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Pharmacokinetic and phase I studies of brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies (1998)

Burris, Howard A. ; Raymond, Eric ; Awada, Ahmad ; [et al.]

Springer

Investigational new drugs 16 (1998), S. 19-27

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ISSN: 1573-0646

Keywords: phase I ; brequinar ; DUP 785 ; cisplatin ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1016066529642

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2

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Progress and Promise (1998)

Von Hoff, Daniel D.

Springer

Investigational new drugs 16 (1998), S. 1-1

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ISSN: 1573-0646

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1006012107134

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3

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Effects of SW 33377, SW 68210 and SW 71425 thioxanthones on in vitro colony formation of freshly explanted human tumor cells (1998)

Izbicka, Elzbieta ; Lawrence, Richard ; Davidson, Karen ; [et al.]

Springer

Investigational new drugs 16 (1998), S. 221-225

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ISSN: 1573-0646

Keywords: thioxanthones ; SW 33377 ; human tumor cloning

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Thioxanthones are aromatic hydrocarbons with cytotoxic activity against several tumor models. Potential mechanisms of action may include DNA intercalation, inhibition of nucleic acid biosynthesis, and topoisomerase inhibition, as well as formation of intracellular DNA single strand breaks. Such a broad spectrum of expected antitumor activity makes this class of compounds particularly interesting and worth pursuing in clinical studies. SW 33377 (Win 33377, SR 233377) was so promising in vitro that it was taken into Phase I clinical trials for further evaluation. The compound had undesirable cardiac effects, so new analogs were sought that would have similar antitumor effects without the undesirable side effects. In the present study, two new analogs SW 68210 (WIN 68210), and SW 71425 (WIN 71425) are compared to the antiproliferative action of SW 33377 against a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. All compounds were more effective with continuous exposure than 1 hour exposure and a concentration-response effect was evident with all compounds. SW 68210 with continuous exposure showed similar activity to SW 33377 at all concentrations. SW 71425 with continuous exposure was less effective at the lower concentrations but was nearly as effective at 10 μg/ml as the other two compounds and was highly effective at 50 μg/ml. At the 10 μg/ml concentration all compounds were similarly effective against breast, colon, non-small cell lung, and ovarian tumors. The two new analogs, SW 68210 and SW 71425 have activity similar to SW 33377 and are both likely candidates for further development.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1006152100299

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4

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A phase I trial of vinorelbine in combination with mitoxantrone in patients with refractory solid tumors (1998)

Peacock, Nancy W. ; Burris, Howard A. ; Dieras, Veronique ; [et al.]

Springer

Investigational new drugs 16 (1998), S. 37-43

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ISSN: 1573-0646

Keywords: vinorelbine ; vinca-alkaloids ; mitoxantrone ; anthracenedione-derivative ; phase I ; combination therapy

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Vinorelbine (Navelbine®) is a unique semi-synthetic vinca-alkaloid with a favorable safety profile that has demonstrated significant antitumor activity in patients with non-small cell lung cancer, advanced breast cancer, advanced ovarian cancer and Hodgkin's disease. The most common dose-limiting toxicity is neutropenia, while other reported toxicities are minimal. Mitoxantrone (Novantrone®) is an anthracene derivative that has demonstrated antitumor activity in patients with breast cancer, ovarian cancer, acute leukemia, and lymphoma. Mitoxantrone also has a very favorable toxicity profile with significantly less nausea and vomiting, alopecia, and stomatitis as compared with anthracyclines. The dose-limiting toxicity for mitoxantrone is leukopenia. The study was designed to determine the safety and maximally tolerated dose of IV vinorelbine used in combination with a fixed dose of mitoxantrone for the treatment of patients with refractory solid tumors. Vinorelbine was administered on days 1 and 8 of the treatment regimen as a short IV infusion. The starting dose was 15 mg/m2. Mitoxantrone was administered as a 20-min infusion on day 1 only at a fixed dose of 10 mg/m2. Seventeen patients with solid malignancies were entered in the study. For personal reasons, one patient decided to discontinue the treatment after day 1 of cycle 1. Therefore, 16 patients were evaluable for toxicity. The main toxicity was myelosuppression which was dose-limiting and resulted in dose reductions and delays. The use of G-CSF had a minimal overall impact on this regimen. Stable disease was observed in three cases. In patients previously treated with chemotherapy, the maximally tolerated dose was defined as vinorelbine 20 mg/m2 on days 1 and 8 and mitoxantrone 10 mg/m2 on day 1 without growth factor support. These doses can be recommended for phase II study of the regimen as salvage treatment.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1016075126007

