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Importance: Universal screening of patients with newly diagnosed cancer for hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV is not routine in oncology practice, and experts disagree about whether universal screening should be performed., Objective: To estimate the prevalence of HBV, HCV, and HIV infection among persons with newly diagnosed cancer., Design, Setting, and Participants: Multicenter prospective cohort study of patients with newly diagnosed cancer (ie, identified within 120 days of cancer diagnosis) at 9 academic and 9 community oncology institutions affiliated with SWOG (formerly the Southwest Oncology Group) Cancer Research Network, a member of the National Clinical Trials Network, with enrollment from August 29, 2013, through February 15, 2017. The data analysis was conducted using data available through August 17, 2017., Main Outcomes and Measures: The accrual goal was 3000 patients and the primary end point was the presence of HBV infection (previous or chronic), HCV infection, or HIV infection at enrollment. Patients with previous knowledge of infection as well as patients with unknown viral viral status were evaluated., Results: Of 3092 registered patients, 3051 were eligible and evaluable. Median (range) age was 60.6 (18.2-93.7) years, 1842 (60.4%) were female, 553 (18.1%) were black, and 558 (18.3%) were Hispanic ethnicity. Screened patients had similar clinical and demographic characteristics compared with those registered. The observed infection rate for previous HBV infection was 6.5% (95% CI, 5.6%-7.4%; n = 197 of 3050 patients); chronic HBV, 0.6% (95% CI, 0.4%-1.0%; n = 19 of 3050 patients); HCV, 2.4% (95% CI, 1.9%-3.0%; n = 71 of 2990 patients); and HIV, 1.1% (95% CI, 0.8%-1.6%; n = 34 of 3045). Among those with viral infections, 8 patients with chronic HBV (42.1%; 95% CI, 20.3%-66.5%), 22 patients with HCV (31.0%; 95% CI, 20.5%-43.1%), and 2 patients with HIV (5.9%; 95% CI, 0.7%-19.7%) were newly diagnosed through the study. Among patients with infections, 4 patients with chronic HBV (21.1%; 95% CI, 6.1%-45.6%), 23 patients with HCV (32.4%; 95% CI, 21.8%-44.5%), and 7 patients with HIV (20.6%; 95% CI, 8.7%-37.9%) had no identifiable risk factors., Conclusions and Relevance: Results of this study found that a substantial proportion of patients with newly diagnosed cancer and concurrent HBV or HCV are unaware of their viral infection at the time of cancer diagnosis, and many had no identifiable risk factors for infection. Screening patients with cancer to identify HBV and HCV infection before starting treatment may be warranted to prevent viral reactivation and adverse clinical outcomes. The low rate of undiagnosed HIV infection may not support universal screening of newly diagnosed cancer patients.

Objective: Value of information (VOI) analyses can align research with areas with the greatest potential impact on patient outcome, but questions remain concerning the feasibility and acceptability of these approaches to inform prioritization decisions. Our objective was to develop a process for calculating VOI in "real time" to inform trial funding decisions within SWOG, a large cancer clinical trials group., Methods: We developed an efficient and scalable VOI modeling approach using a selected sample of 9 randomized phase II/III trial proposals from the Breast, Gastrointestinal, and Genitourinary Disease Committees reviewed by SWOG's leadership between 2008 and 2013. There was bidirectional communication between SWOG investigators and the research team throughout the modeling development. Partial expected value of sample information for the treatment effect evaluated by the proposed trial's primary endpoint was calculated using Monte Carlo simulation., Results: We derived prior uncertainty in the treatment effect estimate from the sample size calculations. Our process was feasible for 8 of 9 trial proposals and efficient: the time required of 1 researcher was <1 week per proposal. We accommodated stakeholder input primarily by deconstructing VOI metrics into expected health benefits and incremental healthcare costs and assuming treatment decisions within our simulations were based on health benefits. Following customization, feedback from over 200 SWOG members was positive regarding the overall VOI framework, specific retrospective results, and potential for VOI analyses to inform future trial proposal evaluations., Conclusions: We developed an efficient and customized process to calculate the expected VOI of cancer clinical trials that is feasible for use in decision making and acceptable to investigators. Prospective use and evaluation of this approach is currently underway within SWOG., (© The Author(s) 2016.)

