Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors.

Rafi, Imran; Boddy, Alan V.; Calvete, J. A.; Taylor, Gordon A.; Newell, David R.; Bailey, N; Lind, Michael; Green, M; Hines, JO; Johnstone, Andrew F.M.; Clendeninn, Neil J.; Calvert, A. H.

doi:10.1200/jco.1998.16.3.1131

Cited by 33 publications

(32 citation statements)

References 7 publications

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“…Other toxicities encountered in this paediatric Phase I study, such as nausea and vomiting, diarrhoea, rash and hepatotoxicity were similar to those reported in the adult 5-day intravenous Phase I study (Rafi et al, 1998). However, the focal desquamation of the hands, feet and scrotal areas observed in the adult study were not encountered in the present study.…”

Section: Discussionsupporting

confidence: 85%

“…The dose-limiting antiproliferative toxicities of oral mucositis and myelosuppression observed with nolatrexed in children are in keeping with the toxicity findings of the adult Phase I study of the drug when administered as a 5-day intravenous infusion (Rafi et al, 1998). However, the MTD defined by the current study, i.e.…”

Section: Discussionsupporting

confidence: 83%

“…Therefore, dose-escalation from the first dose level, which represented 60% of the adult MTD, was undertaken even though the first 3 patients recruited to the study did not strictly satisfy the criteria for toxicity evaluation. However, for all these patients, acute toxicities were not observed in the first 14 days of follow up, during which time acute toxicity would be observed in adults receiving nolatrexed (Rafi et al, 1998), and the plasma pharmacokinetic analyses were in keeping with the adult Phase I study of nolatrexed. However, of the first 8 patients who were entered into the study, only 2 satisfied the requirements for toxicity evaluation, i.e.…”

Section: Discussionmentioning

confidence: 90%

“…No within-patient dose escalations were allowed. The initial dose level of 480 mg/m 2 24 h −1 , which represented 60% of the adult MTD (Rafi et al, 1998), was chosen as prolonged dose-limiting myelosuppression and oral mucositis had been observed in a hevily pre-treated 18-year-old female with metastatic rhabdomyosarcoma, who had received nolatrexed on a compassionate use basis at the adult MTD. In addition, plasma deoxyuridine levels were consistently elevated in adult patients receiving nolatrexed at 480 mg/m 2 24 h Ϫ1 , indicating that systemic inhibition of the target enzyme was being achieved (Rafi et al, 1995).…”

Section: Dose Escalationmentioning

confidence: 99%

“…However, no acute toxicities had been encountered in this patient cohort, and the plasma pharmacokinetic findings were in keeping with those in the adult Phase I study at a comparable dose level (see below). Therefore, since all acute antiproliferative toxicities were experienced within 14 days for adults receiving nolatrexed (Rafi et al, 1998), a decision to doseescalate to the second dose level of 640 mg/m 2 24 h −1 was made. Antiproliferative toxicities were encountered at the second and third dose levels (Table 2).…”

Section: Dose Escalation and Toxicitiesmentioning

confidence: 99%

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A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children’s Cancer Study Group Investigation

et al. 2001

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Summary A phase I study of nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m 2 24 h −1 . 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m 2 24 h −1 , dose-limiting oral mucositis and myelosuppression were observed. Plasma nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg −1 ml −1 min −1 , 50 mg ml −1 min −1 and 80 mg ml −1 min −1 at the 3 dose levels studied. Whereas no toxicity was encountered if the nolatrexed AUC was <45 mg ml −1 min − 1 , Grade 3 or 4 toxicity was observed with AUC values of >60 mg ml −1 min −1 . Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of nolatrexed in children at the maximum tolerated dose of 640 mg/m 2 24 h −1 are warranted.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 90%

Section: Dose Escalationmentioning

confidence: 99%

Section: Dose Escalation and Toxicitiesmentioning

confidence: 99%

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A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children’s Cancer Study Group Investigation

et al. 2001

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Activity of multitargeted antifolate (pemetrexed disodium, LY231514) in patients with advanced colorectal carcinoma

John¹,

Picus²,

Blanke³

et al. 2000

Cancer

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Folate depletion increases sensitivity of solid tumor cell lines to 5-fluorouracil and antifolates

et al. 2000

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Cancer cell lines in standard cell culture medium or in animal models are surrounded by an environment with relatively high folate (HF) levels, compared with folate levels in human plasma. In the present study we adapted 4 colon cancer (C26‐A, C26‐10, C26‐G and WiDr) and 3 squamous cell carcinoma of the head and neck (HNSCC) cell lines (11B, 14C and 22B) to culture medium with low folate (LF) levels (2.5, 1.0 and 0.5 nM, respectively) and investigated whether folate depletion had an effect on sensitivity to antifolates and which mechanisms were involved. All LF cell lines showed a higher sensitivity to 5‐fluorouracil (5‐FU) alone or in combination with leucovorin (LV) (2–5‐fold), to the thymidylate synthase (TS) inhibitors, AG337 (2–7‐fold), ZD1694 (3–49‐fold), ZD9331 (3–40‐fold), LY231514 (2–21‐fold) or GW1843U89 (4–29‐fold) or to the dihydrofolate reductase (DHFR) inhibitor PT523 (2–50‐fold) compared with their HF variants cultured in standard medium containing up to 8 μM folic acid. LV could only increase sensitivity to 5‐FU in HNSCC cell lines 14C and 14C/F. The differences in sensitivity could partially be explained by a 2–7‐fold increased transport activity of the reduced folate carrier (RFC) in LF cell lines, whereas no significant change in folylpolyglutamate synthetase (FPGS) activity was observed. Furthermore, the protein expression and catalytic activity of the target enzyme TS were up to 7‐fold higher in HF colon cancer cells compared with the LF variants (p < 0.05). Although the TS protein expression in LF HNSCC cells was also lower than in HF variants, the TS catalytic activity and FdUMP binding sites were up to 3‐fold higher (p < 0.05). Thus, changes in TS levels were associated with differences in sensitivity. These results indicate that folate depletion was associated with changes in TS and RFC levels which resulted in an increase in sensitivity to 5‐FU and antifolates. The folate levels in LF medium used in this study are more representative for folate levels in human plasma and therefore these data could be more predictive for the activity of 5‐FU and antifolates in a clinical setting than results obtained from cell lines cultured in HF medium or in animal models. Int. J. Cancer 87:771–778, 2000. © 2000 Wiley‐Liss, Inc.

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Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors.

Abstract: Nolatrexed can be safely administered to patients at a dose of 800 mg/m2/d over 5 days by continuous intravenous infusion and this schedule is associated with antitumor effects. The phase II evaluation of nolatrexed is ongoing.

Cited by 33 publications

References 7 publications

A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children’s Cancer Study Group Investigation

A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children’s Cancer Study Group Investigation

Activity of multitargeted antifolate (pemetrexed disodium, LY231514) in patients with advanced colorectal carcinoma

Folate depletion increases sensitivity of solid tumor cell lines to 5-fluorouracil and antifolates

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