Intracerebral penetration and tissue distribution of 2,5-diaziridinyl 3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ,NSC-182986)

[¹⁴C]AZQ (2–4 mg/m², 100–200 mCi) was administered at varying times to five patients undergoing surgical resection of intracerebral tumors. Plasma, cerebrospinal fluid (CSF), edematous brain, and tumor specimens were obtained during surgery and the concentration of AZQ was determined radiochemically and chromatographically. Total [¹⁴C]AZQ equivalent concentration in tumor for two patients was determined to be 47.5% and 85% of concurrent plasma concentration which was similar to that found in normal brain (60.4% and 75.5% respectively). Only 18–45% of the total radioactivity in tumor tissue and 30–56% in plasma were accounted for by unchanged AZQ. These findings suggest that AZQ may be metabolized to a certain extent. Tissue samples from various organs were obtained during autopsy in a patient who expired ten days after AZQ administration. The highest AZQ concentration was found in the liver, followed by the kidney. Comparable amounts were found in normal brain and brain tumor (22 ng/ g vs. 31 ng/ g respectively). These results indicate that AZQ penetrates readily into the normal brain and brain tumor with a tendency to persist.     

Comprehensive phase II evaluation of Aziridinylbenzoquinone (AZQ,Diaziquone) in recurrent human primary brain tumors

Summary Ninety-three patients with primary intracranial brain tumors recurrent after cerebral irradiation were treated with aziridinylbenzoquinone (AZQ; Diaziquone). Twenty-four (26%) had tumor regression lasting a median of 9.2 months. Prior chemotherapy was not significantly associated with tumor regression but was associated with survival (median 7.3 months no prior chemotherapy versus 4.7 months with prior chemotherapy; logrank p = 0.03). AZQ demonstrated anti-tumor activity in a wide variety of primary intracranial neoplasms recurrent after radiation therapy and deserves study in patients at the time of diagnosis. We believe alternating or combining AZQ and BCNU should be rewarding. The principal toxicity of AZQ is myelosuppression.     

The pharmacologic fate of 2,5-diaziridinyl-3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ NSC-182986) by intracarotid or intravenous administration in beagles

Beagle dogs received either intravenous (I.V.) or intracarotid (I.C.) 14C ring labelled 2,5-diaziridinyl-3,6-bis-(carboethoxyamino) 1,4-benzoquinone (AZQ) at a dose of 2 mg/kg. Blood, urine and cerebrospinal fluid (CSF) samples were collected at intervals. At varying times, dogs from each group were sacrificed and histologic examination and drug determinations were performed on the major organs. By both routes of administration, the elimination of AZQ from plasma was biphasic with an initial half-life of 18 min and a terminal half-life of 26 hr. The apparent volume of distribution was 7.9 l/kg and the total clearance was 3.5 ml/kg/h. The 96 hr cumulative urinary excretion of total 14C was 41% of the administered dose, including 4% as the unchanged drug. At 1, 48, and 96 hr after I.C. AZQ, drug concentrations in the brain tissue were twice those by the I.V. route. High drug concentrations in the CSF were produced by both routes, although the CSF to plasma ratio was higher by I.C. than I.V. In extracranial organs, tissue concentrations of AZQ were at least twice as high by I.V. than by I.C. administration. No significant clinical or neurologic toxicity were noted when AZQ was given I.C. In the dog I.C. administration of AZQ seems to accelerate drug entry into the brain tissue.     

Pharmacokinetics of 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ,NSC 224070) during a phase I clinical trial

Plasma levels of 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ, NSC 224070) were measured in nine patients after i.v. administration of the drug during a Phase I trial. Our own isocratic high performance liquid chromatographic (HPLC) method with a sensitivity of 3 ng/ml was used to quantify BZQ. Patients receiving 18–60 mg BZQ i.v. showed α and β plasma decays with half-lives of 6.2 ± 1.5 (mean ± S.D.) and 24 ± 4 min respectively. The apparent volume of the central compartment was 12.2 ± 4.6 l, and the total volume of distribution was 33.6 ± 11.3 l. The calculated plasma AUCs were linearly related to dose. A marked similarity in kinetic parameters was found for BZQ and diaziquone (AZQ, NSC 182986), another diaziridinylbenzoquinone that has recently completed phase II clinical trials.     