The standard phase II trial design has changed dramatically over the past decade. Randomized phase II studies have essentially become the standard phase II design in oncology for a variety of reasons. The use of these designs is motivated by concerns about the use of historical data to determine if a new agent or regimen shows promise of activity. However, randomized phase II designs come with the cost of increased study duration and patient resources. Progression-free survival (PFS) is an important endpoint used in many phase II designs. In many clinical settings, changes in PFS with the introduction of a new treatment may represent true benefit in terms of the gold standard outcome, overall survival (OS). The phase II/III design has been proposed as an approach to shorten the time of discovery of an active regimen. In this article, design considerations for a phase II/III trial are discussed and presented in terms of a model defining the relationship between OS and PFS. The design is also evaluated using 15 phase III trials completed in the Southwest Oncology Group (SWOG) between 1990 and 2005. The model provides a framework to evaluate the validity and properties of using a phase II/III design. In the evaluation of SWOG trials, three of four positive studies would have also proceeded to the final analysis and 10 of 11 negative studies would have stopped at the phase II analysis if a phase II/III design had been used. Through careful consideration and thorough evaluation of design properties, substantial gains could occur using this approach., (©2013 AACR)

Although progression-based endpoints, such as progression-free survival, are often key clinical trial endpoints for anticancer agents, the clinical meaning of "objective progression" is much less certain. As scrutiny of progression-based endpoints in clinical trials increases, it should be remembered that the Response Evaluation Criteria In Solid Tumors (RECIST) progression criteria were not developed as a surrogate for survival. Now that progression-free survival has come to be an increasingly important trial endpoint, the criteria that define progression deserve critical evaluation to determine whether alternate definitions of progression might facilitate the development of stronger surrogate endpoints and more meaningful trial results. In this commentary, we review the genesis of the criteria for progression, highlight recent data that question their value as a marker of treatment failure, and advocate for several research strategies that could lay the groundwork for a clinically validated definition of disease progression in solid tumor oncology.

Aims: The Center for Comparative Effectiveness Research in Cancer Genomics completed a 2-year stakeholder-guided process for the prioritization of genomic tests for comparative effectiveness research studies. We sought to evaluate the effectiveness of engagement procedures in achieving project goals and to identify opportunities for future improvements., Materials & Methods: The evaluation included an online questionnaire, one-on-one telephone interviews and facilitated discussion. Responses to the online questionnaire were tabulated for descriptive purposes, while transcripts from key informant interviews were analyzed using a directed content analysis approach., Results: A total of 11 out of 13 stakeholders completed both the online questionnaire and interview process, while nine participated in the facilitated discussion. Eighty-nine percent of questionnaire items received overall ratings of agree or strongly agree; 11% of responses were rated as neutral with the exception of a single rating of disagreement with an item regarding the clarity of how stakeholder input was incorporated into project decisions. Recommendations for future improvement included developing standard recruitment practices, role descriptions and processes for improved communication with clinical and comparative effectiveness research investigators., Conclusions: Evaluation of the stakeholder engagement process provided constructive feedback for future improvements and should be routinely conducted to ensure maximal effectiveness of stakeholder involvement.

Background: Systematic approaches to stakeholder-informed research prioritization are a central focus of comparative effectiveness research. Genomic testing in cancer is an ideal area to refine such approaches given rapid innovation and potentially significant impacts on patient outcomes., Objective: To develop and pilot test a stakeholder-informed approach to prioritizing genomic tests for future study in collaboration with the cancer clinical trials consortium SWOG., Methods: We conducted a landscape analysis to identify genomic tests in oncology using a systematic search of published and unpublished studies, and expert consultation. Clinically valid tests suitable for evaluation in a comparative study were presented to an external stakeholder group. Domains to guide the prioritization process were identified with stakeholder input, and stakeholders ranked tests using multiple voting rounds., Results: A stakeholder group was created including representatives from patient-advocacy groups, payers, test developers, regulators, policy makers, and community-based oncologists. We identified 9 domains for research prioritization with stakeholder feedback: population impact; current standard of care, strength of association; potential clinical benefits, potential clinical harms, economic impacts, evidence of need, trial feasibility, and market factors. The landscape analysis identified 635 studies; of 9 tests deemed to have sufficient clinical validity, 6 were presented to stakeholders. Two tests in lung cancer (ERCC1 and EGFR) and 1 test in breast cancer (CEA/CA15-3/CA27.29) were identified as top research priorities., Conclusions: Use of a diverse stakeholder group to inform research prioritization is feasible in a pragmatic and timely manner. Additional research is needed to optimize search strategies, stakeholder group composition, and integration with existing prioritization mechanisms.

