Doxorubicin pharmacokinetics and toxicity in patients with aggressive lymphoma and hepatic impairment.

Aggressive lymphomas are curable with doxorubicin-based chemotherapy. In patients presenting with elevated serum bilirubin, doxorubicin is commonly dose reduced or delayed based on limited pharmacokinetic data. We evaluated plasma pharmacokinetics of doxorubicin and its metabolite doxorubicinol as well as toxicity in 59 patients with normal bilirubin levels and 10 patients with elevated bilirubin levels.

Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma.

Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, targets BCR signaling and is particularly active in lymphomas with mutations altering the BCR subunit CD79B and MYD88. We performed a proof-of-concept phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R).

Vincristine Sulfate Liposomes Injection (VSLI, Marqibo®): Results From a Phase I Study in Children, Adolescents, and Young Adults With Refractory Solid Tumors or Leukemias.

Background: Vincristine sulfate liposome injection (VSLI; Marqibo®) is an encapsulated preparation of standard vincristine in sphingomyelin/cholesterol liposomes. Clinical trials in adults have demonstrated safety, tolerability, and activity, leading to Food and Drug Administration (FDA) approval for adults with relapsed acute lymphoblastic leukemia (ALL). Pediatric experience with VSLI is limited.

Plasma and cerebrospinal fluid pharmacokinetics of vincristine and vincristine sulfate liposomes injection (VSLI, marqibo®) after intravenous administration in Non-human primates.

Purpose: Vincristine sulfate liposomes injection (VSLI, Marqibo®) is an FDA approved encapsulated preparation of standard vincristine in sphingomyelin/cholesterol liposomes. Clinical pharmacokinetics show VSLI to be a long-circulating, slow release formulation that is confined to plasma, and prior data on cerebrospinal fluid (CSF) pharmacokinetics are lacking. We report our results comparing CSF and plasma pharmacokinetic parameters of intravenous aqueous vincristine to intravenous VSLI using an established non-human primate (NHP) model.

Pharmacokinetic and pharmacodynamic study of tariquidar (XR9576), a P-glycoprotein inhibitor, in combination with doxorubicin, vinorelbine, or docetaxel in children and adolescents with refractory solid tumors.

Purpose: P-glycoprotein (Pgp), an ATP-dependent transport protein, confers multidrug resistance in cancer cells. Tariquidar binds and inhibits Pgp. To assess the toxicity, pharmacokinetics (PK), and pharmacodynamics of tariquidar, we conducted a phase I trial of tariquidar in combination with doxorubicin, docetaxel, or vinorelbine in children and adolescents with recurrent or refractory solid tumors.

Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model.

Purpose: Central nervous system tumors are histologically and biologically heterogeneous. Standard treatment for malignant tumors includes surgery, radiation and chemotherapy, yet surgical resection is not always an option and chemotherapeutic agents have limited benefit. Recent investigations have focused on molecularly targeted therapies aimed at critical tumorigenic pathways.

Quantitative determination of mithramycin in human plasma by a novel, sensitive ultra-HPLC-MS/MS method for clinical pharmacokinetic application.

Mithramycin is a neoplastic antibiotic synthesized by various Streptomyces bacteria. It is under investigation as a chemotherapeutic treatment for a wide variety of cancers. Ongoing and forthcoming clinical trials will require pharmacokinetic analysis of mithramycin in humans, both to see if target concentrations are achieved and to optimize dosing and correlate outcomes (response/toxicity) with pharmacokinetics.

Low-intensity therapy in adults with Burkitt's lymphoma.

Background: Burkitt's lymphoma is an aggressive B-cell lymphoma that occurs in children and adults and is largely curable with the use of intensive and toxic chemotherapy. Current treatments are less effective and have more severe side effects in adults and patients with immunodeficiency than in children.

Methods: We studied low-intensity treatment consisting of infused etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (EPOCH-R) in patients with untreated Burkitt's lymphoma.

The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates.