A phase II study of diaziquone in children with recurrent or progressive primary brain tumors: A report from the Childrens Cancer Study Group

Summary Seventy-five children with recurrent, progressive or metastatic primary brain tumors were treated with aziridinylbenzoquinone (AZQ; Diaziquone) at 9 mg/m²/day by 30-minute intravenous infusion for five days every three weeks. Sixty-six patients were evaluable for response by imaging studies. There were five partial responses and one complete response for a combined response rate of 9%. A complete response lasting for 35 + months occurred in one of twelve patients with metastatic or locally recurrent ependymoma. Objective responses were also seen in patients with primitive neuroectodermal tumors (PNET) (1/8), low-grade glioma (1/6), and primary central nervous system lymphoma (1/1). Stable disease of greater than six months duration was seen in patients with ependymoma, PNET and medulloblastoma. Profound and prolonged myelosuppression was the significant toxicity observed. As administered in this study, AZQ has marginal activity and severe toxicity.Contributing Childrens Cancer Study Group Investigators, Institutions, and Grant Numbers are given in the Appendix. Grant support from the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and Human Services.     

Superiority of PCNU over AZQ in the treatment of primary brain tumors: results of a prospective randomized trial (81-20) by the brain tumor study group

SummaryPurpose A two-arm randomized clinical trial was performed to determine the efficacy of PCNU and AZQ in the treatment ofde novo or recurrent primary brain tumors. An additional objective was to gather information on the administration and toxicity of these compounds, supplementing that obtained previously in phase I/II studies.Methods During 1982 and 1983 the Brain Tumor Study Group randomized 152 adult patients with primary brain tumors to receive PCNU 75–100 mg/m² intravenously (IV) every 8 weeks or AZQ 15 mg/m² IV once a week for 4 weeks, every 6–8 weeks. All patients who had not received full dose radiotherapy before randomization received it concurrently with the first course of protocol chemotherapy. The data were analyzed for the total randomized population (RP), and for 130 patients in the valid study group (VSG) formed by excluding 22 patients for whom the histologic diagnosis was not documented by central review.Results Median survival times were 11.0 months for the PCNU group and 8.4 months for the AZQ group. The difference in survival curves was statistically significant for the RP (p=0.01) and the VSG (p=0.02). Lifetable analysis of the VSG showed estimated 2-year survivals of 34% for PCNU and 11% for AZQ. The advantage of PCNU remained significant (p=0.006) after adjustment for histopathologic category, age, initial performance status, and interval from initial reported surgery. Myelosuppression was the principal toxicity in both groups.Deceased     

A phase II study of cisplatin therapy in recurrent childhood brain tumors

Thirty-six children with brain tumors were treated with surgery, radiation and/or adjuvant chemotherapy. After tumor recurrence, cisplatin (60 mg/m2/day IV×2) was given every three to four weeks. CT scans were used to measure drug response prior to the first, third and fifth courses. Complete and partial responses were demonstrated in nine of 31 evaluable patients. Dose limiting toxicities were renal and auditory. Seven patients developed the syndrome of inappropriate antidiuretic horm one secretion. This study confirms that cisplatin is active in a spectrum of brain tumors.     

