D-19575 administered by a two-step (fast-slow) intravenous infusion over 6 h every 3 weeks. Thirteen patients received 43 treatment cycles (median 3; range 1-11) at D-19575 doses of 3,200, 4,500, or 6,000 mg/m(2). RESULTS: Hematologic toxicities and other side effects were generally mild. The maximum tolerated dose of D-19575 was 6,000 mg/m(2), at which two patients experienced dose-limiting toxicities (hypophosphatemia, hypokalemia, and metabolic acidosis each of grade 3). Pharmacokinetic analysis revealed a linear relation between the area under the concentration-versus-time curve (AUC) and dose. The AUC values for isophosphoramide mustard were substantially greater than those achieved by bolus administration or continuous infusion of ifosfamide in conventional therapy. One patient with gallbladder cancer previously treated with cisplatin and gemcitabine achieved a partial response lasting for >5 months, and eight patients achieved disease stabilization. CONCLUSIONS: Our results show that D-19575 can be safely administered by infusion over 6 h at 4,500 mg/m(2) every 3 weeks. The safety profile and potential antitumor activity of D-19575 show that phase II studies of this drug are warranted.

A randomised Phase III trial of glufosfamide compared with best supportive care in metastatic pancreatic adenocarcinoma previously treated with gemcitabine.

PURPOSE: There are currently no approved therapies for patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine. This Phase III trial evaluated the efficacy and safety of glufosfamide as compared with best supportive care (BSC) in this patient population. METHODS: Patients were randomised to glufosfamide plus BSC or to BSC alone with baseline performance status as a stratification factor. The primary end-point was overall survival. RESULTS: Three hundred and three patients were randomised: 148 to glufosfamide plus BSC and 155 to BSC alone. There was an 18% increase in overall survival for glufosfamide that was not statistically significant: hazard ratio (HR) 0.85 (95% confidence interval (CI) 0.66-1.08, p=0.19). Median survival was 105 (range 5-875) days for glufosfamide and 84 (range 2+ to 761) days for BSC. Grade 3/4 creatinine increase occurred in 6 patients on glufosfamide, including 4 with dosing errors. CONCLUSION: These results suggest low activity of glufosfamide in this very refractory patient population.

Design of new oxazaphosphorine anticancer drugs.

The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan, or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten) represent an important group of therapeutic agents due to their substantial antitumor and immunomodulating activity. However, several intrinsic limitations have been uncounted during the clinical use of these oxazaphosphorines, including substantial pharmacokinetic variability, resistance and severe host toxicity. To circumvent these problems, new oxazaphosphorines derivatives have been designed and evaluated with an attempt to improve the selectivity and response with reduced host toxicity. These include mafosfamide (NSC 345842), glufosfamide (D19575, beta-D-glucosylisophosphoramide mustard), S-(-)-bromofosfamide (CBM-11), NSC 612567 (aldophosphamide perhydrothiazine) and NSC 613060 (aldophosphamide thiazolidine). Mafosfamide is an oxazaphosphorine analog that is a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxy-CPA. Glufosfamide is IFO derivative in which the isophosphoramide mustard, the alkylating metabolite of IFO, is glycosidically linked to a beta-D-glucose molecule. Phase II studies of glufosfamide in the treatment of pancreatic cancer, non-small cell lung cancer (NCSLC), and recurrent glioblastoma multiform (GBM) have recently completed and Phase III trials are ongoing, while Phase I studies of intrathecal mafosfamide have recently completed for the treatment of meningeal malignancy secondary to leukemia, lymphoma, or solid tumors. S-(-)-bromofosfamide is a bromine-substituted IFO analog being evaluated in a few Phase I clinical trials. The synthesis and development of novel oxazaphosphorine analogs with favourable pharmacokinetic and pharmacodynamic properties still constitutes a great challenge for medicinal chemists and cancer pharmacologists.

Real-time dose adjustment of cyclophosphamide in a preparative regimen for hematopoietic cell transplant: a Bayesian pharmacokinetic approach.

PURPOSE: Dose-related toxicity of cyclophosphamide may be reduced and therapeutic efficacy may be improved by pharmacokinetic sampling and dose adjustment to achieve a target area under the curve (AUC) for two of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM). To facilitate real-time dose adjustment, we developed open-source code within the statistical software R that incorporates individual data into a population pharmacokinetic model. EXPERIMENTAL DESIGN: Dosage prediction performance was compared to that obtained with nonlinear mixed-effects modeling using NONMEM in 20 cancer patients receiving cyclophosphamide. Bayesian estimation of individual pharmacokinetic parameters was accomplished from limited (i.e., five samples over 0-16 hours) sampling of plasma HCY and CEPM after the initial cyclophosphamide dose. Conditional on individual pharmacokinetics, simulations of the AUC of both HCY and CEPM were provided for a range of second doses (i.e., 0-100 mg/kg cyclophosphamide). RESULTS: The results compared favorably with NONMEM and returned accurate predictions for AUCs of HCY and CEPM with comparable mean absolute prediction error and root mean square prediction error. With our method, the mean absolute prediction error and root mean square prediction error of AUC CEPM were 11.0% and 12.8% and AUC HCY were 31.7% and 44.8%, respectively. CONCLUSIONS: We developed dose adjustment software that potentially can be used to adjust cyclophosphamide dosing in a clinical setting, thus expanding the opportunity for pharmacokinetic individualization of cyclophosphamide. The software is simple to use (requiring no programming experience), reads individual patient data directly from an Excel spreadsheet, and runs in less than 5 minutes on a desktop PC.

