Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia.

We previously demonstrated vast expansion of hypoxic areas in the leukemic microenvironment and provided a rationale for using hypoxia-activated prodrugs. PR104 is a phosphate ester that is rapidly hydrolyzed in vivo to the corresponding alcohol PR-104A and further reduced to the amine and hydroxyl-amine nitrogen mustards that induce DNA cross-linking in hypoxic cells under low oxygen concentrations. In this phase I/II study, patients with relapsed/refractory acute myeloid leukemia (n=40) after 1 or 2 prior treatments or acute lymphoblastic leukemia (n=10) after any number of prior treatments received PR104; dose ranged from 1.

PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours.

Background: The purpose of this phase Ib clinical trial was to determine the maximum tolerated dose (MTD) of PR-104 a bioreductive pre-prodrug given in combination with gemcitabine or docetaxel in patients with advanced solid tumours.

Methods: PR-104 was administered as a one-hour intravenous infusion combined with docetaxel 60 to 75 mg/m2 on day one given with or without granulocyte colony stimulating factor (G-CSF) on day two or administrated with gemcitabine 800 mg/m2 on days one and eight, of a 21-day treatment cycle. Patients were assigned to one of ten PR-104 dose-levels ranging from 140 to 1100 mg/m2 and to one of four combination groups.

A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients.

Background: The phosphate ester PR-104 is rapidly converted in vivo to the alcohol PR-104A, a nitrogen mustard prodrug that is metabolised to hydroxylamine (PR-104H) and amine (PR-104M) DNA crosslinking agents by one-electron reductases in hypoxic cells and by aldo-keto reductase 1C3 independently of oxygen. In a previous phase I study using a q 3 week schedule of PR-104, the maximum tolerated dose (MTD) was 1100 mg/m2 and fatigue, neutropenic fever and infection were dose-limiting. The primary objective of the current study was to determine the dose-limiting toxicity (DLT) and MTD of weekly PR-104.

PR-104 plus sorafenib in patients with advanced hepatocellular carcinoma.

Purpose: PR-104 is activated by reductases under hypoxia or by aldo-keto reductase 1C3 (AKR1C3) to form cytotoxic nitrogen mustards. Hepatocellular carcinoma (HCC) displays extensive hypoxia and expresses AKR1C3. This study evaluated the safety and efficacy of PR-104 plus sorafenib in HCC.

A combined pharmacokinetic model for the hypoxia-targeted prodrug PR-104A in humans, dogs, rats and mice predicts species differences in clearance and toxicity.

Background: PR-104 is a phosphate ester that is systemically converted to the corresponding alcohol PR-104A. The latter is activated by nitroreduction in tumours to cytotoxic DNA cross-linking metabolites. Here, we report a population pharmacokinetic (PK) model for PR-104 and PR-104A in non-human species and in humans.

Phase II trial of idiotype vaccination in previously treated patients with indolent non-Hodgkin's lymphoma resulting in durable clinical responses.

Purpose: To evaluate idiotype (Id) vaccination as a single agent in previously treated patients with indolent non-Hodgkin's lymphoma.

Patients And Methods: Patients underwent biopsy for determination of their lymphoma-specific Id sequence. Recombinant Id protein was manufactured and covalently linked with keyhole limpet hemocyanin (KLH) to generate Id/KLH.

Phase I trial of chloroguinoxaline sulfonamide, with correlation of its pharmacokinetics and pharmacodynamics.

To define a maximum tolerable dose, chloroquinoxaline sulfonamide (CQS) was given as a 1-h infusion every 28 days to cancer patients for whom no effective standard therapy was available. Doses were escalated in cohorts of at least three patients each. Plasma for characterization of the pharmacokinetics of free and total CQS was obtained during and after the initial infusion and, when possible, during and after subsequent infusions of CQS if the dose had been reduced.

Immunomodulation of interleukin-2 by cyclophosphamide: a phase IB trial.