A phase I/II study of 24 hour intravenous AZQ in recurrent primary brain tumors

Summary This study was undertaken to determine the maximum tolerated dose of aziridinylbenzoquinone (AZQ given as a 24-hour intravenous infusion every 21–28 days. Thirty-four patients with recurrent or progressive gliomas received AZQ at a dose of 25, 30, 35, 40, or 45 mg/m². At a dose of 45 mg/m², leukopenia and thrombocytopenia of grade 3 or greater was observed in 42% and 25% of patients respectively; no patient required transfusion or antibiotics for fever. For administration of AZQ at a 24-hour intravenous infusion, we recommend a starting dose of 40 mg/m² for patients without previous exposure to cytotoxic agents, and 35 mg/m² for patients treated with such agents. In 14 patients with glioblastoma, tumor regression was observed in 1 patient (14%) and stabilization of disease was demonstrated in 7 patients (50%). In 17 patients with anaplastic astrocytomas there were no responses, but 8 patients (47%6) stabilized. Of two patients with an oligodendroglioma, one continues without progression at 34 weeks after initial response. One patient with malignant ependymoma stabilized and had not progressed at 39 weeks. The median time to tumor progression in patients who stabilized and responded was 18 weeks for those with glioblastoma multiforme and 16 weeks in those with anaplastic astrocytomas.     

Phase II evaluation of diaziquone (CI-904, AZQ) in the treatment of human malignant glioma

Summary Diaziquone, a new alkylating agent which crosses the blood brain barrier, has shown a 20% response rate in phase II studies in heavily pretreated patients. We have treated 23 patients at our institution as part of a multicentric phase II European trial of diaziquone. All had histologically proven malignant glioma unequivocally progressing on CT scan. Prior therapy had consisted of surgical excision (13 patients), cobalt radiotherapy to CNS (13 patients), and chemotherapy with nitrosourea derivatives (11 patients). Six patients had no prior therapy. Median age was 42 years (range 22–69) and performance status was 3+ or better. They were treated with monthly courses of diaziquone 5.5 mg/m² I.V. (10 min.) × 5 days. Dosage adjustments were made according to leucocyte and platelet nadirs. Thrombocytopenia was the dose limiting toxicity. Very mild gastrointestinal toxicity was observed. One patient developed hemolytic anemia. One complete response (clinical and CT scan), 7 partial clinical responses (3: > 50%, 4: 25–50%), and 1 disease stabilization (<25%) were documented. The longest response has now lasted over 26 months. These preliminary results show that chemotherapy with diaziquone can achieve a response rate as high as 35% in malignant glioma even in patients previously treated with a chemotherapy regimen including a nitrosourea (four of the seven objective responses were seen in such patients). Diaziquone is well tolerated and deserves further study in the management of malignant glioma. Address for offprints: Dr J Maral, Medical Oncology Service, Hôpital de la Salpetriere, 75651 Paris Cedex 13, France     

A phase II trial of oral melphalan in recurrent primary brain tumors

Thirty-seven patients with recurrent primary brain tumors were treated with oral melphalan at a dose of 8 mg/m2/day for 5 days every 4-6 weeks. All patients had failed prior nitrosourea-based chemotherapy. Oral melphalan had no activity against glioblastoma, and minimal activity against other anaplastic astrocytomas. One recurrent medulloblastoma did have a clinical and radiographically sustained response that continued for greater than 14 months. We concluded that oral melphalan was not effective in the treatment of recurrent astrocytomas, but might have efficacy in medulloblastoma.     

Phase I study of aziridinylbenzoquinone (AZQ, NSC 182986) in children with cancer