Purpose: In a phase I study, the combination of gemcitabine and imatinib was well tolerated with broad anticancer activity. This phase I trial evaluated the triplet of docetaxel, gemcitabine and imatinib., Experimental Design: Imatinib was administered at 400 mg daily on days 1-5, 8-12 and 15-19. Gemcitabine was started at 600 mg/m(2) at a rate of 10 mg/min on days 3 and 10 and docetaxel at 30 mg/m(2) on day 10, on a 21-day cycle. Diffusion and dynamic contrast-enhanced perfusion MRI was performed in selected patients., Results: Twenty patients with relapsed/refractory solid tumors were enrolled in this IRB-approved study. The mean age was 64, and mean ECOG PS was 1. Two patients were evaluated by diffusion/perfusion MRI. After two grade 3 hematological toxicities at dose level 1, the protocol was amended to reduce the dose of imatinib. MTDs were 600 mg/ m(2) on days 3 and 10 for gemcitabine, 30 mg/ m(2) on day 10 for docetaxel, and 400 mg daily on days 1-5 and 8-12 for imatinib. Dose limiting toxicities after one cycle were neutropenic fever, and pleural and pericardial effusions. The best response achieved was stable disease, for six cycles, in one patient each with mesothelioma and non small cell lung cancer (NSCLC) at the MTD. Two patients with NSCLC had stable disease for four cycles., Discussion: An unexpectedly low MTD for this triplet was identified. Our results suggest drug-drug interactions that amplify toxicities with little evidence of improved tumor control.

Background: The number of cancer survivors in the U.S. has increased from 3 million in 1971, when the National Cancer Act was enacted, to over 12 million today. Over 70% of children affected by cancer survive more than 10 years, and most are cured. Most cancer survivors are adults, with two-thirds of them 65 years of age or older and two-thirds alive at five years. The most common cancer diagnoses among survivors include breast, prostate and colorectal cancers. This review was conducted to better appreciate the challenges associated with cancer survivors and the opportunities healthcare providers have in making a difference for these patients., Methods: Comprehensive review of literature based on PubMed searches on topics related to cancer survivorship, and associated physical, cognitive, socio-economic, sexual/behavioral and legal issues., Results: At least 50% of cancer survivors suffer from late treatment-related side effects, often including physical, psychosocial, cognitive and sexual abnormalities, as well as concerns regarding recurrence and/or the development of new malignancies. Many are chronic in nature and some are severe and even life-threatening. Survivors also face issues involving lack of appropriate health maintenance counseling, increased unemployment rate and workplace discrimination., Conclusions: Advances in the diagnosis and treatment of cancer will lead to more survivors and better quality of life. However, tools to recognize potentially serious long-lasting side effects of cancer therapy earlier in order to treat and/or prevent them must be developed. It is incumbent upon our health care delivery systems to make meeting these patients' needs a priority.

The use of biomarkers to "personalize" cancer treatment--identifying discrete genes, proteins, or other indicators that can differentiate one type of cancer from another and enable the use of highly tailored therapies--offers tremendous potential for improved outcomes and lower treatment costs. However, the rapid development of cancer biomarker, or genomic, tests--combined with a paucity of evidence to support the effectiveness of the tests--presents a challenge for patients, clinicians, and other stakeholders. In this article we propose that comparative effectiveness research be used to strengthen what is now a haphazard process for developing and marketing cancer biomarker tests. We suggest novel funding approaches and a systematic process for moving from regulatory approval to the generation of evidence that meets the needs of stakeholders and, ultimately, patients.

SWOG (formerly the Southwest Oncology Group), a National Cancer Institute-supported cooperative group, conducts multi-institutional, multidisciplinary clinical trials for adult patients with cancer, covering a wide range of solid tumors and hematologic cancers. The group has amassed a large set of biospecimens, collected from patients in numerous studies over many years and linked to clinical data. SWOG is now actively promoting the use of this unique scientific resource by making it available to a much wider group of researchers. This biospecimen resource offers material for research on disease mechanisms, genomic changes associated with cancer progression, markers of response and resistance to therapies, diagnosis or detection of recurrence, and more. By collecting, storing, and distributing the specimens, SWOG provides the framework for translational scientists to complete the feedback loop from "bedside to bench." This article provides an overview of the group's biospecimen resources and guidelines for gaining access to them., (©2011 AACR.)

