Pharmacokinetics, drug metabolism, and tissue distribution of CPX-351 in animals

Wang, Qi; Tardi, Paul; Sadowski, Nicole; Xie, Sherwin; Heller, Dennis; Mayer, Lawrence D.

doi:10.1016/j.nano.2020.102275

Cited by 17 publications

(16 citation statements)

References 18 publications

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“…CPX-351, a liposome-encapsulated drug combining DNR and AraC with a fixed ratio (5:1), has improved pharmacokinetic activity in blood and bone marrow compared to the free drugs 56 , and recently shown to yield higher complete remission rates and prolonged survival in patients with secondary AML 43 . However, more than half of the patients who received CPX-351 relapse within 12 months, with a 31.1% survival rate at 2 years, warranting the search for improved treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia

Haines

Nishida

Carr

et al. 2021

Sci Rep

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Peposertib (M3814) is a potent and selective DNA-PK inhibitor in early clinical development. It effectively blocks non-homologous end-joining repair of DNA double-strand breaks (DSB) and strongly potentiates the antitumor effect of ionizing radiation (IR) and topoisomerase II inhibitors. By suppressing DNA-PK catalytic activity in the presence of DNA DSB, M3814 potentiates ATM/p53 signaling leading to enhanced p53-dependent antitumor activity in tumor cells. Here, we investigated the therapeutic potential of M3814 in combination with DSB-inducing agents in leukemia cells and a patient-derived tumor. We show that in the presence of IR or topoisomerase II inhibitors, M3814 boosts the ATM/p53 response in acute leukemia cells leading to the elevation of p53 protein levels as well as its transcriptional activity. M3814 synergistically sensitized p53 wild-type, but not p53-deficient, AML cells to killing by DSB-inducing agents via p53-dependent apoptosis involving both intrinsic and extrinsic effector pathways. The antileukemic effect was further potentiated by enhancing daunorubicin-induced myeloid cell differentiation. Further, combined with the fixed-ratio liposomal formulation of daunorubicin and cytarabine, CPX-351, M3814 enhanced the efficacy against leukemia cells in vitro and in vivo without increasing hematopoietic toxicity, suggesting that DNA-PK inhibition could offer a novel clinical strategy for harnessing the anticancer potential of p53 in AML therapy.

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Section: Discussionmentioning

confidence: 99%

DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia

Haines

Nishida

Carr

et al. 2021

Sci Rep

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“…Preclinical studies indicate that, in contrast to conventional combination chemotherapy regimens, daunorubicin and cytarabine are maintained within the CPX-351 liposome until the liposome is preferentially taken up by leukemic cells in the bone marrow and the drugs are released intracellularly [ 22 , 23 ]. These properties may help minimize the systemic distribution of daunorubicin and cytarabine [ 24 ]. CPX-351 additionally prolongs drug exposure and maintains the synergistic 1:5 molar ratio of daunorubicin and cytarabine within the liposome for over 24 h after administration in patients with AML [ 25 ], which could contribute to the improved efficacy reported for CPX-351 versus 7 + 3 in this study [ 7 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML

Cortes

Lin

et al. 2021

J Hematol Oncol

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Background CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality‐adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up. Methods Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses. Results The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology. Conclusions This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 (https://clinicaltrials.gov/ct2/show/NCT01696084) and is complete.

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“…With respect to the prevention of CNS relapses, it is to underline that preclinical study of pharmacokinetics after intravenous administration of radio-labelled CPX-351 or non-liposomal drugs, concentrations of total cytarabine and daunorubicin in organs bearing a barrier, such as brain and testis, were lowest among all tissues, with tissue/plasma ratios ≤0.01, suggesting no penetration of CPX-351 liposomes into these organs [9]. This could be explained by reduced distribution of liposomal particles to intact BBB; indeed, free cytarabine and daunorubicin of 3+7 are also not prone to cross the BBB.…”

Section: Discussionmentioning

confidence: 99%

A Relapsing Meningeal Acute Myeloid Leukaemia FLT3-ITD+ Responding to Gilteritinib

et al. 2021

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A patient with a therapy-related acute myeloid leukaemia (AML), NPM1<sup>mut</sup>, and FLT3-ITD+ was treated with induction and consolidation with CPX-351, obtaining a complete response (CR) but minimal residual disease persisted positive. Later, she complained progressive burning leg pain, weakening of the right hand and leg muscles, associated with absence of osteotendinous leg reflexes. Examination of cerebrospinal fluid (CSF) showed a meningeal relapse of AML. Moreover, a magnetic resonance imaging (MRI) showed 2 right meningeal implants of myeloid sarcoma and bone marrow revealed haematologic relapse of disease. She was treated with medicated lumbar punctures (LPs) followed by an FLA-Ida scheme, and she achieved a 2nd CR. Unfortunately, the patient developed hyperleucocytosis and reappearance of meningeal myeloid sarcoma at MRI. For this reason, a monotherapy with gilteritinib (an FLT3 inhibitor) was started: after 3 months of therapy, central nervous system (CNS)-disease shrunken and then faded, while AML in the bone marrow achieved only a partial response. This is the 1st report of a positive biological effect of gilteritinib on CNS (meningeal) myeloid sarcoma. There are no studies of gilteritinib concentration into CSF and penetration of gilteritinib into the blood-brain barrier should be further studied, given the paucity of drugs active on CNS relapse of AML. In patients receiving CPX-351 only, diagnostic LP should be considered after induction.

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Pharmacokinetics, drug metabolism, and tissue distribution of CPX-351 in animals

Cited by 17 publications

References 18 publications

DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia

DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia

Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML

A Relapsing Meningeal Acute Myeloid Leukaemia FLT3-ITD+ Responding to Gilteritinib

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