Aziridinylbenzoquinone is a quinone compound capable of penetrating the central nervous system. It has demonstrated activity against both intracranial and i.p. murine tumors and human tumor xenographs. We have conducted a Phase I trial of aziridinylbenzoquinone in 60 children with advanced cancer who were refractory to conventional therapy. The drug was given by slow i.v. push on a daily schedule for 5 days every 3 to 4 weeks. The dose range explored included 6 dose levels, ranging from 6 to 12 mg/sq m daily for 5 days in patients with solid tumors and leukemia, and in patients with leukemia, 20, 25, and 30 mg/sq m daily for 5 days. Myelosuppression was the dose-limiting side effect. In patients with solid tumor the highest dose studied was 12 mg/sq m, and the median nadir white blood cell and platelet counts were 0.7 X 10(3) and 6.0 X 10(3)/microliter on Days 17 and 22, respectively. The median recovery day for white blood cells was 39. There may be some evidence of cumulative toxicity with prolonged thrombocytopenia. Other side effects were mild nausea, vomiting, and mucositis. Elevations in liver enzymes and bilirubin were transient and dose dependent, occurring 3 to 4 weeks after drug administration. Of the 34 children with solid tumors, 33 were evaluable for hematopoietic toxicity, 3 were early deaths, and 31 receiving a total of 55 courses were evaluable for therapeutic response. Partial responses lasting 3 weeks to 6 months were seen in the 4 patients with Hodgkin's disease, and in a child with a metastatic spinal cord ependymoma. Fifty-two courses were given to 9 patients with acute lymphocytic leukemia and 17 with acute nonlymphoblastic leukemia. Of the 15 patients with acute nonlymphoblastic leukemia treated at doses greater than or equal to 25 mg/sq m/day for 5 days there was one early death and there were 2 M1 (less than or equal to 5% blasts with normal cellularity), 3 M2A (6 to 15% blasts), and 2 M2B (16 to 39% blasts) bone marrow responses lasting 1 to 3.5 months. Aziridinylbenzoquinone demonstrated activity against acute nonlymphocytic leukemia with maximal tolerated doses of 30 mg/sq m daily for 5 days. Its effect in Hodgkin's disease is encouraging; however, further study will be required to determine its efficacy in central nervous system cancers. Recommended doses for Phase II studies, using daily schedule for 5 days in children with solid tumors, is 9 mg/sq m, and in children with leukemia, it is 25 mg/sq m.     

Comparison of the structural and cytotoxic activity of novel 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone analogues

Eight analogues of 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone have been synthesized and tested for cytotoxicity against four different leukemic and lymphomic cell lines. For K562 and BSM cells, the toxicity could be correlated with the ease of reduction of the compounds as determined by the one-electron reduction potentials and the electron spin resonance detection of the reduced compounds produced by the cells. The cell toxicity could also be correlated with the efficiency of the compounds to form cross-links in DNA. However, no such correlations could be observed for the L1210 and Raji cells, although the activity of the NADPH dependent reducing enzymes in these cells was similar to that in the others. It is believed that for the L1210 and Raji cells, the influx/efflux of the different compounds may be more important to the cytotoxicity than their reduction or alkylation.     

Cisplatin,ara-C and etoposide (PAE) in the treatment of recurrent childhood brain tumors

Sixteen patients with recurrent childhood brain tumors were treated with intravenous cisplatin, cytosine arabinoside and etoposide (PAE), daily for three days every three to four weeks. Objective responses were observed in 6 of 15 evaluable patients and an additional six patients had stable disease for > 6 months. The tumor-specific response rate for astrocytoma/glioma was 3 of 7 and for medulloblastoma was 2 of 4. The mean progression-free interval was 11.0 months and the hazard rate for progression was 0.085 per patient-month of observation. The most common toxicities were neutropenia and thrombocytopenia. Clinically significant ototoxicity wasidentified in 7 patients. The activity of PAE chemotherapy for recurrent childhood brain tumors warrants further investigation.     

Interaction of gamma-irradiation with two new antineoplastic agents, aziridinylbenzoquinone (AZQ) and 4'- (acridinylamino)methanesulfon-m-anisidide (AMSA), in murine tumors in vivo

AZQ and AMSA were evaluated in combination with irradiation in murine tumor systems. In mice bearing ascitic P388 leukemia AZQ plus whole-body irradiation was slightly more effective in prolonging lfespan than maximally tolerated doses of either modality alone. Using an assay for cell survival, AZQ did not influence the response of P388 cells to radiation in vivo; the cytotoxicity of the two modalities was simply additive. AMSA, at a therapeutic dose administered prior to irradiation, did alter the response of P388 leukemia to irradiation with both a decrease in shoulder and an increase in slope. AMSA was also evaluated either prior to or after irradiation against B16 melanoma. AMSA alone had no influence on the growth of B16 melanoma. In combination with radiation AMSA pretreatment resulted in somewhat longer tumor growth delay than irradiation alone.     