CC-1065 is a unique alkylating agent that preferentially binds in the minor groove of double-stranded DNA at adenine-thymine-rich sites. Although it has broad antitumor activity in preclinical models its development was discontinued because of deaths observed during preclinical toxicology studies. Adozelesin is a potent synthetic analog that was chosen for clinical development because it had a similar preclinical antitumor spectrum, but did not produce deaths similar to CC-1065 at therapeutic doses. Phase I evaluations using a variety of Adozelesin treatment schedules have been conducted. This report describes our experience using a multiple dose treatment schedule. Endpoints including antitumor response, maximum tolerated dose, dose limiting toxicity as well as other toxicities and the recommended Phase II starting dose were determined. Adozelesin was given as a 10 minute IV infusion for 5 consecutive days every 21 days or upon recovery from toxicity. The dose range evaluated was 6-30 mcg/m2/day. All patients had refractory solid tumors and had received prior cytotoxic treatment. Thirty-three patients (22 men: 11 women) were entered onto the study and 87 courses were initiated. Dose limiting toxicity was cumulative myelosuppression (leucopenia, thrombocytopenia). The maximum tolerated dose was 30 mcg/m2/day. The only other significant toxicity was an anaphylactoid syndrome that occurred in 2 patients. A partial response was observed in a patient with refractory soft tissue sarcoma. The recommended Phase II starting dose of Adozelesin using a 10 minute IV infusion for 5 consecutive days is 25 mcg/m2/day to be repeated every 4-6 weeks to allow recovery from myelotoxicity, based on our experience. Additional Phase I and II studies with Adozelesin are recommended.

Crisnatol mesylate is a rationally designed cytotoxic arylmethylamino-propanediol with broad spectrum cytotoxic activity. A phase I study with an unconventional escalation scheme was developed using a constant drug infusion rate (mg/m2/hr) and prolonging the infusion duration from 6 to 96 hours. Sixty-five patients received crisnatol at doses from 18 mg/m2 in 6 hrs to 3400 mg/m2 in 72 hours. The dose-limiting toxicity in two of five patients at 2700 mg/m2 and two of three patients at 3400 mg/m2 was neurologic and consisted of a syndrome of confusion, agitation, and disorientation. Phlebitis mandated the use of a central line. The mean terminal phase half-life (T1/2 beta) was 3.3 hours with a total body clearance (CL) of 22.8 L/hr/m2 and a volume of distribution (Vdss) of 53 L/m2. The median steady-state peak plasma concentration (Css) at 2700 mg/m2/72 hours was 2.7 micrograms/ml and at 3400 mg/m2/72 hours was 3.8 micrograms/ml. No responses were seen. The maximum tolerated dose (MTD) on this schedule is 2700 mg/m2/72 hours in patients with no liver disease and good performance status.

Pharmacokinetic studies of 5-fluorouracil (5-FUra) were performed on 18 patients divided into three groups: seven patients were given 5-FUra i.v. by rapid injection; five patients received the drug p.o.; and six patients were treated by continuous i.v. infusion for 96 hr. The results showed rapid i.v. injection to be manifested by high early levels of drug achieved both in plasma and bone marrow with a rapid fall afterwards. Administration of 5-FUra p.o. gave rise to erratic plasma values due to greater variability in absorption, whereas 96-hr i.v. infusions showed constant levels of the drug in plasma and significantly (50- to 1000-fold) less 5-FUra in bone marrow. The main difference observed between rapid injection and slow infusion in the kinetics of the drug was the very high level of 5-FUra reached by rapid injection in plasma and bone marrow, which was of short duration (min) when compared to the low sustained levels observed during infusion. This route-dependent pharmacokinetic profile is consistent with the reported absence of myelosuppression in prolonged infusion and may be related to the resultant lower levels of 5-FUra achieved in bone marrow.

This study demonstrates that the gastrointestinal absorption of oral mitomycin C is variable and that myelosuppression correlates most closely with the peak serum concentration. The probable maximal-tolerated dose of oral mitomycin C is 45-50 mg/m2.

Seventeen patients with various histologic types of incurable malignant disease were treated with a combination of vinblastine, bleomycin, and cis-dichlorodiammineplatinum(II). Creatinine and blood urea nitrogen elevations were noted but were not of a severe degree. White blood cell and platelet count depressions were seen and appeared to be cumulative, though not life-threatening. Tinnitus and high-frequency hearing loss were noted. Tumor regression was seen in one patient with adenocarcinoma of the lung and in one patient with a testicular tumor. This appears to be a manageable drug combination with frequent monitoring of renal, hematopoietic, pulmonary, and auditory function. A phase II study establishing the therapeutic efficacy of this combination in advanced testicular neoplasms now appears to be indicated.