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5

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A phase I and pharmacokinetic trial of terephthalamidine (NSC 57155) as a 120-hour continuous infusion (1998)

Rodriguez, Gladys I. ; Kuhn, John G. ; Weiss, Geoffrey ; [et al.]

Springer

Investigational new drugs 16 (1998), S. 57-67

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ISSN: 1573-0646

Keywords: phase I ; pharmacokinetics ; terephthalamidine ; NSC 57155 ; phthalanilides

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels (14, 28, 46, and 70 mg/m2/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 l/hr/m2. Both plasma concentrations achieved during infusion (r2 = 0.9) and area under the curve (AUC) (r2 = 0.8) were proportional to increase in dose (p 〈 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 l/hr/m2. Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1006003718255

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6

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Activity of pivaloyloxymethyl butyrate, a novel anticancer agent, on primary human tumor colony-forming units (1998)

Siu, Lillian L. ; Von Hoff, Daniel D. ; Rephaeli, Ada ; [et al.]

Springer

Investigational new drugs 16 (1998), S. 113-119

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ISSN: 1573-0646

Keywords: butyrate analogs ; differentiation ; investigational agents

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract The anti-proliferative effects of pivaloyloxymethyl butyrate (AN-9), a butyric acid (BA) derivative with potent tumor-differentiating properties both in vitro and in vivo, was evaluated against colorectal, breast, lung, ovarian, renal cell, bladder, and other types of tumor colony-forming units in a human tumor cloning assay. A total of 76 evaluable specimens were exposed to AN-9 continuously, 48 of these were also exposed to BA continuously for direct comparison of the two agents, and 20 specimens were exposed to AN-9 for two hours. An in vitro inhibitory response was defined as a ≥ 50% decrease in tumor colony formation in treated cells compared to untreated controls. Superior anti-tumor activity was observed with the continuous exposure to AN-9 (39% in vitro response at 100 μM and 70% at 200 μM) than with the two-hour exposure (20% at 100 μM and 25% at 200 μM). At a continuous concentration of 200 μM, AN-9 demonstrated greater tumor-specific activity than BA against melanoma (100% vs. 67%), ovarian (67% vs. 40%), breast (63% vs. 0%), non-small cell lung (60% vs. 10%), and colorectal tumor colony-forming units (62% vs. 20%). AN-9 is a novel differentiating agent with activity against colony-forming units derived from a variety of primary human tumors, including those that are considered relatively chemoresistant, and may thus provide a therapeutic alternative or addition to standard cytotoxic agents, if appropriate drug concentrations can be achieved in patients.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1006049227744

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7

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Effect of inhibition of γ-glutamyltranspeptidase by AT-125 (Acivicin) on glutathione and cysteine levels in rat brain and plasma (1985)

Hill, Kristina E. ; Hoff, Daniel D. ; Burk, Raymond F.