Purpose: Sorafenib is a small molecule inhibitor of multiple signaling kinases thought to contribute to the pathogenesis of many tumors including brain tumors. Clinical trials with sorafenib in primary and metastatic brain tumors are ongoing. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of sorafenib after an intravenous (IV) dose in a non-human primate (NHP) model.

Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O4BF) and metabolite in a non-human primate model.

Purpose: O(6)-alkylguanine-DNA alkyltransferase (AGT) repairs DNA damage from alkylating agents by transferring the alkyl adducts from the O(6)-position of guanine in DNA to AGT. The folate analog O(4)-benzylfolic acid (O(4)BF) is an inhibitor of AGT with reported selectivity of the alpha-folate receptor in tumors. We studied plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of O(4)BF in a non-human primate model.

Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome.

Purpose: To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G(2)), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity.

Methods: Patients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n = 35) also received thymidine by continuous IV infusion.

Cognitive and psychodynamic mechanisms of change in treated and untreated depression.

Two patient-level mechanisms of change, defenses, and cognition were tested over 3 time points in 65 depressed adults, approximately half receiving treatment. Early changes in automatic thoughts and immature defenses were associated with symptom change from time-one to time-three. The directionality of early automatic thought change predicting symptom change was partially supported, but immature defense change occurs simultaneously with, or after, symptom change.

Pharmacokinetics of temozolomide administered in combination with O6-benzylguanine in children and adolescents with refractory solid tumors.

Purpose: Temozolomide pharmacokinetics were evaluated in children receiving concurrent O(6)-benzylguanine (O(6)BG), which enhanced the hematological toxicity of temozolomide.

Methods: Temozolomide was administered orally, daily for 5 days starting at 28 mg/m(2) per day with escalations to 40, 55, 75 and 100 mg/m(2) per day with O(6)BG intravenously daily for 5 days at doses of 60, 90 or 120 mg/m(2) per day. Plasma samples were drawn over 48 h after the day 5 dose.

The extent of chromosomal aberrations induced by chemotherapy in non-human primates depends on the schedule of administration.

We utilized a non-human primate model, the rhesus monkey (Macaca mulatta), to quantitate the extent of chromosomal damage in bone marrow cells following chemotherapy. Thiotepa, etoposide, and paclitaxel were chosen as the chemotherapy agents due to their distinct mechanisms of action. Chromosomal aberrations were quantitated using traditional Giemsa stain.

Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2.

The bacterial enzyme carboxypeptidase G2 (CPDG2) rapidly hydrolyzes methotrexate to inactive metabolites. We administered recombinant CPDG2 (2000 U) intrathecally to seven cancer patients 3 to 9 hours after they had received an accidental overdose of intrathecal methotrexate (median dose = 364 mg; range = 155-600 mg). Four of the seven patients had cerebrospinal fluid (CSF) exchange to remove methotrexate before CPDG2 administration.

Loss of Smad3 in acute T-cell lymphoblastic leukemia.

Background: The receptors for transforming growth factor beta (TGF-beta) and their signaling intermediates make up an important tumor-suppressor pathway. The role of one of these intermediates--Smad3--in the pathogenesis of lymphoid neoplasia is unknown.

Methods: We measured Smad3 messenger RNA (mRNA) and protein in leukemia cells obtained at diagnosis from 19 children with acute leukemia, including 10 with T-cell acute lymphoblastic leukemia (ALL), 7 with pre-B-cell ALL, and 2 with acute nonlymphoblastic leukemia (ANLL).

Phase I clinical trial of intrathecal topotecan in patients with neoplastic meningitis.

Purpose: A phase I trial of intrathecal (IT) topotecan was performed to determine the optimal dose, the dose-limiting toxic effects, and the incidence and severity of other toxic effects in patients 3 years and older with neoplastic meningitis.

Patients And Methods: Twenty-three assessable patients received IT topotecan administered by means of either lumbar puncture or an indwelling ventricular access device (Ommaya reservoir). Intrapatient dose escalation from 0.