Glufosfamide: beta-D-Glc-IPM, D 19575.

Glufosfamide [D 19575, beta-D-Glc-IPM] is a next-generation glucose conjugate of ifosfamide that is under development with Threshold Pharmaceuticals for the treatment of cancer. It is an alkylating agent in which isophosphoramide mustard, the alkylating metabolite of ifosfamide, is glycosidically linked to beta-D-glucose. Cellular uptake of glufosfamide is mediated by a sodium-dependent transmembrane transporter protein of glucose and possibly also by other transporter proteins. Threshold is using its Metabolic Targeting technology to exploit unique aspects of tumour metabolism, particularly the elevated glucose utilisation of tumour cells to selectively target glufosfamide to the tumour site. Glufosfamide was originally developed from a research collaboration between Asta Medica (Degussa) and the Cancer Research Centre (DKFZ) in Heidelberg, Germany. In October 2001, Baxter International acquired the oncology division of ASTA Medica, and renamed it Baxter Oncology GmbH. According to its 2002 Annual Report, Baxter announced that it was terminating development of glufosfamide. Subsequently, Baxter and Threshold Pharmaceuticals entered into an exclusive licensing and development agreement in August 2003. Threshold has responsibility for the development and commercialisation of glufosfamide, primarily for use as an antitumour agent. In addition, Baxter manufactures glufosfamide on Threshold's behalf. Threshold received fast-track status for glufosfamide from the US FDA in the treatment of metastatic pancreatic cancer refractory to gemcitabine in November 2004. In December 2004, Threshold initiated a phase I/II trial (TH-CR-301 Study) investigating glufosfamide in combination with gemcitabine as a first-line treatment of pancreatic cancer or advanced solid tumours. The phase I portion of the study may enroll up to 15 patients. The maximum tolerable dose combination determined will then be used in the phase 2 portion of the study. Up to 42 patients with advanced pancreatic cancer will be enrolled at various sites in the US, Latin America and Brazil.Previously, glufosfamide had been in phase II trials among patients with pancreatic carcinoma in Germany with Baxter Oncology and with the EORTC in the UK as well as Greece. However, development has been discontinued.

Hypersensitivity pneumonitis associated with the use of trofosfamide.

Trofosfamide (Ixoten; Baxter Oncology, Germany) is an alkylating agent that, as with other oxazaphosphorine derivatives, has to be activated by hepatic cytochrome P450 oxidases. The bioavailability is nearly 100% after oral application, and the main metabolites are 4-hydroxytrofosfamide, and 4-hydroxyifosfamide. The main side-chain metabolites ifosfamide and cyclophosphamide can be further activated by oxidation and formation of their respective phosphoramide mustards. Oral continuous low-dose therapy has been the most widely used schedule. The toxicity profile consists mainly of dose-dependent hematotoxicity and, rarely, hemorrhagic cystitis. Nausea and vomiting are infrequently seen. Higher grades of nephrotoxicity or neurotoxicity--side-effects that typically limit the use of ifosfamide-have not been reported with low-dose continuous trofosfamide treatment. We report herein a case of a 83-year-old female patient with a disseminated malignant peripheral nerve sheath tumor treated with trofosfamide developing pulmonal toxicity. To our knowledge, this is the first reported case of exogenous allergic alveolitis after exposure to this drug.

Glufosfamide administered by 1-hour infusion as a second-line treatment for advanced non-small cell lung cancer; a phase II trial of the EORTC-New Drug Development Group.

The activity of glufosfamide (beta-D-glucosylisophosphoramide mustard) was tested in a multicentre phase II clinical trial in patients with advanced non-small cell lung cancer (NSCLC) who had received one prior line of platinum-based chemotherapy. Patients were treated with 5000 mg/m(2) glufosfamide by a 1-h intravenous (i.v.) infusion every 3 weeks following registration at the European Organisation for Research and Treatment of Cancer (EORTC) Data Center. Patients were randomised between hydration and no hydration to evaluate the nephroprotective effects of forced diuresis. Patients experiencing >/= 35 micromol/l increase of serum creatinine compared with baseline values were taken off the treatment. The Response evaluation criteria in solid tumours (RECIST) criteria were applied for the response assessment. Blood sampling was performed for a pharmacokinetic analysis. 39 patients from seven institutions were registered and a median of three cycles was given (range 0-6) cycles; 20 patients were randomised to the hydration arm. Haematological toxicity was mild, but treatment-related metabolic and electrolytic abnormalities and increases of serum creatinine occurred in several patients. Hydration did not have any significant influence on the plasma pharmacokinetics of glufosfamide and did not show any nephroprotective effect. Only one confirmed partial remission was observed (response rate 3%; 95% (Confidence Interval (CI) 0-14) and 18 cases with stable disease (49%) were recorded as assessed by an independent panel. Median survival of all patients treated was 5.8 months (95% CI 4.2-7.9). In conclusion, glufosfamide administered by a 1-h infusion every 3 weeks has modest activity in advanced NSCLC patients after one prior platinum-based chemotherapy.