Nafazatrom was evaluated in escalating daily oral doses ranging from 0.25 to 8.0 g/m2 without producing significant toxicities. Malabsorption proved dose limiting at 8.0 g/m2 as a single daily dose, but splitting the same total dose into two or four doses circumvented this problem. Doses of 2.0 g/m2 at 6-h intervals or 4.0 g/m2 every 12 h are reasonable for Phase II and adjuvant trials. Pharmacologic evaluation of nafazatrom confirmed malabsorption at the highest single daily dose level tested and suggests that absorption was impaired in patients with extensive liver metastases.

To evaluate the role of amphotericin B (AmB) in the biochemical modulation of antineoplastic agents, AmB was administered as a continuous infusion over a period of 52 to 120 h to 14 patients (26 courses) with advanced carcinomas. Continuous infusion amphotericin B (CI-AmB) was delivered at a rate of 0.5 to 0.8 mg/kg/d (19-31 mg/m2/d). The AmB plateau levels assayed by HPLC ranged from 0.7 to 1.9 micrograms/mL and were directly related to the infusion rate. The AmB plasma disposition was biphasic, with mean half-lives of 17 h for the first phase and 11 d for the terminal phase, and a mean residence time of 12 d. Biochemical modulation of antineoplastic agents (lomustine, doxorubicin, cyclophosphamide) by CI-AmB was not demonstrated clinically. Acute toxicities of fever and chills were noted in only 3 of the 26 courses. Reversible renal toxicity was observed in 23 courses. Therapeutic antifungal plasma levels were rapidly reached and maintained for the duration of infusion, with a reduction of acute toxicities associated with shorter infusions. These observations provide impetus for further clinical investigation of CI-AmB.

The pharmacokinetic profile of high-dose mitomycin C was determined in blood plasma and urine of twelve patients with advanced malignancies in a program including autologous bone marrow transplantation. A total dose of 60 mg/m2 was given, either as a single 60-min infusion or divided into infusions of 30 mg/m2 on each of 2 days or 15 mg/m2 on each of 4 days. One group was given 15-min infusions. Samples of blood plasma and urine were analyzed by high-performance liquid chromatography. Drug concentrations in plasma followed a biphasic pattern, with a terminal elimination half-life of 45 min. This half-life value and other parameters were unaffected by dose level, infusion time, and repeated doses. The lower peak plasma concentrations following 30 mg/m2 given as 60-min infusions compared to the same dose given over 15 min may have accounted for a dramatic drop in the incidence of a severe hemorrhagic colitis. Mitomycin C was excreted in urine at about the same rate as it was eliminated from plasma, but a larger percentage of the dose appeared in urine after 15-min infusions than after 60-min infusions. The pharmacokinetic profile, together with clinical observations, suggests that the dose-limiting toxicity of mitomycin C may be related to peak drug levels, and that both these levels and the toxicity are lessened as the infusion time is increased.

Thirteen courses of high-dose mitomycin-C with autologous bone marrow transplantation (ABMT) were administered to 12 patients. Four dose schedules were evaluated: A) 60 mg/M2 X 1, 60-min infusion; B) 30 mg/M2/day X 2, 15-min infusion; C) 30 mg/M2/day X 2, 60-min infusion; D) 15 mg/M2/day X 4, 60-min infusion. Pharmacokinetic studies using HPLC technique were done in nine patients. All patients have since died and autopsies were performed in nine patients. Two major nonhematopoietic toxicities were encountered and were dose-schedule dependent: hemorrhagic colitis (six of six courses in Schedules A and B; two of seven in Schedules C and D), and hepatic dysfunction (five of six in Schedules A and B; two of seven in Schedules C and D). Histopathologic evidence of venocclusive disease of the liver was present in four of five autopsies in Schedules A and B, and two of four in Schedules C and D. One patient died as a result of liver failure associated with submassive hepatic necrosis. Saturation kinetics described by other investigators cannot be confirmed by our pharmacokinetic analyses in nine patients. Severe nonhematopoietic toxicities of mitomycin-C were found at three times the conventional dose; thus, this drug is assessed as not being clinically useful as a single agent in ABMT.

Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly X 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness. Traditional criteria for grading neurotoxicity poorly characterized these toxicities. The maximum tolerated dose was 6 mg/m2 every 3 weeks and 3 mg/m2 weekly X 3. Concurrent murine studies confirmed spiromustine as a schedule independent drug with toxicity correlating with peak plasma levels. Physostigmine had little effect on decreasing neurotoxicity in the murine model. The solvating agent used was not responsible for the neurotoxicity. Injection of spiromustine on a split-dose schedule decreased the acute neurological toxicity in mice and allowed a larger total dosage to be delivered (compared to single bolus dosage). Based on these results a split-dose schedule is suggested for future clinical trials.

Because patients treated with 60-90 mg/m2 every three to four weeks reach cardiotoxic doses of 550 mg/m2 within 36 weeks, prolonged treatment with Adriamycin is limited. The purpose of this study was to determine whether lower doses could be given over longer periods without loss of efficacy. Good risk patients treated with 75, 60, or 45 mg/m2 had remission rates of 25, 27, and 19%; poor risk patients treated with 50 and 25 mg/m2 had remission rates of 16 and 12% respectively. Although a dose response was identified, there were no statistically significant differences in remission rates, durations of remission, or toxicities in the dose schedules studied. Irreversible congestive heart failure occurred in five patients with cumulative doses of 240-390 mg/m2. Unless rapid remission induction is urgent, we recommend 60 mg/m2 X four doses and measurement of myocardial function if treatment is to continue.

Gallium nitrate (NSC-15200), a group IIIa metal salt, was evaluated in a phase I-II clinical trial, In phase I trial, exploring bolus administration of the drug at 3-week intervals, dose-limiting renal toxicity was observed at doses exceeding 700 mg/m2. Hematological toxicity was minimal. Ototoxicity was observed in one patient. A phase-II trial was initiated evaluating the drug at 700 mg/m2 given at 2- and 3-week intervals. Antitumor responses were observed in one patient with soft-tissuesarcoma and in two patients with small cell carcinoma of the lung. In two of these responders, pretreatment 67Ga scan was positive. Further clinical trials with the drug appear indicated, utilizing the every 2 week schedule. Pretreatment hydration combined with osmotic diuresis may ameliorate potential nephrotoxicity.

Aclacinomycin-A is a new anthracycline antibiotic with a broad spectrum of antitumor activity in animals. Compared to doxorubicin, it was found to produce less cardiotoxicity and alopecia. A Phase I trial of aclacinomycin-A given as a weekly 15 min IV infusion was conducted in 20 previously treated patients with advanced solid tumors. Four dose levels ranging from 40 to 100 mg/m2 were studied; myelotoxicity was dose-limiting at 85 and 100 mg/m2. Other toxicities were moderate to severe nausea and vomiting in 9 patients, mild phlebitis in 2 patients, and mild abnormality of liver function tests in 3 patients. No cardiac or renal toxicities were seen, but two partial responses were observed. The pharmacokinetic profile of aclacinomycin-A in plasma and urine was studied in 3 patients given 65 mg/m2 using a high performance liquid chromatography assay. The data obtained were consistent with a two compartment model of drug disposition with initial and terminal half-life values of 6.6 min and 13.3 h, respectively. The major fluorescent metabolite was eliminated with a terminal half-life of 25 h. Two metabolites as well as the parent drug were excreted in the urine as less than 10% of the doses given. This pharmacokinetic profile is similar to that of other anthracyclines, although aclacinomycin-A appears to have lower blood levels than doxorubicin given at equivalent doses. On this weekly schedule, the recommended dose is 65 mg/m2 for Phase II trials.

The biologic and antitumor activity of 5-azacytidine has been well demonstrated in the past. The drug at present is thought to be primarily cell cycle phase specific. This study was designed to eliminate undesirable side effects (mainly nausea and vomiting) occurring with a bolus dose and to confirm the recent findings of the relative stability of 5-azacytidine's solution with preserved biologic and antitumor activity. In the study we determined that a dose of 150 mg/m2/day given as a 120-hour continuous iv infusion and repeated at 28-day intervals produced safe, manageable, and reproducible toxicity. The drug was freshly prepared at 4-hour intervals. Eleven courses were administered to seven patients at this dose level and no patient experienced nausea or vomiting. Leukopenia was the major toxic effect. Antitumor activity was shown in one patient with colon cancer and another with American Burkitt's lymphoma.