A phase II trial of 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (PCNU,NSC 95466) in recurrent malignant brain tumors

Twenty-nine with patients recurrent primary malignant brain tumors were treated with 1-(2-chlorethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (PCNU) at an initial dose of 110 Mg/M² with subsequent doses determined by the degree of delayed toxicity. The interval between treatments was usually weeks. Eleven of 25 evaluable patients (44%) showed definite improvement and ten(40%) showed disease stability as determined by sequential CT scans and neurologic examination. The estimated median time to tumor progression for all 25 patients treated with PCNU was 28 weeks, 37 weeks for the responding patients but only 20 weeks for patients with stable disease. Toxicity consisted of delayed myelosuppression which was cumulative and occurred mainly with the platelets. Gastrointestinal toxicity occurred in a minority of the patients. PCNU has definite activity in primary malignant brain tumors which appears to be comparable to that reported for BCNU alone, but with less reported gastointestinal side effects. Further clinical trials in patients with primary malignant brain tumors are indicated.     

Phase II study of aziridinylbenzoquinone (AZQ) in patients with central nervous system malignancies: a Southwest Oncology Group study

Summary AZQ, an alkylating agent with lipophilic characteristics allowing CNS penetration was studied in patients with primary CNS malignancies refractory to surgical and radiotherapeutic modalities. Responses were evaluated by three criteria: neurologic examination, performance status and CT scan of the brain. Improvement in all three parameters with stable or decreasing doses of decadron was required for a partial response. Thirty-six poor risk (prior chematherapy) patients with Grades III and IV astrocytomas were treated with 30 mg/m². Three patients had a partial response (14, 17, 60 weeks duration). Two patients had mixed responses (worsening of one disease parameter with improvement in another), four had stable disease and one patient had improvement in neurologic parameters with a stable CT scan. Twenty-six patients had increasing disease. Fifteen good risk patients (no prior chemotherapy) with recurrent grades III and IV astrocytomas were treated at a dose of 40 mg/m² intravenously every three weeks. There were no objective responses in this group of patients. Three patients with nonastrocytomas were treated and no responses observed. The drug was well tolerated. Myelosuppression in the form of leukopenia and thrombocytopenia was the major toxicity. Myelosuppression required dose reductions in eight patients and discontinuation of therapy due to repeated treatment delays in two patients. AZQ at doses of 30 and 40 mg/m² given on an intermittent bolus schedule is inactive in patients with Grades III and IV recurrent astrocytoma.Presented in part at the Second International Symposium on Biology of Brain Tumours, London, October 1984.     

Phase 11 study of aziridinylbenzoquinone (AZQ: NSC-182986) in the treatment of malignant gliomas recurrent after radiation

Seventeen patients with malignant gliomas recurrent after chemotherapy and/ or radiation failure were treated with aziridinylbenzoquinone (AZQ) at a dose of 20-15 mg/M² weekly for four weeks followed by a two week rest. Regression of disease was observed in four patients, 4/17 (24%) for 35, 15+,40+, and 10 weeks. Toxicity was limited to moderate reversible myelosuppression. AZQ in this dose and schedule has limited but definite activity in patients with malignant gliomas progressive after primary radiation therapy failure.     

