Phase I/II clinical and pharmacokinetic evaluation of liposomal daunorubicin.

Gill, Parkash S.; Espina, Byron M.; Fm, Muggia; Cabriales, Suzanne; Tulpule, Anil; Esplin, Joan A.; Liebman, Howard A.; Forssen, Eric A.; Ross, Michael; Levine, Alexandra M.

doi:10.1200/jco.1995.13.4.996

Cited by 220 publications

(100 citation statements)

References 17 publications

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“…The pharmacokinetic profile of DaunoXome is different from conventional daunorubicin with a 36-fold increase in the area under the plasma concentration curve and a first phase elimination half-life of 5.3 to 8.3 h (Rahman et al, 1984a;Forssen and Ross, 1994;Gill et al, 1995;Bellott et al, 2001). In vivo experiments indicate increased uptake of daunoXome in tumour tissue at 24 h compared to conventional daunorubicin (Forssen et al, 1992(Forssen et al, , 1996.…”

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confidence: 99%

“…In vivo experiments indicate increased uptake of daunoXome in tumour tissue at 24 h compared to conventional daunorubicin (Forssen et al, 1992(Forssen et al, , 1996. DaunoXome (NeXstar Pharmaceuticals) is licensed for the treatment of AIDS-related Kaposi's sarcoma (Gill et al, 1995(Gill et al, , 1996. Given the early encouraging anti-tumour activity of daunorubicin, DaunoXome was evaluated in a phase I study in solid tumours.…”

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A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

et al. 2002

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The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m 2 . Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m 2 , the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m 2 . Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m 2 and grade 2 in two, one who received a cumulative dose of 960 mg m 2 and the other a cumulative dose of 600 mg m 2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m 2 . Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard nonanthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m 2 , we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated.

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A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

et al. 2002

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“…A formulation of daunorubicin encapsulated in liposomal particles (liposomal daunorubicin, DaunoXome®) has an interesting pharmacokinetic profile: increased delivery to leukemic cells, decreased susceptibility to the membrane efflux pump, and reduced extra-hematological toxicity [18][19][20][21][22][23]. We have combined HDARAC, fludarabine and DaunoXome® in a salvage regimen to be applied in a multicenter study for rescuing primary refractory and relapsed AML adult patients.…”

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Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome®) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients

Camera¹,

Rinaldi²,

Palmieri³

et al. 2008

Ann Hematol

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International audienceA large proportion of adult patients with acute myeloid leukemia (AML) relapse after treatment, and some of them are resistant to primary induction chemotherapy. Sixty-one patients from seven hematological centers with poor-risk AML, primary refractory ( = 16), or relapsed ( = 45) were treated with a salvage regimen, including fludarabine (2 days) and cytarabine (3 days) in a sequential continuous infusion, associated with liposomal daunorubicin (3 days) (FLAD). Complete response rate was 44% and 56% for refractory and relapsed patients, respectively, with an overall response rate of 52% (32 of 61). Twenty-two patients (36%) were resistant to the salvage therapy. Seven patients (12%) died early during chemotherapy, four of them because of sepsis. Nineteen patients in complete remission (CR) underwent a stem-cell transplant (SCT) procedure: five autologous, nine from a HL-A identical sibling, and five from HL-A matched unrelated donors. Post-treatment aplasia and mucositis were major toxicities. Twenty patients (62.5%) relapsed after this treatment in a median of 7.3 months; ten patients relapsed after a SCT procedure. Nine patients are alive and disease free; three of them were rescued after a further cytotoxic treatment. The FLAD regimen proved to be an effective and well-tolerated treatment, with acceptable toxicity in this group of high-risk patients. A better response rate was obtained in the subgroup of relapsed patients, compared to patients treated for refractory disease. More then half (five of nine) of long-surviving patients are those who were submitted to a transplant procedure; thus, the main indication for FLAD seems to be to try to induce a rapid CR with minimum toxicity in order to perform a transplant as soon as possible

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“…Most clinical studies with DaunoXome have been in adult patients, and cardiac toxicity has not been a prominent feature even with cumulative doses of over 1000 mg m À2 , although follow-up of patients was short (Money-Kyrle et al, 1993;Presant et al, 1993;Guaglianone et al, 1994;Gill et al, 1995).…”

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A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

et al. 2006

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Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, ‘DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m −2 for Group A and 100 mg m −2 for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.

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Phase I/II clinical and pharmacokinetic evaluation of liposomal daunorubicin.

Abstract: DaunoXome has an improved pharmacokinetic profile compared with free daunorubicin, and is well tolerated. DaunoXome can be given safely at doses up to 60 mg/m2 every 2 weeks and has significant antitumor activity in patients with AIDS-KS.

Cited by 220 publications

References 17 publications

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome®) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

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