The objective of this phase IB trial was to determine if cyclophosphamide (CY) could enhance the immune effects of interleukin-2 (IL-2), and if it could, was there an optimal immunomodulatory dosage. IL-2 alone at 30 million IU/m2 thrice weekly for 6 weeks or in combination with varying dosages of CY (300, 600, and 1,200 mg/m2) administered 3 days before IL-2 and repeated 3 weeks later was given to consecutive cohorts of patients (at least five per group) with advanced malignancies of varying types. To gauge the immune effects of the treatment, the variation in the amount of lymphokine-activated killer (LAK) cells generated in the peripheral blood mononuclear cells of patients and in a control group of normal volunteers was measured weekly over 7 consecutive weeks.

The impact of phase I clinical trials on the quality of life of patients with cancer.

This prospective, non-randomized study was designed to evaluate the quality of life (QOL) of cancer patients receiving new cytotoxic therapy. QOL was measured using a linear analog self assessment scale (LASA). Cancer patients who received a phase I agent (n = 45) had no significant changes in any of the individual QOL variables, overall QOL (p = 0.

Planning and implementing clinical trials.

Careful planning and organization are essential in the design and conduct of a clinical trial. The clinical protocol provides a framework that describes the proposed experiment and outlines the means for achieving specific endpoints. Protecting research participants and assuring quality control are important to the conduct of clinical trials.

Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule.

Tiazofurin (2-B-D-Ribofuranosylthiazole-4-Carboxamide: NSC 286193) is a nucleoside antimetabolite that acts as a potent inhibitor of IMP dehydrogenase resulting in a guanine nucleotide deprivation. Recent in vivo biochemical observations in rats bearing hepatoma suggested a correlation between depletion of guanine nucleotides and antitumor effect. The present phase I trial utilized a weekly x 3 bolus infusion schedule, repeated every 5 weeks.

Phase I clinical investigation of amonafide.

Amonafide (benzisoquinolinedione, NSC 308847) is a new synthetic imide antineoplastic agent with DNA intercalative properties that has been evaluated in a phase I clinical trial. The drug was administered as a single intravenous (IV) infusion over 30 to 120 minutes repeated every 28 days. Ninety-five courses of therapy at doses ranging from 18 to 1,104 mg/m2 were administered to 38 patients with refractory solid tumors.

Phase I trial of echinomycin (NSC 526417), a bifunctional intercalating agent, administered by 24-hour continuous infusion.

Echinomycin was administered to 43 patients with advanced cancer in escalating doses ranging from 60 to 2128 mcg/m2. The dose-limiting toxicity of echinomycin administered as a 24-h continuous infusion every 28 days was nausea and vomiting beginning at the end of the 24 h infusion and lasting from 3 to 8 days. Other toxicities included sporadic thrombocytopenia and biochemical evidence of liver dysfunction characterized by elevations in SGOT.

Phase I trials: role of the nurse investigator.

The role of nurses in the development, conduct, and reporting of phase I trials has in recent years become that of a clinical investigator. In collaboration with physicians and other team members, nurses are involved in every aspect of the clinical trial process and have had a favorable impact on the quality of research conducted and quality of patient care delivered. As phase I trials have achieved increasing sophistication, nursing participation at this level has become both necessary and more widely recognized.

Phase I clinical trial of carbetimer.

Carbetimer (carbethimer, N-137, NED-137, carboxyimamidate) is a low molecular weight polyelectrolyte with antitumor activity in a variety of tumor models. This phase I trial evaluated a single dose of carbetimer infused over 1-2 h every 28 days. Forty-three patients received 71 courses of the drug at doses ranging from 180 to 8500 mg/m2.

Phase I evaluation and pharmacokinetics of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193).

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, TCAR, Riboxamide, NSC 286193) is a novel C-nucleoside with antitumor activity against several murine tumor models, including Lewis lung carcinoma. The mechanism whereby this compound exerts its antineoplastic effects is most likely related to a state of guanine nucleotide depletion whereby the anabolite, thiazole-4-carboxamide adenine dinucleotide, potently inhibits inosine-5'-monophosphate dehydrogenase. This Phase I study was designed to determine the maximally tolerated dose of Tiazofurin administered on a 5-day, every-28-day schedule.

Interferon-alpha therapy of renal cancer.

Thirty-three patients with renal cancer began treatment with human lymphoblastoid interferon (Wellferon) between August 1982 and February 1983. Interferon was administered as an i.m.