Springer

Investigational new drugs 3 (1985), S. 31-34

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ISSN: 1573-0646

Keywords: AT-125 (Acivicin) ; glutathione ; cysteine ; γ-glutamyltranspeptidase

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Summary AT-125 (Acivicin) is an inhibitor of γ-glutamyltranspeptidase (γ-GTP) which initiates glutathione catabolism to cysteine. We measured plasma and brain glutathione and cysteine in rats treated with AT-125. Six h after AT-125 treatment, plasma glutathione had increased 6-fold and plasma cysteine had fallen significantly. Brain cysteine fell after 24 h of AT-125 treatment, and brain glutathione had also decreased 18%. AT-125 pretreatment inhibited brain uptake of 35S when it was given as 35S-GSH but had no effect when it was given as 35S-cysteine. These results suggest that plasma glutathione is catabolized by γ-GTP, and cysteine derived from it is taken up by the brain. N-acetylcysteine was administered to AT-125 treated rats in an attempt to supply cysteine to the brain in the face of γ-GTP inhibition. N-acetylcysteine supported brain glutathione levels, suggesting that it can serve as a source of cysteine under these conditions.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00176821

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8

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Phase II trial of 1,4-dihydroxy-5,8-bis((2-((2-hydroxyethyl)amino)ethyl)amino 9,10-anthracenedione dihydrochloride)(NSC 301739, DHAD) in patients with metastatic malignant melanoma (1985)

Taylor, Sarah A. ; Tranum, Bill T. ; Hoff, Daniel D. ; [et al.]

Springer

Investigational new drugs 3 (1985), S. 67-69

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ISSN: 1573-0646

Keywords: mitoxantrone ; melanoma

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Summary Mitoxantrone, an anthracenedione derivative, was administered by members of the Southwest Oncology Group to thirty patients with metastatic malignant melanoma. The drug was administered as an intravenous infusion over 30 min at a starting dose of 12 mg/m2 and repeated every three weeks. Myelosuppression was the major toxicity. As administered, mitoxantrone is not an effective agent in the treatment of malignant melanoma.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00176827

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9

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A randomized trial of doxorubicin, mitoxantrone and bisantrene in advanced breast cancer (A South West Oncology Group Study) (1985)

Cowan, John D. ; Osborne, C. Kent ; Neidhart, James A. ; [et al.]

Springer

Investigational new drugs 3 (1985), S. 149-152

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ISSN: 1573-0646

Keywords: breast cancer ; chemotherapy ; doxorubicin ; mitoxantrone ; bisantrene

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Summary New agents with increased activity and/or reduced toxicity are needed for the treatment of advanced breast cancer. The anthracene derivatives mitoxantrone and bisantrene had significant activity and acceptable toxicity in phase II trials. In an ongoing phase III trial we have now randomized 150 patients with advanced breast cancer to either doxorubicin (60 mg/m2), mitoxantrone (14 mg/m2) or bisantrene (260 mg/m2) i.v. q 3 weeks with re-randomization for cross-over at the time of progression to determine the relative efficacy and toxicity of these three agents. To be eligible, patients must have had only one previous chemotherapy regimen. ER positive patients must have failed endocrine therapy. Patients with CHF or severe cardiac disease were ineligible. In this preliminary evaluation, 117 patients are evaluable for response and 110 for toxicity. Median age for all patients is 58 years (range 26–78). The majority (86%) are postmenopausal. Fifty-nine percent of the patients have visceral dominant disease. Estrogen receptor is positive in 37%, negative in 39% and unknown in 24% of patients. Median performance status (SWOG) is 1, range 0–2. Objective responses have been observed on each arm (doxorubicin 9/35, mitoxantrone 6/38, bisantrene 6/44). Thirty-two patients are evaluable for cross-over response (doxorubicin 2/13, mitoxantrone 1/11, bisantrene 0/8). The predominant toxicity is leukopenia with a nadir WBC count 〈2000 in 45% of all courses administered. Leukopenia is similar with the three drugs. Significant nausea, vomiting and alopecia are common with doxorubicin and uncommon with the other agents. Congestive heart failure has been observed in one patient (doxorubicin). Definitive conclusions regarding the efficacy and toxicity of these agents await the completion of this trial.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00174162

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