A phase II trial of primary temozolomide in patients with grade III oligodendroglial brain tumors

Glial tumors with oligodendroglial components are considered chemo-responsive. Forty newly diagnosed patients (11 anaplastic oligodendrogliomas [OD] and 29 anaplastic oligoastrocytomas [OA]) were enrolled into this multicenter, open-label, single-arm Phase II trial of first-line temozolomide (200 mg/m² on days 1–5 every 4 weeks for 6 cycles). The primary endpoint was 6-month progression-free survival (PFS) with response rate (RR), median PFS, and median overall survival (OS) as secondary endpoints. Of 39 evaluable patients at the 6-month time point (median follow-up, 34 months), 6-month PFS was 77% (95% confidence interval [CI], 74.5%–79.3%). There were 15 complete responses (CRs, 38%), 6 partial responses (PRs, 15%), and 9 disease stabilization (23%). The median PFS was 21 months (95% CI, 3–39 months), and the median OS was 43 months (95% CI, 20–66 months). Chromosome 1p/19q codeletions were seen in 47% (18 of 38) of the patients, and O-6-methylguanine-DNA-methyltransferase (MGMT) methylation was seen in 48% (10 of 21) of the patients. All patients with OD showed MGMT methylation and most (71%) had chromosome 1p/19q codeletions. Conversely, fewer patients with OA showed MGMT methylation (23%) or had chromosome 1p/19q codeletions (31%). The presence of either 1p/19q codeletion or MGMT methylation was associated with increased RR at 6 months but not with improved PFS or OS. Only 18% of the patients (7 of 40) experienced treatment-related grade 3/4 toxicities. This regimen was active and well tolerated. These data add to the growing body of data showing that primary chemotherapy may be an acceptable alternative to radiotherapy for patients with gliomas containing oligodendroglial histology.     

Phase I trial of 5-day continuous infusion aziridinylbenzoquinone (AZQ, diazaquone, NSC 182968)

AZQ was given to 14 patients with solid tumors in a phase I trial. Eight males and six females with a median Karnofsky performance status of 70% (range 40-90%) and a median age of 64 years (range 24-72) received 18 evaluable courses. All patients received prior chemotherapy and seven had prior irradiation. A continuous infusion for 5 consecutive days at doses of 4-8 mg/m2 per day was given every 3-4 weeks. Dose-limiting toxicity was myelosuppression, especially thrombocytopenia. No patient developed an infection while on this study. There was no evidence of cumulative toxicity in the three patients receiving two or more courses. Nonhematologic toxicity consisted only of mild nausea and vomiting in three patients and mild diarrhea in two patients. No patient experienced any mucosal, hepatic, renal, cardiac, or central nervous system toxicity. No objective antitumor responses were seen in the three patients with measurable disease who received two or more courses of AZQ. The recommended doses for phase II studies for continuous-infusion AZQ are 6 mg/m2/day X 5 repeated every 4 weeks.     

A phase II trial of capecitabine (Xeloda) in recurrent ovarian cancer

Oral capecitabine is a highly active, well-tolerated and convenient treatment for breast and colorectal cancer. This trial assessed the efficacy and safety of single-agent capecitabine in patients with previously treated ovarian cancer. A total of 29 patients with platinum-pretreated relapsed ovarian cancer were enrolled in this prospective, open-label, single-centre, phase II study. Patients received oral capecitabine 1250 mg m(-2) twice daily on days 1-14 of a 21-day cycle. Tumour response was evaluated using serum CA125. Out of 29 enrolled patients, 28 were evaluable, and a response was observed in eight patients (29%, 95% confidence interval (CI), 13-49%). Median progression-free and overall survivals were 3.7 (95% CI, 2.8-4.6) and 8.0 (95% CI, 4.1-11.8) months, respectively. After 6 months of treatment, 28% (95% CI, 13-48%) of patients remained progression-free and 62% (95% CI, 42-79%) were still alive. The most common clinical adverse events were hand-foot syndrome (HFS), nausea and diarrhoea. Grade 3 HFS occurred in 14% of patients, grade 3 vomiting in 10%. Efficacy and safety of capecitabine compare favourably with other monotherapies in platinum-refractory epithelial ovarian cancer. The convenience and improved safety profile of capecitabine compared with intravenous. regimens make it an ideal agent for administration in the outpatient setting.